Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)NCCC(=O)OCc2ccccc2)N3C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)NCCC(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
In 8 ml of ethanol was dissolved 0.38 g of benzyl 3-({[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino)-propionate. Then, 1.90 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C., and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer thus obtained, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.30 g of 3-({[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]-decan-3-yl]carbonyl}amino)-propionic acid was obtained as a colorless oily product.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1N[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[C:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])(=[O:22])[CH3:21]
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Reactant: CC(=O)c1ccccc1N
Product: CC(=O)c1ccccc1NC(=O)C1CCCCC1
Yield: 90 %

Procedure:
This compound was prepared following the procedure described for compound 26A of example 26, except that 2-acetylaniline was used in place of 2-trifluoromethylaniline. Yield: 90%.
Reaction SMILES: CC([O:5][C:6](=[O:58])[C:7]([O:10][N:11]=[C:12]([C:45]1[N:46]=[C:47]([NH:50]C(OC(C)(C)C)=O)[S:48][CH:49]=1)[C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([NH:22][S:23]([N:26]2[C:30](=[O:31])[CH2:29][N:28]([NH:32][C:33]([C:35]3[NH:36][CH:37]=[C:38]([OH:42])[C:39](=[O:41])[CH:40]=3)=[O:34])[C:27]2=[O:43])(=[O:25])=[O:24])=[O:21])[C:17]1=[O:44])=[O:14])([CH3:9])[CH3:8])(C)C>FC(F)(F)C(O)=O>[NH2:50][C:47]1[S:48][CH:49]=[C:45]([C:12](=[N:11][O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:58])=[O:5])[C:13]([NH:15][CH:16]2[CH2:19][N:18]([C:20]([NH:22][S:23]([N:26]3[C:30](=[O:31])[CH2:29][N:28]([NH:32][C:33]([C:35]4[NH:36][CH:37]=[C:38]([OH:42])[C:39](=[O:41])[CH:40]=4)=[O:34])[C:27]3=[O:43])(=[O:25])=[O:24])=[O:21])[C:17]2=[O:44])=[O:14])[N:46]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC(C)(C)C(=O)OC(C)(C)C)C(=O)NC2CN(C(=O)NS(=O)(=O)N3C(=O)CN(NC(=O)c4cc(=O)c(O)c[nH]4)C3=O)C2=O)cs1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2C(=O)CN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-[[[1-[2 [[(1,1-Dimethylethoxy)carbonyl]amino]-4-thiazolyl]-2-[[1-[[[[3-[[(1,4-dihydro-4-oxo-5-hydroxy-2-pyridinyl)carbonyl]amino]-2,5-dioxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl propanoic acid 1,1-dimethylethyl ester (833 mg) is cooled to 0° C. and dissolved in cold trifluoroacetic acid (20 ml). After 45 minutes, the solution is warmed to room temperature, stirred for 2 hours and concentrated. The residue is dissolved in 1:1::acetonitrile:water (6 ml) and chromatographed over HP-20 to give the title compound. Physical characteristics are as follows:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36]CC3C=CC=CC=3)=[C:32]([NH:44][CH:45]=[O:46])[CH:31]=2)[OH:29])[CH3:25])=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)C>[Pd].CO>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:44][CH:45]=[O:46])[CH:31]=2)[OH:29])[CH3:25])=[CH:19][CH:20]=1
Reactant: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Yield: 53.7 %

Procedure:
A mixture of compounds 27 (029 g, 0.45 mmol), palladium catalyst (0.2 g, 10% Pd on carbon, 50% wet), ethanol (10 mL) and methanol (5 mL) underwent hydrogenation at room temperature for 4 h under one H2 pressure. The catalyst was vacuum filtered and washed with ethanol (3×5 mL). The filtrate and the washings were combined and concentrated. The residue was subjected to column chromatography, eluting with a mixture of methanol (0-22%), concentrated ammonium hydroxide (0-2.2%) and dichloromethane (100-75.6%), to afford the desired product 28 (0.10 g, 54%) as a colorless, glass solid: 1H NMR (300 MHz, CD3OD) δ 1.08 (d, 3H), 1.32 (m, 2H), 1.48-1.78 (m, 6H), 2.59 (m, 4H), 2.78 (m, 5H), 3.44 (m, 2H), 4.75 (m, 1H), 6.82 (m, 1H), 7.00 (m, 1H), 7.08 (m, 5H), 8.06 (s, 1H), 8.31 (s, 1H); m/z (ESI) 414 [C31H41N3O3+H]+. The diastereoisomer 29 (13 mg, 7%) was also isolated as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 1.26 (d, 3H), 1.48-1.90 (m, 8H), 2.50 (m, 4H), 2.82-3.08 (m, 3H), 3.50 (m, 2H), 4.60 (m, 1H), 6.82-6.82 (m, 2H), 7.10 (m, 5H), 8.00 (s, 1H), 8.28 (s, 1H); m/z (ESI) 414 [C31H41N3O3+H]+.
