Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[C:30]([O:32]CC)=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CCOC(=O)C(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethylamino)-2-oxoacetate (100 mg, 0.20 mmol) was dissolved in ethanol (2.0 mL) before crushed potassium hydroxide (23 mg, 0.41 mmol) was added and stirred at ambient temperature for 30 min. The reaction mixture was concentrated, suspended in water, acidified with 2 N HCl, filtered, and washed with water. The title compound was obtained after purification via preparatory LC. MS (ESI) m/z: Calculated: 461.1; Observed: 462.0 (M++H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[C:20](OC)(=[O:22])C>CO.C[O-].[Na+].Cl.[Cu]Br>[CH3:20][O:22][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Reactant: COC(C)=O
Agent: [Cu]Br
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: COc1ccc2nn(C)cc2c1C1CC1CNC(C)=O
Yield: 16 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29, copper(I) bromide (89.0 mg, 0.621 mmol) and methyl acetate (148 μL, 1.863 mmol) were dissolved in 28% sodium methoxide methanol solution (8 mL), and the mixture was heated under reflux for 1.5 hr. The reaction mixture was diluted with aqueous hydrochloric acid solution, and the aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=3/97→10/90), HPLC and recrystallization (ethyl acetate/hexane) to give the title compound (27.1 mg, yield 16%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene (3.89 g, 16.49 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (10.3 mL, 16.5 mmol, 1.6 M in hexane) dropwise. After 15 minutes, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.05 g, 16.49, mmol) in tetrahydrofuran (10 mL) was added over 5 minutes. The reaction continued to stir at −78 °C. for 15 minutes and was then quenched by the addition of saturated NH4Cl (150 mL) and diethyl ether (150 mL). After warming to room temperature, the layers were separated, and the aqueous was extracted with additional diethyl ether (2×100 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 50% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 342 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:17]=[CH:18][N:19]=2)[N:24]=1
Reactant: COc1ccc2nccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nccc(OCC3CCNCC3)c2n1
Yield: 100.7 %

Procedure:
A solution of carbamate (a) (0.95 g) in dichloromethane/trifluoroacetic acid (20 ml/20 ml) was stirred for 1 hour then evaporated to dryness, azeotroping with toluene and chloroform. The residue was dissolved in water and extracted with ethyl acetate. The aqueous extract was basified with solid potassium carbonate and evaporated. The residue stirred with 10% methanol in chloroform. Filtration and evaporation afforded an oil (0.7 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: C1COCCN1
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2[nH]1

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)-methanone (23.00 g, 65.6 mmol) and morpholine (17.2 mL, 197 mmol) was heated to 90° C. in DMSO (165 mL). After complete consumption of the starting material, the hot solution was dripped into ice water which caused a yellow solid to precipitate. The solid was slurried in boiling EtOH (600 mL) and enough tetrahydrofuran was added to completely dissolve the solids. The solution was transferred to the freezer for crystallization. The solid was collected by filtration and air-dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 402.1 (M+1). IC50 (uM) ++++.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[Br:27]>>[Br:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[NH:20][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: COC(=O)c1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Product: COC(=O)c1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1
Yield: 41.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene (646 mg, 2.04 mmol) and 5-amino-4-bromo-3-methylisoxazole (361 mg, 2.04 mmol). Purification by column chromatography using 10% MeOH/CHCl3 gave 384 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide as a brown oil (41% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH:46]=[N:47][CH:48]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.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.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:43]4[CH:48]=[N:47][CH:46]=[C:45]([N:49]5[CH2:50][CH2:51][O:52][CH2:53][CH2:54]5)[CH:44]=4)[C:10]=23)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cncc(N3CCOCC3)c2)OC1(C)C
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cncc(N4CCOCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 120 °C
Yield: 67 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]morpholine (Description 81) (214 mg, 0.737 mmol), potassium carbonate (71.0 mg, 0.514 mmol), tetrakis(triphenylphosphine)palladium(0) (19.79 mg, 0.017 mmol) and bis(triphenylphosphine)palladium(II) chloride (12.02 mg, 0.017 mmol) were weighed into a microwave vial. 1,4-Dioxane (2 mL), DMF (1 mL) and water (0.5 mL) were added and the mixture heated in a microwave at 120° C. for 15 min. At this point, both mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (75 mL) and then with 2M NH3 in MeOH (150 mL). The basic methanolic solution was concentrated and purified by normal phase chromatography, eluting with 0-10% MeOH in DCM, to give the title compound (65 mg). LCMS (A) m/z: 567 [M+1]+, Rt 0.72 min (acidic).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 2 h
Yield: 19 %

