Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: COc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methoxybenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methoxyphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:24]1C=CC([N+]([O-])=O)=NC=1.C(OC(N1CCN[C@@H](C)C1)=O)(C)(C)C>>[CH3:24][C@@H:15]1[N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 50 %

Procedure:
Following the procedures as described for compound 101g, reaction of 5-bromo-2-nitropyridine (10.5 g, 50 mmol), and (3S)-tert-butyl-3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) afforded 130a as a yellow solid (8.05 g, 50%). LCMS: [M+H]+ 323
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>CC(O)=O.CCOC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:20]([N+:17]([O-:19])=[O:18])[CH3:21])([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=Cc1ccccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 33.4 %

Procedure:
A solution of 2-nitrobenzaldehyde (5.0 g, 33.1 mmol) and ammonium acetate (2.55 g, 33.1 mmol) in AcOH (20 mL) was treated dropwise at 20° C. with nitroethane (2.84 mL, 39.7 mmol). The resulting solution was heated under reflux for 2 h, then cooled and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, then dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified on silica gel (gradient elution, 0-40% EtOAc/hexanes) to give the title compound as an oil (2.3 g, 33%). LCMS (ES+) m/z 209 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C=O.[C:14]1(B(O)O)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[CH2:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: C=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=C1Cc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 6-bromo-2,3-dihydro-1H-inden-1-one (0.3 g, 1.36 mmol), paraformaldehyde (0.4 g, 13.6 mmol), phenylboronic acid (0.2 g, 1.64 mmol) and trifluoroacetic acid (0.1 mL, 0.15 g, 1.36 mmol) in dry toluene (10 mL) was refluxed for 5 hours. When starting material was totally consumed, the crude mixture was cooled to room temperature, neutralized with saturated aqueous Na2CO3, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, petroleum ether-ethyl acetate, 95:5) to give compound 6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (89 mg, 30%) as a white solid. 1H NMR (CDCl3, 400 MHz): 3.71 (s, 2H), 5.68 (s, 1H), 6.39 (s, 1H), 7.38-7.40 (d, 1H), 7.70-7.72 (d, 1H), 7.99 (s, 1H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCN(C[C@H](C)O)CC6)nc5)cc34)cn2)c1
Yield: 32.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) propan-2-ol (100 mg, 0.151 mmol) was hydrolyzed with lithium hydroxide (19 mg, 0.453 mmol) in THF/methanol/water (2/2/0.5 mL) to yield 25 mg (21% yield) of desired product. 1H NMR (CD3OD, 400 MHz): δ 8.559-8.553 (d, 1H), 8.479-8.474 (d, 1H), 8.425-8.420 (d, 1H), 8.17 (s, 1H), 8.08-8.06 (dd, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.28-7.22 (t, 1H), 7.15-7.10 (m, 4H), 5.39 (s, 2H), 4.25-4.32 (m, 1H), 3.10-3.30 (m, 2H), 2.34 (s, 3H), 1.28-1.27 (d, 3H). MS: m/z=508.2 (M+1), HPLC: 98.90% in method A.
Reaction SMILES: [O-]Cl.[Na+].C([O-])(O)=O.[Na+].[CH3:9][C@@H:10]([C@@H:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH3:14])[CH2:11][OH:12].CC1(C)N([O])C(C)(C)CCC1.[Br-].[Na+]>O.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:9][C@@H:10]([C@@H:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH3:14])[CH:11]=[O:12]
Reactant: C[C@H](CO)[C@H](C)OC1CCCCO1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](C=O)[C@H](C)OC1CCCCO1
Yield: 92.3 %

Procedure:
An aqueous NaOCl solution (11 mmol, 5.3 ml of a 12.5% solution) and NaHCO3 (2.43 g, 29 mmol) was added dropwise, over a period of 1 hour, to a cold (0° C.), rapidly stirred (>1000 rpm), biphasic mixture consisting of (2R,3S)-2-methyl-3-tetrahydropyranyloxybutanol (5) (1.88 g, 10 mmol), TEMPO with free radicals (31.25 mg, 2%), sodium bromide (1.029 g, 10 mmol), toluene (30 ml), EtOAc (30 ml) and H2O (5 ml). The aqueous phase was separated and washed with Et2O (50 ml). The combined organic phases were washed with a KI solution (80 mg) dissolved in aqueous 10% KHSO4 (20 ml), and then with a 10% aqueous sodium thiosulfate solution (10 ml), brine (20 ml), and dried (MgSO4). Filtration and concentration under vacuum gave the desired aldehyde 6 (1.72 g, 92%) which was used for the next reactions without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: Clc1cc(N2CCNCC2)nc(N2CCCC2)n1

