Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6](I)[CH:7]=1.[OH-:12].[Na+].N1C=CC=CC=1.O>Cl.C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:12])[CH:7]=1
Reactant: [OH-]
Reactant: CC(=O)c1cc(Br)cc(I)c1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(O)cc(Br)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 64.1 %

Procedure:
To a mixture of 1-(3-bromo-5-iodo-phenyl)-ethanone (2.28 g, 7.0 mmol), sodium hydroxide (1.4 g, 35.1 mmol), and Cu2O (143 mg, 1.0 mmol) were added pyridine (20 mL) and water (40 mL) at room temperature. The resulting suspension was heated to 110° C. and stirred for 24 h. Then the reaction mixture was cooled to room temperature and diluted with 1N hydrochloric acid (200 mL). Then, the organic compound was extracted into ethyl acetate (3×100 mL) and the combined organic extracts were washed with 1N hydrochloric acid (200 mL) and brine solution (200 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent under vacuum gave the crude dark brown solid which was tried to dissolve in acetonitrile (50 mL) at reflux, but it did not dissolve completely. Then, it was diluted with ethyl acetate (˜10 mL) and hexanes (˜15 mL). The dark suspension was stored in the refrigerator. Only few solids were formed and they were coolected by filtration and washed with acetonitrile. Then, the mother liquor was removed under vacuum and the dark brown solids were now dissolved in acetonitrile (50 mL) at reflux and it was treated with charcoal to remove some color. It was then filtered and the solvent was removed under vacuum to afford reasonably pure 1-(3-bromo-5-hydroxy-phenyl)-ethanone (965 mg, 64%) as a brown solid: ES(−)-HRMS m/e calcd for C8H7BrO2 (M−H)− 212.9556. found 212.9556.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[C:12](=[CH:13][C:14]4[C:15](=O)[C:16]([C:22]#[N:23])=[CH:17][NH:18][C:19]=4[CH:20]=3)[N:11]=[CH:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:28])=O>CN(C=O)C>[Cl:28][C:15]1[C:14]2[CH:13]=[C:12]3[N:11]=[CH:10][N:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:21]3=[CH:20][C:19]=2[N:18]=[CH:17][C:16]=1[C:22]#[N:23]
Reactant: N#Cc1c[nH]c2cc3c(cc2c1=O)ncn3CCN1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Yield: 61 %

