Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:9][C:10]([C:12]1[N:13]=[C:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:16]=12)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[OH-].[Li+]>C1COCC1.O>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]2[C:14]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:13][C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:7])([CH3:8])[CH3:6])[C:3]([OH:34])=[O:2])=[O:11])=[C:16]2[CH2:17]1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
Intermediate 22A (2.73 g, 5.80 mmol) was dissolved in THF (20 mL) and cooled to 0° C. Lithium hydroxide (0.70 g, 29 mmol) solution in water (4 mL) was added and the mixture was stirred on ice bath for 6 hours. The mixture was concentrated under reduced pressure, cooled in an ice bath and acidified to pH 4 with 1N HCl. The resulting white precipitate was filtered, washed with water and dried in a vacuum oven at 40° C. to provide Intermediate 22B (2.29 g, 86%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 0.97 (s, 9H), 1.44 (s, 9H), 3.67 (m, 2H), 4.14 (t, 2H), 4.48 (d, 1H), 4.84 (s, 2H), 7.49 (m, 3H), 7.72 (m, 2H); LCMS (+ESI) m/z 457.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[CH2:15][O:16][CH3:17])=[CH:11][C:10]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:9][CH:8]=3.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]1[CH:4]=[N:3][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([CH2:15][O:16][CH3:17])[C:13]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCc1c(Br)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCc1c(-c2ccccc2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
476 mg of 3-bromo-6-benzyloxy-4-methoxymethyl-β-carboline is introduced in 10 ml of toluene and 5 ml of ethanol, mixed with 41 mg of tetrakis(triphenylphosphine)-palladium(0) and stirred for 5 minutes. Then 177 mg of phenylboronic acid and 1.5 ml of a 2 m- soda solution are added and then heated for 3 hours to 95° C. After concentration by evaporation it is taken up in a lot of ethyl acetate and washed once each with water and saturated common salt solution. After drying, filtration and concentration by evaporation, it is recrystallized. 372 mg of 6-benzyloxy-3-phenyl-4-methoxymethyl-β-carboline of a melting point of 205°-206° C. (ethanol, methylene chloride, hexane) is obtained.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16]C1C=CC(C(O[C@H](C)CCCCCC)=O)=CC=1F>CN(C)C1C=CN=CC=1.ClCCl>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N,N′-Dicyclohexylcarbodiimide (0.64 g, 3.1 mmol) and 4-(dimethylamino)pyridine (0.10 g, 0.1 mmol) was added to a stirred solution of compound 42 (1.23 g, 3.1 mmol) and compound 15 (0.83 g, 3.1 mmol) in dichloromethane. The reaction mixture was left stirring at room temperature for 72 h until completion of the reaction. Tile dicyclohexylurea formed was filtered off and the solvent removed in vacuo to yield a viscous colourless oil which was purified by column chromatography (ethyl acetate) on silica. The colourless material was then heated in ethanol and cooled to −60°, filtered off and dried in vacuo (P2O5). Yield 1.83 g (91%), [α]D=−22.35° at 24° C.
Reaction SMILES: [OH:1][C:2]1([CH2:20][NH:21]C(=O)OC(C)(C)C)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:11][CH:10]=2)[CH2:4][CH2:3]1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:21][CH2:20][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2cnc(-c3ccccn3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1(O)CCN(Cc2cnc(-c3ccccn3)s2)CC1

Procedure:
A solution of the compound prepared in Example 252 (0.108 g) in dichloromethane (1.3 mL) was treated with trifluoroacetic acid (0.3 mL) at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was azeotroped from toluene twice to obtain the title compound (0.104 g) having the following physical data.
Reaction SMILES: [OH-].[K+].C/C=C/[CH2:6][C@H:7]([C@@H:9]([OH:16])[C@H:10]([NH:14][CH3:15])[C:11]([OH:13])=[O:12])[CH3:8]>>[OH:16][CH:9]([CH:7]([CH3:8])[CH3:6])[C@@H:10]([C:11]([OH:13])=[O:12])[NH:14][CH3:15]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H](NC)C(=O)O
Agent: [K+]
Agent: [OH-]
Product: CN[C@H](C(=O)O)C(O)C(C)C

