Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:16]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=3[S:18][CH:19]=2)[C:6]=1[C:25]([OH:27])=[O:26])(O)=[O:2].FC1C=CC2SC=C([CH2:36][N:37]3C4C(=CC=CC=4)C4CC(=O)OC(=O)[C:38]3=4)C=2C=1.CNC>>[CH3:36][N:37]([CH3:38])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:16]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=3[S:18][CH:19]=2)[C:6]=1[C:25]([OH:27])=[O:26])=[O:2]
Reactant: O=C1Cc2c(n(Cc3csc4ccc(F)cc34)c3ccccc23)C(=O)O1
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12

Procedure:
3-Carboxymethyl-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid (from Example 59) was converted to 9-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was converted according to Example 68.2. but using dimethyl amine to give 3-dimethylcarbamoylmethyl-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 409.4 ([M−H]−).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:27][C:26]=3[F:46])=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:47][CH3:48].C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N:31]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[C:32]([C:34]6([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]6)=[O:33])=[CH:27][C:26]=5[F:46])=[CH:19][CH:20]=[N:21]4)=[CH:16][C:15]=3[O:47][CH3:48])[CH2:5][O:4]2)[CH2:1]1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OC1COC2(CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 24 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (138 mg, 0.72 mmol), N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.616 mmol), and Cs2CO3 (602.5 mg, 1.848 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (2:1 (v/v) EtOAc/n-hexane). The title compound was obtained as a white solid (186.7 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][C:27]1[N:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([C:30]4[O:29][N:28]=[C:27]([CH3:26])[N:31]=4)=[CH:40][CH:39]=3)[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Product: Cc1noc(-c2ccc(C(=O)N3CC(c4ccc(Cl)c(Cl)c4)C(N(C)C(=O)Cc4ccc(F)cc4)C3)cc2)n1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 567.1 [M]+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]#N)=[CH:14][C:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.[K+]>C(O)=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18](=[O:2])[O:16][C:15](=[O:17])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Agent: [K+]
Solvent: O=CO
Product: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Temperature: 50 °C

Procedure:
With stirring, 80 ml of concentrated sulfuric acid were added dropwise to 138 g (0.57 mol) potassium 3-(4-chlorophenyl)-3-cyanoacrylate in 1.2 l of 88% strength formic acid. During the addition, the temperature increased to 50° C. The mixture was refluxed for 3 h and, after cooling, put into 10 l of ice-water and then stirred for 1 h, and the product was filtered off, washed with water and dried under reduced pressure. Yield: 86.0 g of m.p. 144-145° C.
Reaction SMILES: CC(C)C[N:4]1[C:8]2=[C:9]3[N:19]=[CH:18][N:17]=[C:10]3[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[N:7]2N=N1.[H][H]>[Pt]=O.FC(F)(F)C(O)=O.Cl>[CH3:10][CH:11]([CH3:12])[CH2:16][N:17]1[C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:16]=3[N:7]=[C:8]([NH2:4])[C:9]=2[N:19]=[CH:18]1
Reactant: CC(C)Cn1nnn2c3ncccc3c3ncnc-3c12
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCCN3