Procedure:
A suspension of 190.0 mg (0.59 mmol) of 3-[2-(4-morpholinyl)ethyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 5.45 mL of 2M oxalyl chloride (in methylene chloride) and 5 drops of DMF is heated at reflux temperature for 1.5 hours. After cooling, the solvent is evaporated to dryness. The residue is cooled in an ice bath and neutralized to pH 7 by slow addition of ice-cooled, aqueous saturated sodium bicarbonate solution. The aqueous solution is extracted with methylene chloride. The organic phase is washed with cold brine and dried over sodium sulfate. Removal of the solvent in vacuo gives the crude product. Purification of the crude product by preparative TLC (developing solvent: 5:95 methanol/methylene chloride) gives 122.8 mg (61%) of the product as a yellow solid, mp 205–207° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:15][Si:16]([CH3:26])([CH3:25])[O:17][C:18]([CH3:24])([CH3:23])[C:19](OC)=[O:20]>C1COCC1.CCCCCC>[CH3:15][Si:16]([CH3:26])([CH3:25])[O:17][C:18]([CH3:24])([CH3:23])[C:19]([C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: COC(=O)C(C)(C)O[Si](C)(C)C
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)C(C)(C)O[Si](C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
A solution of 204 mg (1.0 mmol) of 4-bromothioanisole in 2.5 mL of THF was cooled to -78° C. and treated with 0.42 mL of 2.5M n-BuLi solution in hexane. After stirring at -78° C. for 1 h, a solution of 380 mg (2.0 mmol) of methyl 2-trimethylsilyloxyisobutyrate in 2 mL of THF was added. The mixture was stirred at -78° C. for 2 h and then quenched with NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 19:1 hexane/EtOAc to give 95 mg of the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:22][S@](C(C)(C)C)=O)[C:10]1[CH:15]=[CH:14][C:13]([P:16]([CH3:21])(=[O:20])[O:17][CH2:18][CH3:19])=[CH:12][CH:11]=1.[ClH:29].O1CCOCC1>>[ClH:29].[NH2:22][C@H:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]1[CH:11]=[CH:12][C:13]([P:16]([CH3:21])(=[O:20])[O:17][CH2:18][CH3:19])=[CH:14][CH:15]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-((S)-(2,4-difluorophenyl)((S)-1,1-dimethylethylsulfinamido)methyl)phenyl(methyl)phosphinate, 21-c, (950 mg, 2.2 mmol) was dissolved in HCl/dioxane (5 ml) and the mixture was stirred at room temperature for 1 h. Then it was concentrated under vacuum and the residue was washed with ethyl acetate to provide the product, 21-d, (700 mg, 88%).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([NH:21][CH2:18][CH2:19][CH3:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Product: CCCNC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 62° C. and MS: m/e=267 (M+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and propylamine.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[N:5]1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:25]3[CH:24]=[C:23]([CH3:22])[O:27][N:26]=3)=[O:29])[CH3:21])[N:5]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: Cc1cc(C(=O)O)no1
Product: Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)-benzonitrile (120 mg, 0.408 mmol) and 5-methylisoxazole-3-carboxylic acid (62 mg, 0.489 mmol). The product was purified with flash-chromatography. Yield 88 mg (53%). 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.43 (s, 3H), 4.32-4.34 (m, 2H), 4.40-4.50 (m, 1H), 6.43 (s, 1H), 7.02 (d, 1H), 7.84 (d, 1H), 8.18 (d, 1H), 8.23-8.25 (m, 1H), 8.29 (s, 1H), 8.71 (d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:25]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:25]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:24])=[CH:8][CH:9]=3)[N:35]=2)[CH:26]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3,4-difluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 45, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.23 (bs, 1H), 7.94 (d, 1H, J=8.0 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.65 (d, 2H, J=7.6 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.48–7.43 (m, 2H), 7.40–7.35 (m, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.97 (q, 1H, J=9.6 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (ddd, 1H, J=12.0, 7.2, 3.2 Hz), 6.62–6.58 (m, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.23 and 3.10 (d of ABq, 2H, J=14.0 Hz), 3.08 (t, 2H, J=6.4 Hz), 2.44 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:13]([CH:17]=2)[C:14]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(-c2cnc(N3CCOCC3)c(C(=O)O)c2)c1
Reactant: COc1ccc(CN)cc1OC
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(Cl)c3)cnc2N2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-chloro-5-methylphenyl)-2-morpholin-4-ylnicotinic acid (4-2, 2.8 g, 8.41 mmol) and 3,4-dimethoxybenzylamine (6.30 mL, 42.1 mmol) in DCM (42 mL) was added EDC (4.84 g, 25.2 mmol), HOBt (3.87 g, 25.2 mmol) followed by N-methylmorpholine (9.25 mL, 84 mmol) and the system was stirred at 25° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate and dried over magnesium sulfate. The reaction mixture was filtered, concentrated and triturated with diethylether to afford the title compound (4-3) as a bone powder. 1H NMR (400 MHz, CDCl3) δ 8.82 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 1H), 6.90 (m, 2H), 6.84 (m, 1H), 4.56 (d, J=5.6 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.55 (m, 4H), 3.12 (m, 4H), 2.37(s, 3H). HRMS [M+H] C26H28ClN3O4 calc'd 482.1841, found 482.1847.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCOCC.O>[Br:1][C:2]1[C:11]([Cl:12])=[C:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH:9]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cc(CO)cc(Br)c1Cl
Reaction time: 2 h
Yield: 88.4 %