Procedure:
At the same time, an elegant asymmetric glycine enolate reaction was developed by Evans and Weber for the synthesis of MeBmt and other chiral amino acids. (See, Evans, D. A. and Weber, A. E., J. Am. Chem. Soc., 108:6757 [1986]). The approach was also applied to prepare MeLeu(OH) (See, FIG. 6). In the reaction sequence, the chiral glycine synthon isothiocyanate was obtained from corresponding chloroacetate and followed by azide replacement in 56% yield. The isothiocyanate chiral auxiliary was condensed with isobutyraldehyde under stannous triflate-mediated aldol reaction (-78° C. for 4 h) to give the aldol adduct in 63% yield (>90% e.e). Transesterification with a solution of magnesium methoxide in methanol at room temperature for 3 min gave the methyl ester in 78-82% yield. The yield of the bis-methylation was low, 52% as compared to 76% of Evans in MeBmt synthesis. Two epimers are usually obtained in a ratio of 1:5, which was not found by Evans for the MeBmt synthesis. The 1H NMR spectra of the epimers were compared as shown in Table 4 and FIG. 7. Hydrolysis of the desired trans-oxazolidinone with 2N KOH under reflux gave the pure β-hydroxy-N-methylleucine (see 1H NMR spectra in FIG. 8) after chromatographic purification over Sephadex LH-20.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:11](=[O:12])[C:10]([CH:13](O)[C:14]([F:17])([F:16])[F:15])=[CH:9][NH:8][C:7]=1[CH3:19].CO.[Cl:22]CCl>C(#N)C>[Cl:22][CH:13]([C:10]1[C:11](=[O:12])[C:6]([OH:5])=[C:7]([CH3:19])[NH:8][CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: ClCCl
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1[nH]cc(C(Cl)C(F)(F)F)c(=O)c1O
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.5 mL, 33.7 mmol) was added to a suspension of 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.50 g, 6.7 mmol) in acetonitrile (33 mL) at room temperature. The resulting mixture was stirred for 30 min as a clear solution resulted. The progress of the reaction was monitored by TLC (methanol:dichloromethane, 1:10, v:v), which indicated consumption of the starting material. The reaction mixture was evaporated to dryness to give crude 5-(1-chloro-2,2,2-trifluoro-ethyl)-3-hydroxy-2-methyl-1H-pyridin-4-one as a solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:29]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccoc2)c1

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 60 mg, 0.134 mmol), furan-3-ylboronic acid (22.6 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol), Na2CO3 (42.8 mg, 0.403 mmol), DME (570 μL), water (163 μL) and EtOH (81 μL) in a MW vial was sealed, evacuated/purge with argon and subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 25% for 0.2 min then 25% to 55% in 14 min) to yield the title compound as a white solid. LC-MS (Condition 2) tR=1.92 min, m/z=434.1-435.2 [M+H]+, m/z=432 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.81 (m, 1H) 1.82-1.92 (m, 1H) 3.07 (d, J=11.49 Hz, 1H) 3.30-3.45 (m, 1H) 3.48-3.57 (m, 2H) 4.21-4.27 (m, 1H) 6.68 (s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.76 (t, J=1.59 Hz, 1H) 7.83 (s, 1H) 7.84-7.88 (m, 2H) 7.98 (d, J=2.45 Hz, 1H) 8.70 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH2:11][C@H:10]([OH:17])[CH2:9][OH:8]
Reactant: O[C@H](COCc1ccccc1)Cc1ncc[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OC[C@@H](O)Cc1ncc[nH]1
Reaction time: 24 h
Yield: 89.5 %

