Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:23]1[C:24]2([CH2:28][CH2:27][N:26]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:25]2)[CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1CC2(CC2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(CC2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-azaspiro[2.4]heptane hydrochloride (3659-21-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=364.5 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>ClCCCl>[Br:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1csc(CBr)n1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of ethyl-2-methylthiazole 4-carboxylate (500 mg, 2.9 mmol), N-bromosuccinimide (877 mg, 4.9 mmol), and benzoyl peroxide (5–10 mg) in 1,2-DCE (3 mL) was heated at 70° C. for 85 h. After cooling to room temperature, DCM (10 ml) was added and washed with water (3 times). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative chromatography to yield the above-titled compound (58 mg). 1H NMR (CDCl3): 8.23 (1H, s), 4.77 (2H, s), 4.43 (2H, q), 1.42 (3H, t).
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([CH:19]([CH3:21])[CH3:20])[C:15]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)O)=[O:13])[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([CH:19]([CH3:21])[CH3:20])[C:15]=1[CH:22]([Cl:1])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:13])[CH3:10]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(C#N)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccn(C(C)C)c1C(Cl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine [26189-59-3] (4.80 mmol) was added to a solution of 2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H4) (3.20 mmol) in CH2Cl2 (15 mL) and the mixture was stirred at rt for 2.5 h. CH2Cl2 was added and the reaction mixture was concentrated to dryness (2×) to afford the title compound as a yellow-orange oil. tR: 5.71 min (sample in MeOH) (HPLC 4); ESI-MS: tR=1.26 min (LC-MS 1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4].S(=O)(=O)(O)O.[CH3:19]O>>[NH2:2][C@@H:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CO
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([C@@H](C)N)cc1
Yield: 70 %

Procedure:
To a solution of (R)-4-(1-amino-ethyl)-benzoic acid hydrochloride (0.20 g, 0.99 mmol) in methanol (3.2 mL) was added sulfuric acid (5.29 μL, 0.0992 mmol). The resulting solution was heated at reflux overnight. The methanol was removed under reduced pressure leaving a light brown oil which was partitioned between half-saturated sodium bicarbonate solution (50 mL) and ethyl acetate (75 mL). The aqueous phase was extracted with additional ethyl acetate (50 mL). The extracts were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica chromatography (0-50% EtOAc/hexane) afforded product as a white solid (0.124 g, 70%). LC-MS: (FA) ES+ 180.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2C(=O)NCC[C:6]3=[C:7](C4C=CC(C=O)=CC=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1(C2NC3C=CC=C4C(=[O:43])NCCC=2C=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.N1CCCC1>>[N:8]1[C:9]2[C:5]([CH:4]=[CH:3][C:2](=[O:43])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Solvent: C1CCNC1
Product: O=C1C=CC2=CC=NC2=C1