Procedure:
(I8A): Methyl 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (5 g, 13.71 mmol, Intermediate 4) was dissolved in THF (91 mL) at 0° C. under N2. Lithium aluminum hydride solution (10 ml, 10.00 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred for 2 hours at which point reaction appeared complete by LC/MS. Water (1.4 mL) was added slowly and resulted in a vigorous quench. 1 M aq. NaOH soln (1.4 mL) was added dropwise, followed by a final addition of H2O (4.2 mL). The mixture was stirred vigorously for 15 minutes and then several scoops of MgSO4 were added. The reaction was diluted with Et2O, stirred for 1 hour and then filtered through celite. Concentrated afforded tert-butyl (3-bromo-2-chloro-5-(hydroxymethyl)phenyl)carbamate (4.08 g).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:15])[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[F:15])[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[NH:30][CH2:29]2)=[O:7])[NH2:1])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccncc1F
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccncc1F

Procedure:
The title compound was prepared from (2S,3S)-2-azido-3-(4-chlorophenyl)-3-(3-fluoropyridin-4-yl)propanoic acid (Example 1040, step 1) and the product from step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=656 (M+H)+.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26].C(Cl)(=O)C>>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[S:19][CH:20]=1
Reactant: CCCC(=O)Cl
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Agent: Cl
Solvent: CC(=O)Cl
Product: CCCC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 47.2 %

Procedure:
This compound is prepared according to a protocol identical to that described for Example 355, with the compound of Example 362 and butanoyl chloride respectively replacing intermediate 355.2 and the acetyl chloride in Stage 355.3. The expected product is obtained in the form of a yellow solid with a yield of 47.2%. Melting point: 218.0-220.0° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13](Cl)(=[O:15])=[O:14])(=[O:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[CH:17]1([NH:20][S:13]([C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:15])=[O:14])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(F)ccc1S(=O)(=O)NC1CC1

Procedure:
(Step 1) A solution of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride (1.5 g), cyclopropylamine (0.43 ml) and triethylamine (0.87 ml) in tetrahydrofuran (15 ml) was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from methanol-water to give N-[2-(cyclopropylsulfamoyl)-5-fluorobenzyl]acetamide (1.06 g) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[C:44]([CH:45]=1)=[N:43][N:42]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=2>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[C:44]([CH:45]=2)=[N:43][N:42]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=3)=[CH:9][CH:10]=1
Reactant: COCCCn1cc2ccc(CCl)cc2n1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCn1cc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc2n1