Procedure:
Prepared using General Procedure 12: To a stirring solution of 4-formylphenyl 4-(heptyloxy)benzoate INT-12 (6.0 g, 17.6 mmol) in THF (30 mL) was added tert-butyl 2-aminoacetate hydrochloride (3.3 g, 19.7 mmol). After stirring for 2 h, sodium triacetoxyborohydride (7.5 g, 32.3 mmol) was added. After stirring for 12 h, the reaction mixture was diluted with NaHCO3 and the organic layer was separated. The remaining aqueous layer was extracted with DCM. The organic layers were combined, dried over Na2SO4, concentrated and purified by chromatography (EA/hexanes) to afford 155 mg (19%) of 4-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)phenyl 4-(heptyloxy)benzoate INT-13. LCMS-ESI (m/z) calculated for C27H37NO5: 455; found 456 [M+H]+, tR=3.27 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.18-8.09 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.18-7.08 (m, 2H), 7.01-6.88 (m, 2H), 4.08-3.98 (m, 2H), 3.78 (s, 2H), 3.23 (s, 2H), 1.89-1.75 (m, 2H), 1.55-1.41 (s, 9H), 1.45-1.21 (m, 6H), 1.15-1.06 (m, 2H), 0.88 (dd, J=8.5, 5.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([OH:24])=O)[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:24])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: C[C@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (R)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (63%). MS: m/e=608(M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH3:29])[CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.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.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH3:29])[CH:23]=2)([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:17]1)=[O:36]
Reactant: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)O)C2c2cccc(Cl)c2F)ccc1Cl
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)NCC[C@H](O)CO)C2c2cccc(Cl)c2F)ccc1Cl
Yield: 62.1 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 100c (0.44 g, 0.76 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.33 g, 2.3 mmol), HATU (0.52 g, 1.37 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 64%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>ClCCl>[CH3:40][O:39][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:36]=1[O:37][CH3:38])[C:31]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:32]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3ccccc3C3(Cc4ccccc4O3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
To a cold solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (8.0 g) and triethylamine (4.0 g) in dry dichloromethane (100 ml) is added dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (9.5 g) in dry dichloromethane (50 ml). After stirring at ambient temperature for 24 hours, the mixture is washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is evaporated to an oil, which solidifies upon trituration with hexanes. The solid is recrystallized twice from hexane/methanol to yield 10.0 g (66%) of product, mp 122° (dec.).
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[C:11]([N:14]1[CH2:41][CH2:40][CH2:39][C@H:15]1[C:16]([NH:18][C@H:19]([C:21]([N:23]1[CH2:38][CH2:37][CH2:36][C@H:24]1[C:25]([NH:27][CH:28]([CH3:35])[CH:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[O:22])[CH3:20])=[O:17])(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:14]1[CH2:41][CH2:40][CH2:39][C@H:15]1[C:16]([NH:18][C@H:19]([C:21]([N:23]1[CH2:38][CH2:37][CH2:36][C@H:24]1[C:25]([NH:27][CH:28]([CH3:35])[C:29]([OH:3])([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[O:22])[CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C(O)C(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)C(O)(O)C(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of oxalyl chloride (0.12 ml, 1.43 mmol) in methylene chloride (1.5 ml) under an argon atmosphere and cooled in a dry ice-acetone bath was added dropwise a solution of dimethylsulfoxide (0.20 ml, 2.86 mmol) in methylene chloride (1.5 ml). After 5 minutes, a solution of the product of example 59 (0.32 g, 0.72 mmol) in methylene chloride (1.5 ml) was added and the reaction mixture stirred for 25 minutes. Triethylamine (0.50 ml, 3.58 mmol) was added and the reaction mixture warmed to room temperature. The reaction mixture was placed directly onto a silica gel column and eluted with methylene chloride-methanol. Evaporation of the appropriate fractions on a rotary evaporator, addition of water (3 ml) to the residue and evaporation gave the above-named product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12](O)=[O:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[CH2:12][OH:13]
Reactant: O=C(O)C1CCOc2c(Br)cccc21
Solvent: C1CCOC1
Product: OCC1CCOc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 8-bromo-3,4-dihydro-2H-chromene-4-carboxylic acid (3.1 g, 12 mmol) in 50 mL THF was added BH3 (24 mL, 24 mmol, C=1.0 M in THF) dropwise at 0° C. The mixture was stirred at 0° C. for 2-3 hours before quenched with MeOH (8 mL), and evaporated. The residue was partitioned between water and EtOAc. The organic phase was washed with 3N HCl, saturated Na2CO3, and brine, dried over anhydrous Na2SO4 and concentrated to afford (8-bromo-3,4-dihydro-2H-chromen-4-yl)methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16].Cl>>[OH:16][C:15]1[C:14]([OH:18])=[N:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(O)c(O)nc2c1
Yield: 74.6 %

