Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1.[F:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:19][CH2:20][O:18][C:14]1[CH:13]=[C:12]([C:10]2[N:11]=[C:5]3[N:4]=[C:3]([NH2:2])[CH:8]=[CH:7][N:6]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn2cc(-c3cccc(OCF)c3)nc2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
In a sealed tube 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (260 mg, 0.85 mmol) was combined in DMF (3 ml) to give a brown solution. Toluene-4-sulfonic acid fluoromethyl ester (249 mg, 1.22 mmol; CAS Nr. 114435-86-8) was dissolved in DMF and added. Cs2CO3 (527 mg, 1.62 mmol) was added. The reaction mixture was heated under argon to 70° C. for 9 h, then stirring was continued overnight at RT. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were dried (MgSO4) and concentrated under vacuum and the crude product was purified by flash chromatography (50 g SiO2, DCM/MeOH/NH3aq. 140:10:1). The title compound (105 mg, 48%) was obtained as a yellow solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, off-white solid (104 mg, 80%), MS (ISP) m/z=520.5 [(M+H)+], mp 228.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-morpholin-4-yl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14]3)[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14]3)[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN3CC(C)(C)OC[C@@H]3C2)c1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC1(C)CN2CCN(c3cc(C#N)cc(N)c3Cl)C[C@H]2CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
(S)-tert-butyl (2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)phenyl)carbamate (87 mg, 0.207 mmol) was taken up in DCM (2 mL) and cooled to 0° C. 2,6-Lutidine (0.072 mL, 0.620 mmol) was added, followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0.112 mL, 0.620 mmol). The reaction was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 30 min. The solvent was removed in vacuo and the material was purified by flash column chromatography, eluting with 0-2% (2N NH3/MeOH)/DCM. (S)-3-amino-4-chloro-5-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)benzonitrile (22 mg) was obtained as a yellow glass.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[Br:18][CH2:19][CH2:20]Br>CC#N>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH2:19][Br:18])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCCBr)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
To a solution of 4-(methylsulfonyl)phenol (0.30 g, 1.74 mmol) in MeCN (5 mL) was added Cs2CO3 (0.71 g, 2.18 mmol) and 1,2-dibromoethane (1.64 g, 8.71 mmol). The resulting mixture was heated in a sealed tube at 100° C. After 1.5 h, additional Cs2CO3 (0.4 g, 1.21 mmol) was added and heated at 100° C. for another 2 h. Upon cooling, the mixture was partitioned between EtOAc and 1N NaOH. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-70% EtOAc-hexanes gradient) to afford the title compound as a white solid (0.255 g, 53% yield): MS (ES) m/z 279 and 281 (M+1 Br isotopes).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1(=O)[O:15][C:13](=[O:14])[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1cc(N)ccc1Br
Product: Cc1cc(N2C(=O)C=CC2=O)ccc1Br

Procedure:
4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g,
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Br:14])([CH3:4])([CH3:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Br:14][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][C:9]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Product: CN1CCN(c2cc(C(C)(C)C)c(Br)cc2[N+](=O)[O-])CC1
Temperature: 130 °C

Procedure:
A mixture of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3 g) and N-methylpiperazine (8 g) was heated neat at 130° C. for 4 h. The residue was purified by column chromatography to give 1-[4-bromo-5-(tert-butyl)-2-nitrophenyl]-4-methylpiperazine, which was hydrogenated to furnish 4-(tert-butyl)-2-(4-methylpiperazinyl)-phenylamine.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11]CC)=O)[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1.CO.[CH3:16][NH2:17]>>[NH2:1][C:2]1([CH2:8][C:9]([NH:17][CH3:16])=[O:11])[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1
Reactant: CCOC(=O)CC1(N)CS(=O)(=O)C1
Reactant: CN
Solvent: CO
Product: CNC(=O)CC1(N)CS(=O)(=O)C1
Temperature: 45 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
ethyl 2-(3-amino-1,1-dioxo-thietan-3-yl)acetate (example 160c, 548 mg, 2.64 mmole) was dissolved in a solution 2.0M of methylamine in methanol (19.8 mL, 39.7 mmole) and the reaction mixture was stirred at 45° C. overnight. Removal of volatiles in vacuo yielded the title compound (505 mg, 99%) as crude light brown oil which was used without any further purification; MS (ESI, m/z): 193.1 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH:16]([CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:17][CH2:18][N:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])(C)(C)C>ClCCl>[NH2:14][CH2:15][CH:16]([CH2:27][O:28][C:29]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:17][CH2:18][N:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]
Reactant: CC(C)(C)OC(=O)NCC(CCn1ccc(=O)[nH]c1=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(CCn1ccc(=O)[nH]c1=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
TFA (2 ml) was added to a solution of compound 42 (100 mg, 0.18 mmol) in dichloromethane (4 ml) and the solution was stirred at room temperature. After 30 min the solvents were evaporated in vacuo and the afforded residue was purified by column chromatography on silica gel which gave the title compound (52 mg, 65%).
Reaction SMILES: [H-].[Na+].C([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][N:26]=[C:25]([CH3:28])[C:24]=4[CH2:29]Br)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])C.[CH2:31]([OH:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH3:28][C:25]1[C:24]([CH2:29][O:39][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:8]4([C:6]([OH:5])=[O:7])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[CH:22][CH:21]=2)[O:27][N:26]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% in mineral oil, 0.027 g, 0.68 mmol) was added to a solution of 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.45 mmol) and phenethyl alcohol (0.06 mL, 0.45 mmol) in DMF (5 mL). The reaction was stirred at 55° C. overnight, then partitioned between EtOAc and H2O and acidified with 1 N aqueous HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: COC([C:5]1[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:7][N:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=12)=O.[OH-].[Na+]>OS(O)(=O)=O.O>[Br:14][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([N:7]=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=2)[CH:13]=1
Reactant: COC(=O)c1c(C(C)(C)C)nn2cc(Br)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc2ccc(Br)cn2n1
Yield: 41.4 %