Procedure:
Analogously to Method D, 0.178 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.090 g of 6-chloromethyl-2(3-methoxypropyl)-2H-indazole are reacted. The title compound is obtained as a colourless oil. Rf=0.15 (2:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]([F:27])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16].FC(F)(F)C(O)=O>C(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([F:27])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(F)(CCC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(F)(CCC(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
A solution of tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-4-fluoro-4-ethoxycarbonylbutanoate (1.1 g, 3 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (5 mL) is stirred for 18 hours and then with methylene chloride (50 mL) for 10 min. The organic layer is washed with water and brine (30 mL each), and dried over sodium sulfate. The solvent is removed in vacuo to yield 4-(1,3-dioxoisoindolin-2-yl)-4-(ethoxycarbonyl)-4-fluorobutanoic acid which can be purified by chromatography or used in the next step without further purification.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]1([CH2:50][NH:51][C:52]([C:54]2[NH:58][C:57]3[C:59]([N:63]([CH3:72])[S:64]([C:67]4[S:68][CH:69]=[CH:70][CH:71]=4)(=[O:66])=[O:65])=[C:60]([CH3:62])[S:61][C:56]=3[CH:55]=2)=O)[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)C1C=CC=CC=1>ClCCl>[CH3:72][N:63]([C:59]1[C:57]2[NH:58][C:54]([C:52]3[S:43][C:44]4([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]4)[CH2:50][N:51]=3)=[CH:55][C:56]=2[S:61][C:60]=1[CH3:62])[S:64]([C:67]1[S:68][CH:69]=[CH:70][CH:71]=1)(=[O:66])=[O:65]
Reactant: Cc1sc2cc(C(=O)NCC3(SCc4ccccc4)CCNCC3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1sc2cc(C3=NCC4(CCNCC4)S3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To a solution of triphenylphosphine oxide (1.5 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.45 mL) at 0° C., and the mixture was stirred for 10 min. N-{[4-(Benzylthio)piperidin-4-yl]methyl}-2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxamide (1.03 g) was added, and the mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-methyl-N-[2-methyl-5-(1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-4H-thieno[3,2-b]pyrrol-3-yl]thiophene-2-sulfonamide (240 mg, yield 29%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 196° C.
Reaction SMILES: OC(C(F)(F)F)=O.C1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:32]([O:34]C)=[O:33])=[CH:19][C:20]=3[N:21]3[C:27]=2[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH2:22]3)CCCCC1.C1(N=C=O)C=CC=CC=1>C(N(CC)CC)C.C(Cl)Cl.CO>[CH:28]1[C:26]2[C:27]3[N:21]([C:20]4[CH:19]=[C:18]([C:32]([OH:34])=[O:33])[CH:17]=[CH:16][C:15]=4[CH:14]=3)[CH:22]=[CH:23][NH:24][C:25]=2[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Solvent: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2cc3n(c2c1)C=CNc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate TFA (80 mg, 0.17 mmol) in triethylamine (0.20 mL) and CH2Cl2 (5 mL) which had been stirred for 5 min. was added phenyl isocyanate (0.20 mL, 1.84 mmol). The reaction solution was stirred for 2 h at rt, diluted with CH2Cl2 (˜10 mL) and MeOH (˜2 mL) and washed with ½ saturated aqueous NH4Cl (10 mL) and brine (10 mL). The organics were concentrated to dryness, dissolved into MeOH/THF (1:1, 3 mL) and treated with 1M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (3 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The solids were collected by filtration, washed with water and purified by preparative HPLC (MeOH/H2O with NH4OAc buffer) to yield 5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-5-[(phenylamino)carbonyl] (21 mg, 0.044 mmol, 25%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.75-7.59 (m, 5H), 7.19-6.92 (m, 5H), 4.78-4.47 (m, 2H), 4.00-3.51 (m, 2H), 3.10-2.96 (m, 1H), 2.20-1.14 (m, 10H). LCMS: m/e 480 (M+H)+, ret time 1.54 min, column A, 3 minute gradient.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:25])[N:15]([CH3:24])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2ccccc21
Yield: 69.5 %

Procedure:
Cyclohexylamine (2.0 mL, 18.20 mmol) was added to a solution of Compound 1 (2.25 g, 9.1 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered to yield 1.9 g (70%) of white solids. M.P. 145° C. 1H NMR (DMSO-d6): δ 1.26 (m, 1H), 1.38 (m, 4H), 1.54 (m, 1H), 1.68 (m, 2H), 1.86 (m, 2H), 3.62 (s, 3H), 3.87 (m, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 10.46 (s, 1H), 17.46 (s, 1H),. EIMS m/z 301 (M+1), 323 (M+23). Anal. (C17H20N2O3) C, H, N.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[CH3:20][OH:21]>C[O-].[Na+].O>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:21][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(CCl)nnc12
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.1 %

Procedure:
The mixture of 9-butyl-3-(chloromethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (35 mg, 125 mmol) in 4 M of sodium methoxide in methanol (0.5 mL, 2 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo to yield the desired product (6 mg, 17.42%). LCMS calculated for C13H19N6O2 (M+H): 290.2. Found 290.2.