Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:8])([O-:3])=[O:2].[F:23][C:24]([F:51])([O:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][C:47]([F:50])([F:49])[F:48])=[CH:39][CH:38]=1)[C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33](O)=[O:34])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:33](=[O:34])/[CH:32]=[CH:31]/[C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:51])[O:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][C:47]([F:50])([F:49])[F:48])=[CH:39][CH:38]=2)=[CH:30][CH:29]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=C(OCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
3.68 g (11.8 mmol) of 6-hydroxyhexyl 3,5-dinitrobenzoate, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 6.85 g of 6-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]methyl}phenyl)prop-2-enoyl]oxy}hexyl 3,5-dinitrobenzoate as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-].C1CCCCC=1>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: [O-][n+]1ccccc1NCCCO
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: OCCCNc1ccccn1
Reaction time: 48 h
Yield: 88.1 %

Procedure:
A mixture of 2-(3-hydroxypropyl)aminopyridine N-oxide (3.0 g, 17.9 mmol), as prepared in the preceding step, cyclohexene (10 ML, 100 mmol), and 10% palladium(0) on carbon (300 mg) in ethanol (50 mL) was heated to reflux. After two days, the reaction mixture was cooled. The catalyst was removed by filtration through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 5% methanol in methylene chloride) to give the title compound as a colorless oil (2.4 g, 88%). 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J=5.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 6.54 (d, J=6.0 Hz, 1H), 6.39 (t, J=8.0 Hz, 1H), 4.69 (br s, 2H), 3.65 (t, J=5.5 Hz, 2H), 3.53 (q, J=5.9 Hz, 2H), 1.77 (t, J=5.6 Hz, 2H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[C:18]2[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1>C1COCC1>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([O:13][C:17]3[C:18]4[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Reactant: OC1CCC(N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cc2c(OC3CCC(N4CCOCC4)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 4-(morpholin-4-yl)cyclohexan-1-ol (143 mg, 0.77 mmol, 1.10 equiv) in THF (20 mL) was added sodium hydride (140 mg, 3.50 mmol, 5.00 equiv, 60% dispersion in mineral oil) at 0° C. The solution was stirred for 30 min at room temperature under nitrogen. Then tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (220 mg, 0.70 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of brine and extracted with EtOAc. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was purified by a silica gel column with DCM/MeOH (30:1-10:1) to provide 127 mg (39%) of tert-butyl N-[2-(4-[[4-(morpholin-4-yl)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate as a white solid. MS (ES): m/z 463 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][C:13]1[N:12]=[N:11][C:10]([NH2:14])=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nncc(-c2ccc(F)cc2)n1
Product: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Yield: 51.8 %

Procedure:
6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1.95 g, 49%) was prepared from 5-(4-fluorophenyl)-1,2,4-triazin-3-amine (2.8 g, 14.00 mmol) and N-bromosuccinimide (7.87 g, 44.00 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([CH:21]=[C:22]2[S:26][C:25](SC)=[N:24][C:23]2=[O:29])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:20]=[C:19]([CH:21]=[C:22]2[S:26][C:25]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:24][C:23]2=[O:29])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:15])([F:14])[F:16]
Reactant: C1COCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc(Oc3ccc(C#N)cc3C(F)(F)F)c(F)c2)S1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2F)c(C(F)(F)F)c1

Procedure:
4-[2-Fluoro-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using 4-[2-Fluoro-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile and morpholine as described in Example 5C. 1H NMR (400 Hz, DMSO-d6) δ 8.40 (bs, 1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.69 (s, 1H), 7.55 (m, 2H), 7.18 (d, 1H), 3.92 (bs, 2H), 3.71 (m, 6H); LC/MS (m/z) [M+1]+478.2 (calculated for C22H16F4N3O3S, 478.43).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[NH:10][CH:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3Cl)[C:6]=2[N:7]=1.O.NN>C(O)C.[Pd]>[NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[NH:10][CH:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Nc1nc2c(Cc3ccccc3Cl)c[nH]c2c(=O)[nH]1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1nc2c(Cc3ccccc3)c[nH]c2c(=O)[nH]1