Procedure:
(2S)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol (1.725 g) was dissolved in ethanol (30 ml); 10% palladium carbon (1.04 g) was added, followed by vigorous stirring in a hydrogen atmosphere at 60° C. and 5 atm for 24 hours. The catalyst was filtered off and the solvent was distilled off; the residue was purified by silica gel flush column chromatography to yield the titled compound (0.945 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:11][O:12]C(C)(C)C)=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:11][OH:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1COC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]nc1CO
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [3.46 g, Reference Example 42] in dichloromethane (25 ml) was treated with trifluoroacetic acid (25 ml). The mixture was stirred for 1.5 hours and then concentrated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was dried over magnesium sulfate and then evaporated to give 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.49 g) as a brown solid which was used without further purification. LC-MS (METHOD B): RT=2.54 minutes; 171 (M+H)+. (b) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide
Reaction SMILES: FC1C(C)=NC2C(N=1)=C([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)C=CC=2.NC1CCCC(O)C1>>[NH:20]1[C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: NC1CCCC(O)C1
Product: O=C1NCCc2[nH]ccc21
Temperature: 100 °C
Yield: 17 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 3-aminocyclohexanol (37.0 mg, 0.324 mmol, AB Chem, Inc., Dorval, Canada; mixture of racemic cis- and trans-isomers) and heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2434(3-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (17% yield; mixture of racemic cis- and trans-isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 1H) 1.32-1.51 (m, 3H) 1.55-1.69 (m, 1H) 1.70-1.83 (m, 1H) 1.87 (d, J=12.72 Hz, 1H) 2.00 (br. s., 2H) 2.27 (d, J=11.93 Hz, 1H) 2.55 (d, J=4.11 Hz, 3H) 2.86-3.05 (m, 3H) 3.41-3.72 (m, 4H) 4.02-4.48 (m, 2H) 4.69-4.83 (m, 1H) 6.73-7.02 (m, 2H) 7.07-7.18 (m, 1H) 7.32 (td, J=7.82, 2.15 Hz, 1H) 7.53-7.60 (m, 1H) 7.85-7.96 (m, 1H) 11.86-12.16 (m, 1H). MS (ESI, pos. ion) m/z: 392 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:20])([C:13]([O:15]C(C)(C)C)=[O:14])[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:12])([C:13]([OH:15])=[O:14])[CH3:20])=[O:9])=[CH:6][N:5]=[C:4]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1cnc(-n2cccn2)nc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)c1cnc(-n2cccn2)nc1O)C(=O)O

Procedure:
The product of Step A (3.0 g, 8.64 mmol) was combined with DCM (18 ml) and TFA (2.5 mL). The reaction was aged at reflux for about 5 h and then concentrated. The product was then treated with Et2O, isolated by filtration, and washed with hexane to afford the title compound. HPLC/MS: 292.0 (M+1); Rt=1.42 min.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH:12]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])Cl)(C(C)(C)C)(C)C.[CH3:30][C@H:31]1[CH2:36][NH:35][C@@H:34]([CH3:37])[CH2:33][NH:32]1.C(Br)C=C.C(N(CC)C(=O)C1C=CC=CC=1)C>>[CH3:30][C@H:31]1[CH2:36][NH:35][C@@H:34]([CH3:37])[CH2:33][N:32]1[CH:12]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[O:18])[C:11]1[CH:27]=[CH:28][CH:29]=[C:9]([OH:8])[CH:10]=1
Reactant: CCN(CC)C(=O)c1cccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1
Reactant: C[C@H]1CN[C@@H](C)CN1
Agent: CCN(CC)C(=O)c1ccccc1
Solvent: C=CCBr
Product: CCN(CC)C(=O)c1cccc(C(c2cccc(O)c2)N2C[C@H](C)NC[C@@H]2C)c1