Procedure:
A solution of 2.0 g (9.17 mmoles) of 4,6-dichloro-2-pyrrolidinopyrimidine and 3.95 g (45.9 mmoles) of piperazine in ethanol is boiled under reflux for 1 hour and then evaporated. The evaporation residue is distributed between 100 ml of chloroform and 100 ml of 1% sodium hydroxide solution. After separation the organic phase is twice washed with 50 ml of water each, then dried and evaporated. After recrystallizing the residue from hexane, the title product is obtained in a yield of 2.25 g (91.6%), m.p. 89°-100° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(#N)C>[N+:8]([C:7]1[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-nitropyridine (4.76 g, 30 mmol) and piperazine (5.9, 69 mmol) in acetonitrile, (75 mL), was stirred at reflux for 5 h. After concentrating under reduced pressure, the residue was partitioned between ethyl acetate and 10% NaOH. The ethyl acetate extract was washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography over Al2O3 and elution with 2% MeOH-98% CHCl3 afforded the title compound, m.p. 82°-87° C. An analytical sample, m.p. 83.5°-86.5° C., was obtained upon recrystallization from CHCl3 -hexane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Br[CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCCBr
Product: CC1(C)c2cc(OCCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromo-ethanol.
Reaction SMILES: [CH2:1]([S:3]([N:6]([CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[CH:22]=2)[O:17][C:16]([CH3:26])([CH3:25])[CH2:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])(=[O:5])=[O:4])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52]([N:54]([CH2:57][CH2:58][NH2:59])[CH2:55][CH3:56])[CH3:53]>CN(C=O)C.CC(=O)OCC.O>[CH2:52]([N:54]([CH2:55][CH3:56])[CH2:57][CH2:58][NH:59][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[CH:22]=2)[O:17][C:16]([CH3:26])([CH3:25])[CH2:15]1)[CH3:53]
Reactant: CCN(CC)CCN
Reactant: CCS(=O)(=O)N(CCCCC(=O)O)C1CC(C)(C)Oc2ccc(C)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)CCCCN(C1CC(C)(C)Oc2ccc(C)cc21)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A solution of 0.3 g (0.78 mmol) of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid, 0.11 g (0.78 mmol) of HOBT and 0.18 g (0.86 mmol) of DCC in 4 ml of DMF is stirred at 0° C. for 1 h. 0.09 g (0.78 mmol) of diethylaminoethylamine is then added and the mixture is stirred overnight at RT. It is treated with 50 ml of water and 50 ml of EA, and the organic phase is washed twice with 25 ml each of saturated sodium bicarbonate solution and additionally twice with water. After drying over magnesium sulfate and concentrating in vacuo, 0.3 g of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid (2-diethylaminoethyl)amide is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]([O:16]C)(OC)[C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1>>[OH:18][C:3]1([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:4](=[O:16])[C:5]([C:6]2[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)=[C:2]1[CH3:1]
Reactant: COc1ccc(C2=C(C)C(=O)C2(OC)OC)cc1
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(C2=C(C)C(O)(c3ccc(OC)cc3)C2=O)cc1

Procedure:
Synthesized according to the procedure utilized for Example 46 (Step 2) using 2-methyl-4,4-bis(methyloxy)-3-[4-(methyloxy)phenyl]-2-cyclobuten-1-one (260) and 4-methoxyphenylmagnesium bromide. 1H NMR (CDCl3, 300 MHz) δ 7.39-7.29 (m, 4H), 7.10-6.88 (m, 4H), 3.88 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H). TLC (60:40; hexanes/EtOAc): Rf=0.23.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19](Br)[C:5]([C:6]([C:8](=[CH:14][NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([CH3:22])[C:3]=1[F:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:16]1([N:15]2[C:19]3[C:5](=[C:4]([CH3:22])[C:3]([F:23])=[C:2]([Br:1])[CH:20]=3)[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(Br)cc(Br)c(F)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)c(C)c2c1=O
Temperature: 0 °C
Yield: 91.1 %