Procedure:
A mixture of 225 g (1.47 moles) of 4-nitro-o-phenylenediamine, 375 g. (2.97 moles) of oxalic acid dihydrate and 2250 ml. of 6 N hydrochloric acid is combined in a 3 necked 5 liter round bottom flask which is fitted with a reflux condenser and a teflon paddle stirrer. The suspension is heated at reflux temperature for one hour and allowed to stand at room temperature over night. The material is filtered and the dark brown solid collected is washed with five 300 ml. portions of hot distilled water. The solid is slurried in two equal portions each in 40 ml. of 2 N sodium hydroxide. Each mixture is heated to near boiling with stirring and filtered hot. The red-brown hot filtrate is treated with about two liters of 4 N hydrochloric acid for each batch and the slightly acidic mixtures are filtered while still hot. The brown solid collected is washed with water several times, air dried and finally dried in vacuo over phosphorous pentoxide at 78° C. to give 227.2 g of 2,3-dihydroxy-6-nitroquinoxaline. The reference for the above compound is H. I. X. Mager and W. Berends, Rec. Trav. Chim. 78, 5-21 (1959). An additional reference is F. H. S. Curd, D. G. Davey, and G. J. Stacy, Journ. Chem. Soc. 275, 1271-1277 (1949).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][N:11]([C:24]([C:26]3([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]3)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:38]>O1CCOCC1>[ClH:38].[NH2:30][C:26]1([C:24]([N:11]2[CH2:10][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)[CH2:14][CH:13]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:12]2)=[O:25])[CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CCC3)C2)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(N)CCC3)C2)cc1C

Procedure:
55 mg (0.14 mmol) of tert-butyl [1-({3-(3,4-dimethylphenyl)-5-[(phenylcarbonyl)amino]piperidin-1-yl}carbonyl)cyclobutyl]carbamate were dissolved in 7 ml of dioxane, 1.5 ml of concentrated hydrochloric acid were added and the mixture was immediately concentrated on a rotary evaporator. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 19 mg (39% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C1C(=O)N([Cl:21])C(=O)C1.C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[Cl:21][C:12]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:13])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(=O)NCC2
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a mixture of 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1c, 13.0 g, 73.9 mmol) in conc. H2SO4 (120 mL) was added portionwise NCS (10.4 g, 77.6 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice-water (200 mL). The solution was basified with Na2CO3 (s) to pH 8. The reaction mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 1:1) to give 8-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1d, 7.8 g, 50%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH:16]([NH:18][C:19](=[O:34])[CH2:20][NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[NH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:20][NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)=[O:34])[CH2:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
A solution of {4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-carbamic acid tert-butyl ester (less polar isomer, as prepared in the previous step 5.6 g, 11.2 mmol) in DCM 10 mL and TFA (10 mL) was stirred for 4 hours at room temperature. The solvent was removed and the residue was dried in vacuo to afford the title compound as colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([C:15]([O:17]C)=[O:16])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>CO.O>[CH3:3][C:4]1[N:5]=[C:6]([C:15]([OH:17])=[O:16])[S:7][C:8]=1[C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)O)sc1-c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
Potasium hydroxide (1 g) was added to a stirred solution of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (2 g) in methanol (50 ml) at room temperature and the mixture was stirred at room temperature for 1.5 hours, diluted with water (150 ml), and washed with chloroform. Then the solution was adjusted to pH 3 to 4 by addition of 2N hydrochloric acid aqueous solution. The resulting precipitate was collected by filtration, and air-dried to give 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylic acid (1.8 g, 96%) as colorless powder.