Procedure:
A solution of 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (example 41, step 2) (1.1 g, 3.53 mmol) in H2SO4 (5 ml) and H2O (5 ml) was heated at 80° C. for 36 hours. The reaction mixture was neutralized with 2N sodium hydroxide and extracted with ethyl acetate (4×60 ml). The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (heptane:EtOAc 95:5→90:10). The desired 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (370 mg, 38% yield) was obtained as a white solid, MS: m/e=254.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C@H:32]([CH3:35])[CH2:33][OH:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][C@H:32]([CH3:35])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H](C)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and (R)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-20% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 116-122°, LC MS m/z=423 (MH+) Retention time=2.04 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[N:30]=[C:31]=[O:32]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18][C:31]([NH:30][C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[O:21][CH3:20])=[O:32])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCC2OCCc3c2sc(N)c3C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (64 mg, 0.22 mmol) in dichloromethane (1 ml) was added 2,4-dimethoxyphenylisocyanate (40 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (30 ml), washed with saturated sodium carbonate (3×25 ml), brine (3×25 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to preparative thin layer chromatography (100% dichloromethane). Rf=0.8 was isolated and the solvent evaporated in vacuo which afforded 55 mg (53%) of 2-amino-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[CH2:7]([Mg]Br)[CH2:8][CH2:9][CH3:10].P([O-])([O-])([O-])=O>O1CCCC1>[CH2:2]([C:8]([CH:9]=[CH2:10])=[CH2:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CC=CCBr
Reactant: CCCC[Mg]Br
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C=CC(=C)CCCCC
Reaction time: 4 h

Procedure:
n-bromosuccinimide (5.34 g) is added to a solution of isoprene (2.45 g) in carbon tetrachloride (100 ml), and the solution is stirred for 24 hours. The product and solvent are then fractionally distilled away from the succinimide, resulting in a partially concentrated solution of c-bromomethylbutadiene. The bromomethylbutadiene solution is chilled (-20° C.), and a 2N tetrahydrofuran solution of butylmagnesium bromide (15 ml) is then added. After stirring for 4 hours, the solution is treated with a 1 M phosphate buffer solution (pH 7). The organic layer is dried over sodium sulfate, and the reaction mixture is fractionally distilled to produce the product, 2-pentyl-1,3-butadiene, as a non-viscous liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:8][C:7]=2[CH:31]=1)#[N:2].CI.[Li+].[CH3:35][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH3:35])=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)c1nc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (277 mg, 0.664 mmol) in THF (3.3 mL) was added MeI (0.050 mL, 0.796 mmol) at −78° C. At this point, LHMDS (0.730 mL, 0.730 mmol) was added at the same temperature and the reaction was allowed to warm up to rt over one hour and stirred at rt for 16 hrs. The reaction mixture was quenched at −78° C. with a saturated ammonium chloride (aq.) solution, diluted with water and DCM, passed through a phase separator, concentrated and purified via FCC (12 g column): Heptane/AcOEt:100/0 to 50/50 to obtain the title compound. MS (ESI+) m/z 432.4 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Si](C)(C)C)=[CH:20][C:19]=1[F:28])=[O:5])[CH3:2].[I:29]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:29])=[CH:20][C:19]=1[F:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cncc(Cl)c2n1C
Reactant: ClI
Solvent: ClCCl
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cncc(Cl)c2n1C
Temperature: 25 °C
Yield: 73 %