Procedure:
A mixture comprising ethyl 2-(4,6-dibromo-3-fluoro-2-methylbenzoyl)-3-cyclopropylaminoacrylate (45.0 g), potassium carbonate (16.7 g) and dimethylformamide (450 ml) is reacted at 140° C. for 30 minutes. After cooling, the reaction mixture is poured into ice-water and the precipitated crystals are filtered, which are recrystallized from ethanol to give ethyl 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (33.6 g), as white crystals, m.p. 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][C@@H:21]3[N:27]([CH:28]=2)[C:26](=[O:29])[C:25]2[CH:30]=[C:31]([O:72][CH3:73])[C:32]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]4[C:69]([O:70][CH3:71])=[CH:68][C:42]5[C:43](=[O:67])[N:44]6[CH:59]=[C:58](S(C(F)(F)F)(=O)=O)[CH2:57][C@H:45]6[C:46](=[O:56])[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:41]=5[CH:40]=4)=[CH:33][C:24]=2[N:23]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[C:22]3=[O:82])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([C:58]2[CH2:57][C@@H:45]3[N:44]([CH:59]=2)[C:43](=[O:67])[C:42]2[CH:68]=[C:69]([O:70][CH3:71])[C:39]([O:38][CH2:37][CH2:36][CH2:35][O:34][C:32]4[C:31]([O:72][CH3:73])=[CH:30][C:25]5[C:26](=[O:29])[N:27]6[CH:28]=[C:19]([C:16]7[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=7)[CH2:20][C@H:21]6[C:22](=[O:82])[N:23]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:79])([CH3:81])[CH3:80])[C:24]=5[CH:33]=4)=[CH:40][C:41]=2[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[C:46]3=[O:56])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(S(=O)(=O)C(F)(F)F)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Solid 3-aminobenzeneboronic acid (0.143 g, 0.92 mmol) was added to a solution of the mono triflate (17)(0.619 g, 0.58 mmol), sodium carbonate (195 mg, 1.84 mmol) and palladium tetrakis triphenylphosphine (26.6 mg, 0.023 mmol) in toluene (10 mL), ethanol (5 mL) and water (5 mL). The reaction mixture was allowed to stir at room temperature for overnight at 30° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulphate. Excess solvent was removed by rotary evaporation under reduced pressure and the resulting residue was subjected to flash column chromatography (silica gel; gradient elution EtOAc/hexane 70/3085/15). Removal of excess eluent from selected fractions afforded the desired product (0.502 g, 0.49 mmol, 85%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[Br:11][CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.O>CN(C=O)C>[C:1]1([NH:7][C:8]([NH:15][CH2:14][CH2:13][CH2:12][Br:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCBr)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
Phenyl isocyanate (1.4 ml, 13 mmol) was added to a solution of 3-bromopropylamine hydrobromide (2.5 g, 11 mmol) and triethylamine (1.7 ml, 12 mmol) in DMF (50 ml) at 0° C., and the mixture was stirred at 0° C. for 1.5 h. After adding water, the mixture was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to afford N-phenylcarbamoyl-3-bromopropylamine (2.7 g, 96%); MS(FD) m/e 256 M+; 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 4H), 7.11 (m, 1H), 6.45 (br, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.41 (t, J=6.6 Hz, 2H), 2.10 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:19]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cccc2cc[nH]c12
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
To a solution of 7-hydroxypropyl-1H-indole (4.45 g, 25.4 mmol) in methylene chloride (50 mL), was added imidazole (2.31 g, 34.0 mmol), followed by tert-butyldimethylsilyl chloride (5.44 g, 36.1 mmol). The reaction mixture was stirred at room temperature for 12 h, filtered and concentrated to a brown oil. Flash chromatography (SiO2, 10% EtOAc/hexanes) gave the title compound (4.9 g, 66%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 9.38 (bs, 1H), 7.54 (m, 1H), 7.22 (m, 1H), 7.18–6.06 (m, 2H), 6.60 (m, 1H), 3.71 (m, 2H), 3.07 (m, 2H), 1.98 (m, 2H), 1.03 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[S:24]1(=[O:34])=[O:33]>>[O:33]=[S:24]1(=[O:34])[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Product: O=C1CCc2ccccc2N1C1CCN(CCCCN2C(=O)c3ccccc3S2(=O)=O)CC1