Procedure:
3-(α-((2S,5S)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was prepared as a mixture of epimers from 3-(3-((tert-butyldimethylsilyl)oxy)-α-chlorobenzyl)-N,N-diethylbenzamide (Example 1, infra) and (+)-(2S,5S)-2,5-dimethylpiperazine [prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described by Jung and Rohloff (J. Org. Chem. 50, 4909-13 (1985))] according to the methods of Example 1. This material was then alkylated with allyl bromide by methods similar to that in Example 4 to give a mixture of diastereomers that was separated by chromatography on silica gel (Waters Prep 500A, 0.1% triethylamine in dichloromethane). The first isomer to elute was deprotected by the method in Example 4 to give 3-((αR or αS)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. NMR (DMSO-d6, 200 MHz): δ0.890 (d, J=5.6 Hz, 3H); 0.981 (d, J=6.4 Hz, 3H); 1.00-1.25 (m, 6H); 2.10-2.48 (m, 4H); 2.59 (d, J=11.1 Hz, 1H); 2.73 (dd, J1 =7.8 Hz, J2 =14.1 Hz, 1H); 2.90-3.60 (m, 6H); 4.54 (s, 1H); 5.13 (d, J=9.0 Hz, 1H); 5.19 (d, J=16.2 Hz, 1H); 5.84 (m, 1H); 6.58 (d, J=8.0 Hz, 1H); 6.86 (s, 1H); 6.88 (d, J=7.1 Hz, 1H); 7.08 (t, J=7.6 Hz, 1H); 7.14 (d, J=7.8 Hz, 1H); 7.34 (t, J=7.6 Hz, 1H); 7.43 (s, 1H); 7.48 (d, J=7.7 Hz, 1H); 9.32 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].[N:31]1([CH2:36][CH2:37]O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:37][CH2:36][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: OCCN1CCCC1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OCCN4CCCC4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 1, 100 mg, 0.23 mmol), 2-(pyrrolidin-1-yl)ethanol (35 μL, 0.30 mmol), triphenylphosphine (79 mg, 0.30 mmol), and diisopropyl azodicarboxylate (60 μL, 0.30 mmol) in THF (5 mL) was stirred at room temperature for 2 days. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water, 0.1% TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 30 mg of 5-(5-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (d, 1H), 8.74 (d, 1H), 7.40 (t, 1H), 7.35 (dd, 1H), 7.22 (d, 1H), 4.24 (t, 2H), 2.86 (t, 2H), 2.65-2.42 (m, 8H), 1.98-1.95 (m, 1H), 1.70 (m, 4H), 1.60-1.54 (m, 1H). LCMS [M+1]+ 534.9.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:32])[C@@H:20]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Reaction time: 0.03 h
Yield: 68.7 %

Procedure:
Add aqueous 37% formaldehyde (45 mL, 0.55 mmol) to a solution of 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene (200 mg, 0.5 mmol) in dichloroethane (30 mL). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (159 mg, 0.75 mmol). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry (MgSO4), filter and concentrate. Purify the residue via chromatography eluting with methylene chloride/methanol (90:10) to provide the title compound as a yellow solid (143 mg, 67%): mp 87–91° C.: 1H NMR (CDCl3): δ1.78 (m, 1H), 1.96 (m, 1H), 2.22 (m, 1H), 2.32 (s, 3H), 2.35 (s, 3H), 2.38 (ddd, 1H), 2.58 (ddd, 1H), 2.75 (ddd, 1H), 2.86 (ddd, 1H), 2.94 (dd, 1H), 3.16 (ddd, 1H), 3.90 (m, 1H), 4.05 (m, 1H), 4.94 (s, 1H), 6.30 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.98 (t, 1H), 7.04 (d, 1H), 7.17–7.32 (m, 5H); MS (APCI) m/z (rel intensity) 417 (100).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][S:20][CH2:21][CH2:22][CH2:23][OH:24].[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37](O)=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37]([O:24][CH2:23][CH2:22][CH2:21][S:20][CH3:19])=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: CSCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCSC
Temperature: 5 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (1.56 g, 6.2 mmol) followed by 3-(methylthio)-1-propanol (0.32 ml, 3 mmol) was added to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 48), and tributylphosphine (1.42 ml, 6.1 mmol) in methylene chloride (20 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then for 18 hours at ambient temperature. The insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol (100/0 increasing to 95/5) to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline (400 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[CH3:33][S:34]([C:37]1[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].Cl>>[CH3:33][S:34]([C:37]1[CH:38]=[C:39]([NH:43][C:28]([C:27]2[CH:26]=[N:25][N:18]3[C:19]([C:21]([F:22])([F:23])[F:24])=[CH:20][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:13])([F:14])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:32])[F:31])[CH:6]=4)=[N:16][C:17]=23)=[O:29])[CH:40]=[CH:41][CH:42]=1)(=[O:35])=[O:36]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (EI) 626.3 [M]; mp 227° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[C:10]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:9]2=[O:30])C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[NH:8][C:9](=[O:30])[C:10]12[C:29]2[C:20](=[CH:21][C:22]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:28]=2)[O:19][CH2:18]1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Yield: 26.9 %

Procedure:
To a solution of 1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.59 g, 1.2 mmol) in trifluoroacetic acid (25 mL) was added triethylsilane (0.6 mL, 3.7 mmol). The reaction mixture was heated at reflux for 1 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography and eluted with a gradient of ethyl acetate in hexanes, followed by sequential trituration in acetonitrile and ethyl acetate, to afford 7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.101 g, 26%) as an off-white solid: MS (ES+) m/z 314.2 (M+1).