Procedure:
A solution of 2-amino-3,5-dihydro-7-(2-chlorophenylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one (0.5 g, 1.8 mmol) in hot ethanol (80 mL) is treated with 30% Pd-C (1.0 g) under N2 and then hydrazine monohydrate (1.5 mL) is added dropwise during a period of 10 minutes. The reaction mixture is held at reflux for 16 hours and then filtered hot through Celite. The filtrate is evaporated to dryness, and the residue triturated and sonicated with H2O (3 mL). The product is collected, washed with H2O and dried to yield 2-amino-3,5-dihydro-7-(phenylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-one melting at 269°-270° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([NH:25][C:26](=[O:27])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N=C=O
Reactant: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 0 °C
Yield: 83.7 %

Procedure:
0.5 g (2.1 mmole) 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde was dissolved in tetrahydrofuran, cooled to 0° C. and 0.092 g (2.1 mmole) sodium hydride in tetrahydrofuiran was added. The reaction mixture was stirred until gas development ceased, then 0.4 g (4 mmole) tert-butyl isocyanate in tetrahydrofuran was added and the temperature was allowed to rise to room temperature. The reaction was followed by TLC. More 0.4 g (4 mmole) tert-butyl isocyanate was added. After 3 days the reaction was quenched with ice and sodium hydroxide (aq), extracted with dichloromethane, dried and evaporated. Purification by chromatography on silica gel using ethyl acetate:petroleum ether (1:2) as eluent gave 0.6 g (yield 84%) of 4-[2-(4-formylphenoxy)ethyl]phenyl N-(tert-butyl)carbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cn1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccc(I)cn2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 4-fluorophenol (1.12 g, 10 mmol), 2-bromo-5-iodopyridine (2.84 g, 10 mmol) and Cs2CO3 (3.83 g, 10 mmol) in DMF was stirred at 120° C. for 4 hrs. The reaction was worked up with EtOAc to give 2-(4-fluoro-phenoxy)-5-iodo-pyridine which was used for next step without further purification (crude yield 100%, yellowish solid). LC/MS: m/z=317 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH2:24][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH2:16][N:15]4[CH2:17][CH:11]([C:6]2=3)[CH2:12][CH2:13][CH2:14]4)=[CH:21][CH:20]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC3C1
Reactant: C=Cc1ccc(Cl)cc1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C2CCCN(C1)C2

Procedure:
The coupling of 10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (245.1 mg, 1.083 mmol; Example 201) and 4-chlorostyrene (256.3 mg, 1.709 mmol, Aldrich) was performed as described in Example 202, except that the material was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.13-1.45 (m, 3H), 1.67-1.79 (m, 1H), 2.31-2.35 (m, 1H), 2.42 (s, 3H), 2.63-2.69 (m, 1H), 2.96-3.11 (m, 5H), 3.82 (d, J=16.3 Hz, 1H), 4.07-4.15 (m, 1H), 4.24 (d, J=16.3 Hz, 1H), 4.34-4.42 (m, 1H), 6.78-6.83 (m, 2H), 6.97-7.00 (m, 1H), 7.12-7.19 (m, 3H), 7.27-7.31 (m, 1H); MS (DCI/NH3) m/z 365 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[CH:6]=1.C1COCC1.C([Mg]Cl)(C)C.CO[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1.[NH4+].[Cl-]>>[CH3:9][C:8]([OH:10])([CH3:11])[CH2:7][N:5]1[CH:6]=[C:2]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[C:3]([CH3:12])=[N:4]1
Reactant: Cc1nn(CC(C)(C)O)cc1I
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(CC(C)(C)O)cc1B1OC(C)(C)C(C)(C)O1
Reaction time: 1 h