Procedure:
From the hydrochloride salt of 3,4-dihydro-1-(4-piperidyl)-2(1H)-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained 1,1-dioxido-2-(4-(4-(3,4-dihydro-2-oxo-(1H)-quinolin-1-yl)-piperidin-1-yl)-butyl)-1,2-benzisothiazol-3(2H)-one as a white solid: 1H NMR (300 MHz, CDCl3) 8.07 (dd, J=6.5, 2.3 Hz, 1H), 7.92 (t, J=6.73 Hz, 1H), 7.84 (m, 2H), 7.21 (t, J=8.73 Hz, 2H), 7.19 (m, 1H), 6.99 (t, J=7.13 Hz, 1H), 4.35 (tt, J=12.2, 4.2 Hz, 1H), 3.83 (t, J=7.32 Hz, 2H), 3.04 (d, J=11.42 Hz, 2H), 2.81 (t, J=6.59 Hz, 2H), 2.61 (m, 3H), 2.43 (t, J=7.19 Hz, 2H), 2.09 (t, J=11.71 Hz, 2H), 1.88 (m, 2H), 1.69 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:9]=1.[O-:27][N+:28]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[C:30]([C@H:38]([NH2:40])[CH3:39])[CH:29]=1.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:40][C@@H:38]([C:30]3[CH:29]=[N+:28]([O-:27])[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:31]=3)[CH3:39])=[O:19])=[CH:14][CH:15]=2)[N:10]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:9]=1
Reactant: Cc1ccc(-n2cc(-c3ccccc3Cl)c3ccc(C(=O)O)cc32)cc1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cc(-c3ccccc3Cl)c3ccc(C(=O)N[C@H](C)c4ccc(C(F)(F)F)[n+]([O-])c4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1-(4-methylphenyl)-1H-indole-6-carboxylic acid (9.5 mg, 26.0 μmol) in N,N-dimethylformamide (0.5 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (7.3 mg, 30.0 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (12.5 mg, 65.0 μmol), 1-hydroxy-7-azabenzotriazole (2.2 mg, 16.0 μmol) and N-methylmorpholine (12.0 μL, 0.11 mmol). The mixture was stirred at ambient temperature for 30 min. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the bistrifluoroacetate salt of the title compound (9.7 mg): HRMS [M+1] found=550.1505; 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H); 8.08 (s, 1H); 7.67 (t, J=7.7 Hz, 3H); 7.61-7.47 (m, 4H); 7.44-7.21 (m, 6H); 6.66 (d, J=6.6 Hz, 1H); 5.31-5.23 (m, 1H); 2.44 (s, 3H); 1.64 (dd, J=20.9, 7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:44]I.O>CN(C=O)C>[F:41][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:31][CH2:32]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:44])[N:12]=1
Reactant: FC(F)(F)c1cc(CN(Cc2cnc3ccccc3c2N(CC2CC2)CC2CC2)c2nn[nH]n2)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cnc3ccccc3c2N(CC2CC2)CC2CC2)n1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine (300 mg, 0.52 mmol) and sodium hydride (31 mg, 0.78 mmol) were taken in DMF (10 mL) at 0° C. and stirred for 20 min, then methyl iodide (0.067 mL, 1.04 mmol) was added at that temperature and stirred for 1 h. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL×3) and the organic layer was washed with water (75 mL). Drying over sodium sulfate and concentration under vacuum yielded the crude product that was purified by column chromatography using 230-400 mesh silica gel eluting with 5% ethyl acetate in petroleum ether to afford 0.107 gm (yield: 35%) of yellow colored gummy mass.