Procedure:
In a manner similar to that described for Compound PPP, 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl) benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with pyrrolidine (115 mg, 1.62 mmol) to yield 8-fluoro-2-(4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepinop5,4,3-cd]indol-6-one, 16 mg (14%) as a yellow solid: m.p. 264-265° C. (dec), 1H NMR (300 MHz, d6-DMSO) δ 1.72 (m, 4H), 2.49 (m, 4H), 3.04 (m, 2H), 3.39 (m, 2H), 3.64 (br s, 2H), 7.31 (dd, J=9.3, 2.4 Hz, 1H), 7.43 (m, 3H), 7.58 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.66 (br s, 1H). HRMS (MALDI MH+) Calcd for C22H22N3OF: 362.1825. Found: 364.1810. Anal. (C22H22N3OF.0.5 H2O) C, H, N.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:15](=O)[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[C:13]#[N:14])=[CH:11][C:6]=2[N:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[NH2:14][C:13]1[O:29][N:28]=[C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[C:12]=1[C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6]=2[CH:11]=1
Reactant: NO
Reactant: CCn1c(=O)n(CC)c2cc(C(C#N)C(=O)c3cccc(C)c3)ccc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(=O)n(CC)c2cc(-c3c(-c4cccc(C)c4)noc3N)ccc21
Temperature: 30 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a pyridine (1.5 mL) solution of 2-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-oxo-3-m-tolyl-propionitrile (0.113 g) at 23° C. was added hydroxylamine hydrochloride (0.071 g). The reaction was heated to 30° C. for 1 hour then to 55° C. for 3 hours, cooled and extracted into ethyl acetate from 10% citric acid. The organic layer was dried over sodium sulfate and concentrated. The resulting powder was triturated with methanol and filtered to give 5-(5-Amino-3-m-tolyl-isoxazol-4-yl)-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (0.085 g).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=N[CH2:24][CH2:25][CH2:26][N:27](C)C.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C(N(CC)CC)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13](=[O:15])[NH:27][CH:26]1[CH2:24][CH2:25]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDAC (2.3 g, 2 eq.), HOBt (0.8 g, 2 eq.) in DMF (20 mL) was added triethylamine (1.5 mL) and cyclopropylamine (0.8 mL, 2 eq.). After stirring at RT for 18 h, the reaction was basified with sodium bicarbonate, poured to brine, and followed by extraction with dichloromethane. After concentration of the combined extracts, the residue was purified on a silica gel column eluting with 100% EtOAc to give 1.6 g (92%) of (R)-2-cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2](=[O:40])[CH:3]([OH:39])[CH:4]([NH:12][C:13](=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CS(C)=O.ClC(Cl)C(O)=O>ClCCl>[NH2:1][C:2](=[O:40])[C:3](=[O:39])[CH:4]([NH:12][C:13](=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(c3ccccc3)CC2)n1
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
To a solution of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-((4-phenylpiperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinamide (100 mg, 0.186 mmol) in dichloromethane (3 mL) at room temperature DMSO (300 μL), N,N′-dichyclohexyl-carbodiimide (380 mg, 1.842 mmol) and 2,2-dichloroacetic acid (40 μL, 0.487 mmol) were added, and the mixture stirred for 1.5 h at room temperature. After completion of the reaction the mixture was filtered, the filtrate diluted with 30 mL of water, extracted with ethylacetate, the aqueous layer then adjusted to pH 8 by adding NaHCO3, then extracted again with ethyl acetate (3×30 mL), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated to give 80 mg of a yellow amorphous solid. Purification by chromatography over silica gel (CH2Cl2/methanol) and concentration afforded 25 mg of the title compound as white amorphous solid; ESI-MS [M+H]+: 537.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[Si:13]([O:20][C:21]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1)([CH3:23])[CH3:22])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>O.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>[Si:13]([O:20][C:21]([C:24]1[N:25]=[CH:26][C:27]([C:2]2[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=2)=[CH:28][CH:29]=1)([CH3:23])[CH3:22])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (602 mg, 2.40 mmol), 2-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (905 mg, 2.40 mmol), and Pd(PPh3)4 (139 mg, 0.12 mmol) were combined in a vial and evacuated/backfilled with nitrogen. THF (5.6 mL) and 2 N Na2CO3 (2.4 mL) were added, and the reaction was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography of the crude residue (10-100% EtOAc/hexanes) afforded the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:36]CCl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([Cl:36])=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (b) (0.25 g, 0.5 mmol) in dichloromethane (7 mL) oxalyl chloride (0.15 mL, 1.75 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 1 hour, then the mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in a form of a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]CC)=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][CH3:20])=[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]3=[C:11]([O:25][CH:26]([F:28])[F:27])[C:10]=2[CH2:9]1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][CH3:20])=[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]3=[C:11]([O:25][CH:26]([F:28])[F:27])[C:10]=2[CH2:9]1
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OC(F)F)C2=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c2c(c(OC(F)F)c3ccccc13)CN(c1ccc(CC(=O)O)cc1Cl)C2=O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
Ethyl {3-chloro-4-[4-[(difluoromethyl)oxy]-9-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]phenyl}acetate (0.141 g, 0.288 mmol) was heated to reflux in a 1:1 mixture of 2N sodium hydroxide:ethanol (6 ml) for 1.5 hours. The reaction was cooled to room temperature. The ethanol was evaporated and the mixture acidified with 2N aqueous hydrochloric acid. The resulting white solid was collected by filtration, washed with water and dried under vacuum to give the title compound (0.125 g, 0.271 mmol). LC/MS: Rt=3.19, [MH]+ 462.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[NH2:53][C@@H:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH2:55]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[C@@H:54]1([NH:53][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:44])[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH2:55]1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: N[C@H]1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H]1CCc2ccccc21)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (S)-(+)-1-aminoindane (0.239 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30–60% ethyl acetate/hexanes gave the title compound (0.277 g, 60% yield). ES-MS (m/z) 505 [M+1(−Tr)]+
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2>>[O:19]=[C:18]1[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15](=[O:20])[N:1]1[CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)C2=C(CCCC2)C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.91 g, 69%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.78 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15]OC1C=CC=C(C)C=1C.CC1C(C)=CC=CC=1OCCCC(O)=O.[CH3:41][O:42][C:43](C1(C(O)=O)CC1)=[O:44]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([C:13]1([C:43]([O:42][CH3:41])=[O:44])[CH2:14][CH2:15]1)=[O:25]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)O)c1C
Product: COC(=O)C1(C(=O)N2CCCc3c(Br)cccc32)CC1