Reaction SMILES: COCCOC.Br[C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Reactant: CCOC(=O)c1cccc(Br)n1
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: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2ccccc2CNC(=O)OC(C)(C)C)n1
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
83 ml of 1,2-dimethoxyethane were aerated with argon, and 481 mg (0.41 mmol) of Pd(PPh3)4 and 1.9 g (8.3 mmol) of ethyl 6-bromopicolinate were added. After 10 min, 3.16 g (12.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 8.3 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux under argon for 18 h, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 2.12 g (72%) of a viscous orange oil were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:21])=[C:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]4[NH:30][N:29]=[N:28][N:18]=4)=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:21])=[C:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(OCC#N)cc3)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(OCc4nnn[nH]4)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dimethyl-2-phenyl-1H-indol-4-yl)-phenoxy]-acetonitrile (0.311 g, 0.882 mmol) was reacted with NaN3 (0.287 g, 4.412 mmol) and NH4Cl (0.236 g, 4.412 mmol) in DMF (5 ml) to give the product (0.246 g, 0.622 mmol, 71%) as a white solid, dec. 208-210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29]([OH:31])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][C:23]1=[O:28])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[C@@H:42]([O:46][Si](C(C)(C)C)(C)C)[C@H:41]([NH:54]C(=O)OC(C)(C)C)[CH2:40]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>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[NH2:54][C@H:41]1[C@H:42]([OH:46])[C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:19]=3)[N:14]=2)=[O:31])[CH2:40]1
Reactant: O=C(Nc1cc2ccc(N3CCOCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(3-oxomorpholin-4-yl)quinoline-2-carboxylic acid (0.014 g, 0.033 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.019 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was diluted with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined and concentrated under reduced pressure. To the resulting residue, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound. LCMS calc. for C33H36N7O6 [M+H]+: m/z=626.3. found: 626.3.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=O>C(O)C>[CH3:5][C:6]12[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]1=[N:4][CH2:1][CH:2]=[CH:3]2
Reactant: C#CCN
Reactant: CC1C(=O)CCc2ccccc21
Solvent: CCO
Product: CC12C=CCN=C1CCc1ccccc12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Propargylamine (0.21 mL) is added to a microwave oven suited vessel charged with a stir bar, 1-methyl-2-tetralone (0.50 mL), NaAuCl4*2H2O (27 mg), and ethanol (3 mL) (caution: a very exothermic reaction may evolve afterwards→keep an ice bath at hand). The resulting mixture is stirred under microwave irradiation at 100° C. for 10 min. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 25:75→0:100) to afford the title compound as an oil. Yield: 0.29 g (50% of theory); LC (method 1): tR=1.78 min; Mass spectrum (ESI+): m/z=198 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=Cc1cccc(C(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1C(=O)c1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol) was dissolved in DCM (2 ml). Aniline (18.08 mg, 0.194 mmol) and acetic acid (9.26 μL, 0.162 mmol) were added, and the mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (51.4 mg, 0.243 mmol) was added, and the mixture was stirred at RT overnight to achieve completion. The reaction mixture was diluted with DCM and extracted with water (2×). The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-((phenylamino)methyl)benzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (120 mg, 0.161 mmol, 100% yield). The compound was used in the next step without any further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[OH:18][C@:19]1([C:47]([F:50])([F:49])[F:48])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=O)=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1.[CH3:51][C:52]1[C:57]([NH2:58])=[CH:56][CH:55]=[CH:54][N:53]=1>C1COCC1>[OH:18][C@:19]1([C:47]([F:49])([F:48])[F:50])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([NH:58][C:57]3[C:52]([CH3:51])=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:42])=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Reactant: Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1[C@H]1CC[C@@](O)(C(F)(F)F)Cc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
1 M lithium bis(trimethylsilyl)amide in toluene (0.13 mL, 0.13 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 0.04 mmol) and 2-methylpyridin-3-amine (6.4 mg, 0.06 mmol, Appollo) in THF (1 mL) at 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (4.2 mg, 0.04 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.04 mL, 0.04 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM) to give rac-4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.001 g, 5%): LC-MS (Table 1, Method g) Rt=1.94 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.81 (s, 1H), 8.37-8.34 (m, 1H), 8.31-8.27 (m, 1H), 7.79-7.75 (m, 1H), 7.71-7.62 (m, 3H), 7.56-7.51 (m, 1H), 7.26-7.22 (m, 1H), 7.13-7.08 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.32 (s, 1H), 5.28-5.21 (m, 1H), 3.86 (s, 3H), 3.36-3.32 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.22-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.76 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:39][C:40]1[S:41][S:42][C:43](=[S:45])[N:44]=1>O1CCCC1.O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][C:15]([NH:39][C:40]3[S:41][S:42][C:43](=[S:45])[N:44]=3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(=S)ss1
Reactant: O=C(O)Cc1cccc(OCc2ccc(F)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cccc(OCc2ccc(F)cc2)c1)Nc1nc(=S)ss1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
2-{3-[(4-Fluorobenzyl)oxy]phenyl}acetic acid (1.00 g, 3.84 mmol) was dissolved in tetrahydrofuran (13 ml), and 1,1′-carbonyldiimidazole (0.748 g, 4.61 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at 0° C. Sodium hydride (60% oil suspension 0.154 g, 3.84 mmol) was suspended in tetrahydrofuran (13 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.577 g, 3.84 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 13 hours at room temperature. The mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-{3-[(4-fluorobenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 8) (0.097 g, 6%).