Procedure:
A solution of 1-(4-iodo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (250.0 mg, 0.8925 mmol) in THF (10 mL, 200 mmol) was added 2 M of isopropylmagnesium chloride in THF (1.339 mL, 2.678 mmol) at rt, and the reaction was allowed to stir for 1 h. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5850 mL, 3.570 mmol) was then added, and the mixture was stirred at rt for 2 h. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])[C:12]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[S:25][C:11]=2[C:10](=[O:32])[N:9]=1)[CH3:7]>CN(C)C=O.O>[N:1]([CH:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])[C:12]2[N:23]=[C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[S:25][C:11]=2[C:10](=[O:32])[N:9]=1)[CH3:7])=[N+:2]=[N-:3]
Reactant: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C(C)N=[N+]=[N-])nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 65 °C
Yield: 52.2 %

Procedure:
To a solution of sodium azide (20.16 mg, 0.310 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL) was added 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (100 mg, 0.207 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL). The reaction was heated to 65° C. for 2 hr, and then the solution was cooled to room temperature. The reaction contents were diluted with water, producing a precipitate. The suspension was filtered using a fritted funnel, providing 5-(1-azidoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (48 mg, 0.108 mmol, 52.1% yield) as a crude brown solid that was used directly in the next reaction. LC/MS m/z MH+=446 (theoretical), found=446.1, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67 (d, J=6.82 Hz, 4H) 2.47 (s, 3H) 3.48-3.66 (m, 5H) 3.68-3.87 (m, 5H) 3.97 (q, J=6.57 Hz, 1H) 5.42 (d, J=17.18 Hz, 1H) 5.76 (d, J=17.18 Hz, 1H) 6.41 (d, J=7.58 Hz, 1H) 7.07 (t, J=7.83 Hz, 1H) 7.35 (d, J=8.08 Hz, 1H)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]1[CH2:30][CH:29]2[N:31]([C:32]3[C:33]4[C:48]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:47][S:46][C:34]=4[N:35]=[C:36]([N:38]4[CH2:42][CH2:41][CH:40]([C:43]([NH2:45])=[O:44])[CH2:39]4)[N:37]=3)[CH:26]([CH2:27][CH2:28]2)[CH2:25]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[O:23]=[C:24]1[CH2:30][CH:29]2[N:31]([C:32]3[C:33]4[C:48]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:47][S:46][C:34]=4[N:35]=[C:36]([N:38]4[CH2:42][CH2:41][CH:40]([C:43]([NH2:45])=[O:44])[CH2:39]4)[N:37]=3)[CH:26]([CH2:27][CH2:28]2)[CH2:25]1
Reactant: NC(=O)C1CCN(c2nc(N3C4CCC3CC(O)C4)c3c(-c4ccccc4)csc3n2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)C1CCN(c2nc(N3C4CCC3CC(=O)C4)c3c(-c4ccccc4)csc3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.5 %

Procedure:
Dess-Martin Periodinane (50 mg, 0.12 mmol) was added to a suspension of 1-[4-[3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]pyrrolidine-3-carboxamide (40 mg, 0.089 mmol) in dichloromethane (4 mL). The mixture was stirred overnight at room temperature. Saturated aqueous sodium thiosulfate solution (2 mL) was added and the layers were separated. The aqueous was extracted with dichloromethane (2×2 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (1×2 mL), filtered through a hydrophobic frit and evaporated to give the target compound as a white solid (46 mg). m/z [M+H]+448.1. Retention time 3.59 min (LCMS method+ve 6 min).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)[CH2:17]3)[C:13]2=[O:32])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[O:32]=[C:13]1[C:14]2([CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][N:23]=3)[CH2:17]2)[CH2:15][CH2:16][N:12]1[CH:9]1[CH2:10][CH2:11][N:6]([C:2]([O:4][CH3:5])=[O:3])[CH2:7][CH2:8]1
Reactant: O=C1N(C2CCNCC2)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(N2CCC3(CCCN(c4ccc(C(F)(F)F)cn4)C3)C2=O)CC1
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of 2-piperidin-4-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (18.3 mg, 0.0000478 mol) and N,N-diisopropylethylamine (27 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 0.5 h. The volatiles were removed in-vacuo and the product was purified by prep-HPLC. LC-MS: 441.2 (M+H)+.
Reaction SMILES: CO[N:3]=[C:4]1[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]1=2>C(O)(C(F)(F)F)=O.[Pd]>[N:9]1[C:10]2[CH2:11][CH2:12][CH:4]([NH2:3])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CON=C1CCc2ncccc21
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2ncccc21