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that 4-(2,3-dimethylphenoxy)butanoic acid was replaced with 1-(methoxycarbonyl)cyclopropanecarboxylic acid. LCMS, [M+H]+=338.0.
Reaction SMILES: CN1CCOCC1.[F:8][C:9]([F:29])([F:28])[C:10]1[N:18]2[C:13]([C:14]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=32)=[CH:12][CH:11]=1.[C:30]([S:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)=[O:35])([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:30]([S:34]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([N:25]2[CH2:24][CH2:23][C:14]3([C:13]4=[CH:12][CH:11]=[C:10]([C:9]([F:8])([F:28])[F:29])[N:18]4[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15]3)[CH2:27][CH2:26]2)=[O:41])=[CH:43][CH:44]=1)=[O:35])([CH3:33])([CH3:31])[CH3:32]
Reactant: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reactant: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C(F)(F)F)ccc23)cc1
Temperature: 50 °C
Yield: 45.2 %

Procedure:
4-methyl morpholine (1.96 mL, 17.8 mmol) was added to a mixture of 1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (1.45 g, 3.56 mmol), 4-tert-butylsulfinylbenzoic acid (807 mg, 3.56 mmol), EDCI (1.03 g, 5.35 mmol), 1-hydroxybenzotriazole (723 mg, 5.35 mmol) and DMF (14.5 mL) at room temperature. The mixture was heated at 50° C. overnight before it was cooled to room temperature and partitioned between ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0-30% ethyl acetate/CH2Cl2, then 0-100% ethyl acetate/hexanes) to provide (4-tert-butylsulfinylphenyl)-[1′-(trifluoromethyl)spiro-[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (831 mg, 44%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.68-7.62 (m, 4H), 7.57 (d, J=8.1 Hz, 1H), 7.33-7.26 (m, 2H), 7.24-7.17 (m, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.41 (d, J=4.0 Hz, 1H), 4.52-4.37 (m, 1H), 3.49 (s, 2H), 3.26-3.13 (m, 1H), 2.16-1.96 (m, 3H), 1.96-1.80 (m, 1H), 1.09 (s, 9H). ESI-MS m/z calc. 516.2, found 517.2 (M+1)+; Retention time: 1.94 minutes (3 min run).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:56][C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=1[C:64]1[CH2:68][NH:67][CH:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:65]=1>CN(C=O)C>[F:56][C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=1[C:64]1[CH2:68][N:67]([C:13]([C@@H:9]([NH2:8])[CH:10]([CH3:12])[CH3:11])=[O:14])[CH:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:65]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 20 h

Procedure:
N-(tert-butoxycarbonyl)-L-valine (101 mg, 0.464 mmol, 2.00 equiv), PYBOP (243 mg, 0.467 mmol, 2.00 equiv), and triethylamine (0.163 mL, 1.17 mmol, 5.00 equiv) were added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (24, 0.233 mmol, 1 equiv) in DMF (10 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between a 3:1 mixture of saturated aqueous sodium bicarbonate solution and brine (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane (10 mL), and the resulting solution was allowed to stand for 45 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TPA present) to provide (1S)-1-{[4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2-methylpropylamine (15-1) as a 1:1 mixture of diastereomers (tan gum) (isolated as the TFA salt). LRMS m/z (M+H) 357.2 found, 357.2 required.
Reaction SMILES: [C:1]([N:18]1[CH2:23][CH:22]([CH2:24][OH:25])[NH:21][C:20](=[O:26])[C:19]1([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].P([O-])([O-])([O-])=[O:36].CC1(C)N([O])C(C)(C)CCC1.Cl([O-])=O.[Na+].Cl[O-].[Na+].S([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C>[C:1]([N:18]1[C:19]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[C:20](=[O:26])[NH:21][CH:22]([C:24]([OH:36])=[O:25])[CH2:23]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCCC1(CCCC)C(=O)NC(CO)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCC1(CCCC)C(=O)NC(C(=O)O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 43 °C
Reaction time: 4 h

Procedure:
To a solution of 8 mmol alcohol (89) in 81 mL of acetonitrile kept at room temperature, is added phosphate buffer solution (prepared with 0.72 g of sodium phosphate monobasic and 1.43 g of sodium phosphate dibasic in 29.5 mL of water), followed by the addition of 0.33 g (2.1 mmol) of TEMPO, and 1.86 g (16.5 mmol) of sodium chlorite, and the biphasic solution is placed in an oil bath kept at 43° C. A solution of 4.3 mL (2.6 mmol) of sodium hypochlorite solution (prepared by mixing 1.9 mL of 10-13% sodium hypochlorite solution, and 2.4 mL of water) is added slowly. The reaction is stirred at 43° C. for 4 hours, cooled to room temperature, 20 mL of 10% sodium hydrogen sulfite added, stirred for 10 minutes, diluted with 50 mL of ethyl acetate, and the layers separated. The organic layer is washed with 1×10 mL of brine, 1×10 mL of 1N hydrochloric acid solution, dried over sodium sulfate, and concentrated. Compound (90) is purified by silica gel column chromatography.