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:14].[I:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[ClH:14].[C:1]12([NH:11][C:12]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[I:15])=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccccc1I
Agent: Cl
Product: N=C(Nc1ccccc1I)NC12CC3CC(CC(C3)C1)C2
Yield: 4.2 %

Procedure:
Adamantan-1-ylcyanamide (299 mg, 1.70 mmol) and o-iodoaniline hydrochloride (433 mg 1.70 mmol) were finely ground together and heated at 200° for 10 min. The resultant black glassy solid was pulverized, and recrystallized 5 times from EtOH/Et2O. The resultant faintly blue needles (80 mg) were dissolved in 4 ml EtOH, and passed through a short (<1 cm) column packed from bottom to top with Celite, charcoal, activated alumina, and sand. The colorless eluate was then diluted with 5 ml Et2O, and allowed to stand in an Et2O diffusion chamber overnight. The white needles were collected by suction filtration, 40 mg, mp 274°-275° C. Addition of another 5 ml Et2O yielded a second crop (31 mg) of identical material. Combined yield: 21%. 1H (CD3OD) 1.779 (s, 6H), 2.090 (s, 6H), 2.164 (s, 3 H), 7.168 (t, 1H, J=8.1 Hz), 7.388 (d, 1 H, J=9.1 Hz), 7.503 (t, 1 H, J=7.8 Hz), 8.004 (d, 1 H, J=7.8 Hz).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](C)(C)N[Si](C)(C)C.[Li].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C(OCC)(=O)C>[C:26]1([NH:25][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In a 50 mL round-bottomed flask, 2-chloro-6-(trifluoromethyl)-nicotinic acid (5 g, 22.2 mmol) was combined with THF (20 mL) to give a dark red solution. The reaction solution was cooled to −78° C., lithium hexamethyldisilazane (LiHMDS, 1.0 M in THF) (66.5 mL, 66.5 mmol) was added and stirred for 2 hr. A solution of aniline (19.6 g, 19.2 mL, 210 mmol) in THF (20 mL) was added dropwise to the reaction and the reaction was allowed to gradually warm at room temperature. The resultant reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate (250 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (2×150 mL), H2O (1×50 mL), and brine (1×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The compound was triturated in ether to give of 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.19 g, 98.9%) as a light brown solid. The material was not further purified.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[CH2:27]([NH:29][C:30](=[O:44])[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[C:33]([F:43])[CH:32]=1)[CH3:28].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[CH2:27]([NH:29][C:30](=[O:44])[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:39][CH2:38]2)=[C:33]([F:43])[CH:32]=1)[CH3:28]
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 34.5 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (146 mg, 0.581 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (169 mg, 0.697 mmol) and N-ethyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (167 mg, 0.581 mmol) and DIEA (304 μl, 1.743 mmol)). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (97 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 8.35 (t, J=5.6 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.55-7.65 (m, 2H), 6.97-7.08 (m, 2H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd, J=10.9, 3.0 Hz, 1H), 3.38 (d, J=2.0 Hz, 2H), 3.20-3.30 (m, 2H), 2.95-3.15 (m, 5H), 2.65-2.87 (m, 3H), 2.51 (br. s., 4H), 2.45 (dd, J=13.4, 1.8 Hz, 1H), 1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C24H29FN6O2S, 484; found, 484.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:6]1[C:5]2[O:11][CH:2]([CH2:3][OH:17])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCc1cccc(Br)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2cccc(Br)c2O1
Yield: 74.3 %

Procedure:
Treatment of 2-allyl-6-bromophenol (61.4 g 0.288 mol) with 3-chloroperoxybenzoic acid (77%, 149.18 g, 0.864 mol)) followed by potassium carbonate (99.56 g, 0.72 mol) generally according to the procedure described for Intermediate 9 provided 49.00 g (78%) (86%) of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol as an amber oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:9) 1H NMR (DMSO-d6) δH 7.23 (dd, 1H); 7.14 (dd, 1H); 6.71 (t, 1H); (5.01 m, 1H); 4.85 (m, 1H); 4.99 (m, 2H); 3.36 (d, 2H).