Procedure:
A solution of 6,7-dihydro-[1]pyrindin-5-one O-methyl-oxime (5.43 g, 33.5 mmol) and Pd/C (150 mg) in TFA were hydrogenated under 50 psi for 14 hours. Filtration via celite and concentration afforded the title amine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.66-1.77 (m, 2H), 2.17-2.27 (m, 2H), 2.45-2.50 (m, 1H), 3.24-3.33 (m, 2H), 8.42-8.58 (m, 1H), 8.61-8.72 (m, 1H), 9.37-9.50 (m, 1H).
Reaction SMILES: CO.C([O:10][C:11]1[CH:38]=[C:37]([N:39]([CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[CH3:40])[CH:36]=[CH:35][C:12]=1[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])C1C=CC=CC=1>[C].[Pd].C(Cl)(Cl)Cl>[CH3:45][N:43]([CH3:44])[CH2:42][CH2:41][N:39]([CH3:40])[C:37]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[C:11]([OH:10])[CH:38]=1
Reactant: CN(C)CCN(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a methanol (3.0 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)benzamido)-4-phenylbenzoate (0.071 g), 10% palladium-carbon (0.035 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 45 minutes. Methanol (2.0 mL) and chloroform (1.0 mL) were added to the reaction mixture, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.045 g of tert-butyl 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](Cl)(=[O:27])=[O:26])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:27])(=[O:26])[NH2:29])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)c1cc(SCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)Cl)c1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Oc1ccccc1
Reaction time: 1 h

Procedure:
3-Benzylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (0.6 g) is added to concentrated aqueous ammonia (10 ml). After 1 hour, the reaction mixture is heated on a steam-bath for 15 minutes, and crude 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of a 1 N hydrochloric acid until pH 2.5. The crude product is dissolved in aqueous sodium hydrogen carbonate by heating. After cooling, the precipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is redissolved in hot water (20 ml) and 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of 1 N hydrochloric acid. After cooling and collecting by filtration, and drying in vacuo at 80° C, the compound is obtained with a melting point of 235°-236° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([CH2:16][CH3:17])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(CC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of [4-ethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.11 g, 0.32 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (0.040 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography to give [4-ethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.080 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.20 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 5.56 (s, 1H), 3.05 (M, 1H), 2.65 (m, 2H), 2.19 (M, 1H), 1.20 (M, 3H). MS (ES) m/z: 315 (M+1)+. HPLC purity: 99.19% (220 nm), 98.31% (Maxplot).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[F:9][C:10]([F:17])([CH2:15][CH3:16])[C:11](OC)=[O:12]>C1COCC1>[F:9][C:10]([F:17])([CH2:15][CH3:16])[C:11](=[O:12])[CH2:7][C:6]#[N:8]
Reactant: CCC(F)(F)C(=O)OC
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(F)(F)C(=O)CC#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flame-dried flask was charged with 2.9 ml (4.6 mmol) of n-butyllithium solution (1.6 M in hexanes) in dry THF (14 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.213 ml (4.06 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.40 g (2.9 mmol) methyl 2,2-difluorobutanoate were slowly added over 5 min maintaining the temperature below −69° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of 2 N hydrochloric acid (4.8 ml) while keeping the temperature below −20° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure. The crude product thus obtained (2.5 g of 17% purity, 98% of th.) was stored at −21° C. and used in the next step without further purification.