Procedure:
To a cooled (0° C.) solution of 7-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (3.25 g, 7.74 mmol) in DCM (50 mL) was added iodine monochloride (1M in DCM, 17.0 mL) dropwise over 15 minutes. The mixture was allowed to warm to ambient temperature then partitioned between ethyl acetate and a saturated solution of sodium thiosulphate. The organic layer was separated, washed with water then brine, dried (Na2SO4), filtered and evaporated to give a residue. The residue was triturated with diethyl ether to provide the title compound as a yellow solid (2.62 g, 73%). LCMS (method B): RT=3.95 min, M+H+=474.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](#[N:12])[CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:9]#[N:12])[CH2:5][CH2:4]1
Reactant: N#CCO
Reactant: FC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CCN1CCC(F)CC1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
4-Fluoropiperidine HCl (801 mg, 5.74 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (647 uL of a 52% aqueous solution, 6.31 mmol) at 5° C. Sodium carbonate (912 mg, 8.60 mmol) was added and the solution was stirred at 70° C. for 1.5 h. The solution was cooled, diluted with water (2 mL), washed with Et2O (3×4 ml). The organic fraction was dried and the solvent evaporated to give 2-(4-fluoropiperidin-1-yl)acetonitrile as a colourless oil. The oil was then dissolved in a 7 N solution of ammonia in MeOH (25 mL) and submitted to hydrogenation on the H-Cube using 75 bar of hydrogen pressure at 55 C with a flow rate of 0.8 mL/min and using a Raney nickel catalyst cartridge. After the reaction was complete the solvent was stripped in vacuo to give 2-(4-fluoropiperidin-1-yl)ethanamine as a translucent oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])C.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:14])[C:9](=[O:13])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)O)c(Cl)cc1=O
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.925 g, 4.29 mmol) in a 4:1 mixture of THF:MeOH (20 mL) was added a 1 M solution of LiOH (8.6 mL). After stirring for 30 minutes, the reaction mixture was acidified to pH 1 with 10% HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give 0.732 g t91%) clean desired product.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[OH:13])[C:6]([O:24][CH3:25])=[N:5]1)([CH3:3])[CH3:2].[CH2:26]1COCC1.CI.[H-].[Na+]>CCOC(C)=O>[CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([C@@H:12]([O:13][CH3:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=2)[C:6]([O:24][CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](OC)c1ccc(C(F)(F)F)cc1
Temperature: 10 °C
Yield: 88 %

Procedure:
To a mixture of (S)-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol (4.09 g, 11.4 mmol) (prepared as shown in Scheme 27) and THF (60 mL) at 0° C., was added methyl iodide (4.28 mL, 68.5 mmol) and sodium hydride (60% dispersion in mineral oil, 0.55 g, 13.7 mmol). The mixture was stirred and gradually warmed to 10° C., then diluted with EtOAc and washed with saturated NH4Cl. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The resulting product was purified by chromatography on silica gel (0-10% EtOAc-hexane) to provide the title product as a white solid (3.7 g, 88%). LCMS (API-ES) m/z: 373 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17](O)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:28][N:29]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17]([NH:29][OH:28])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)SCCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)C(C)(C)SCCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid (500 mg, 1.2 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole (194 mg, 1.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (322 mg, 1.68 mmol) followed by N-methylmorpholine (0.198 mL, 1.8 mmol) and the resulting mixture was stirred for 1 h at room temperature. A 50% aqueous solution of hydroxylamine (0.367 mL, 6 mmol) was added and the mixture was stirred for 15 h at room temperature. The solvent was removed and the product was partitioned between ethyl acetate and water. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, brine, and dried over anhydrous sodium sulfate. Removal of the solvent gave (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanamide, which was triturated with hexanes to obtain 130 mg (25%) of the pure product; HRMS (C18H26N2O6S2)(M+H);
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH3:18][C@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH3:18][C@H:19]([NH:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@H](C)N
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Product: CCC[C@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 70 from 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine and (2S)-2-pentanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>O.CC(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCCCC(=O)O)c2)C1
Temperature: 25 °C

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (1.75 g.) is added to a solution of 4-aminobutyric acid (0.54 g.) in water (30 ml.), acetone (30 ml.) and 1N sodium hydroxide (10 ml.). After stirring at room temperature for a half hour, the acetone is removed by evaporation, and the aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is dissolved in 50 ml. of hot acetone-methanol (1:1) and concentrated to half volume. Hexane is added to crystallize the product, m.p. 193°-195° C.