Procedure:
Platinum oxide catalyst was added to a solution of 1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure for 5 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water and sodium bicarbonate. The resulting precipitate was isolated by filtration. The solid was dissolved in 1N hydrochloric acid and charcoal filtered. The filtrate was treated with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethyl acetate/methanol. The recrystallized material was dissolved in dichloromethane/methanol and placed on a silica gel column. The column was eluted with 10% methanol in ethyl acetate. The eluant was concentrated under vacuum and the residue was recrystallized from methanol/water to provide 0.9 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine as a solid, m.p. 231-233° C. Analysis: Calculated for C13H19N5: %C, 63.65; %H, 7.81; %N, 28.55. Found: %C, 62.99; %H, 7.74; %N, 28.33.
Reaction SMILES: N#N.C([Li])(C)(C)C.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([O:19][CH3:20])[CH:10]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]([OH:23])=[O:22])=[CH:10][C:11]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1cc(Br)ccc1OC(C)C
Reactant: O=C=O
Agent: N#N
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Under a balloon of N2, tert-butyllithium (2.14 mL of 1.6 M, 3.43 mmol) was added drop-wise to a solution of 4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF (6.0 mL) at −78° C. The mixture was allowed to stir for 1 h at −78° C. before it was added drop-wise to a flask containing CO2 (1.80 g, 40.8 mmol)(solid, dry ice) in THF (2.0 mL). The mixture was allowed to stir for 30 min as it warmed to room temperature (caution: CO2 gas evolution). Water (20 mL) was added and the volatiles were removed under reduced pressure. The resultant aqueous layer was acidified with 1N HCl to pH ˜1-2 and the mixture was extracted with ethyl acetate (3×15 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-isopropoxy-3-methoxy-benzoic acid (≧94% pure, 310 mg, 85%) as a white solid. ESI-MS m/z calc. 210.1, found 210.9 (M+1)+; Retention time: 1.23 min. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 4.67 (dt, J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d, J=6.0 Hz, 6H).
Reaction SMILES: [NH2:1][C:2](=[O:100])[CH2:3][NH:4][C:5](=[O:99])[C@@H:6]([NH:13][C:14](=[O:98])[C@@H:15]([N:17]([CH3:97])[C:18]([C@H:20]([CH2:86][C:87](=[O:96])[S:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45]C(=O)OC(C)(C)C)=[O:19])[CH3:16])[CH2:7][O:8]C(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:45][CH2:44][C:43](=[O:53])[NH:42][C@@H:41]([CH3:54])[C:40](=[O:55])[N:39]([CH3:56])[C@@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:37](=[O:64])[NH:36][CH2:35][C:34](=[O:65])[N:33]([CH3:66])[C@@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:31](=[O:71])[NH:30][C@@H:29]([CH3:72])[C:28](=[O:73])[NH:27][C@@H:26]([CH:74]([CH3:75])[CH3:76])[C:25](=[O:77])[NH:24][C@@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:22](=[O:85])[NH:21][C@H:20]([C:18](=[O:19])[N:17]([C@@H:15]([CH3:16])[C:14]([NH:13][C@@H:6]([CH2:7][OH:8])[C:5]([NH:4][CH2:3][C:2]([NH2:1])=[O:100])=[O:99])=[O:98])[CH3:97])[CH2:86][C:87](=[O:96])[S:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](CO)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
S-Benzyl (9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,9,11,17,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontane-32-thioate (Compound P-146) (11.8 mg, 0.0083 mmol) was dissolved in dichloromethane (150 μL), TFA (75.0 μL, 0.973 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0.1% aqueous FA solution: 0.1% FA-acetonitrile solution) to afford the title compound (7.3 mg, 69.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].C1C(=O)N([Br:18])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:18][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[C:2]([Cl:1])[C:7]=1[CH2:8][OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cccc(O)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: OCc1c(Br)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the flask charged with 2-chloro-3-(hydroxymethyl)phenol from Step A and a stir bar was added NBS (10.8 g, 60.5 mmol) and TFA (50 mL). The reaction was allowed to stir for 16 hours at RT. TLC showed complete reaction at that point. The solvent was removed under vacuum. The residue was re-dissolved in EtOAc, washed with water, and purified by silica gel flash chromatography. A pair of regio-isomers was collected from the separation. The less polar spot was the desired 4-bromo-2-chloro-3-(hydroxymethyl)phenol according to one NMR analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)=[N:30][CH:31]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromo-5-fluoropyridine in Step 4. LC-MS Method 2 tR=1.363, m/z=390.9; 1H NMR (CDCl3) 1.11 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.16-2.30 (m, 4H), 2.32-2.43 (m, 1H), 2.86 (m, 1H), 5.71 (m, 1H), 7.03 (d, 2H), 7.30 (m, 1H), 7.36 (m, 4H), 7.44 (m, 1H), 7.69 (dd, 1H), 7.68 (d, 2H), 8.43 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:14][C:13]([OH:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:22])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:15][C:13]1[CH2:14][N:10]([C:2]([CH3:1])([CH3:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11](=[O:22])[C:12]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(c1ccccc1)N1CC(O)=C(c2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
5 g (17 mmol) of 1-(α,α-dimethylbenzyl)-4-hydroxy-2-oxo-3-phenyl-3-pyrroline prepared by the method of Reference Example 13, was dissolved in a solution of 10 ml of acetic anhydride and 20 ml of pyridine, and the solution was stirred at room temperature for one day and night. Ice water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was thoroughly washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether to obtain 4.2 g (yield: 81%) of the desired compound.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH3:8][C:9]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH3:8][C:9]1([NH:16][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S1(=O)CCCO1
Reactant: CC1(N)CCCCCC1
Solvent: Cc1ccccc1
Product: CC1(NCCCS(=O)(=O)O)CCCCCC1
Temperature: 25 °C

Procedure:
A solution of 1,3-propanesultone (4.3 g, 35 mmol) in toluene (10 mL) was added dropwise to a the crude solution of 1-methyl-1-cycloheptylamine in MTBK (total volume 30 mL). The mixture was heated to reflux for 18 hours then was cooled to room temperature. The solid was collected by suction filtration, rinsed with acetone (2×5 mL). The solid was dried overnight at 45° C. in the vacuum oven. The title compound was obtained as a fine white solid (7.77 g, 31.2 mmol, 80% overall yield). 1H NMR (500 MHz, D2O) δ 1.27 (s, 3H), 1.40-1.60 (m, 8H), 1.71-1.81 (m, 4H), 2.00-2.06 (m, 2H), 2.95 (t, J=6.3 Hz, 2H), 3.13 (t, J=7.1 Hz, 2H); 13C NMR (125 MHz, D2O) δ 22.0, 22.1, 23.3, 29.5, 37.1, 40.0, 48.3, 64.0; ES-MS 250(M+H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][OH:16].CCN(CC)CC.[O:24](S(C1C=CC(C)=CC=1)(=O)=O)[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=O)=[O:26]>C(Cl)Cl.[NH4+].[Cl-]>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:26])=[O:24])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCc1ccccc1COC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2COC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A solution of {2-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl}methanol (5.52 g, 24.84 mmol) in CH2Cl2 (100 ml) was cooled to 0° C. and treated with Et3N (6.92 ml, 49.68 mmol) followed by the addition of Ts2O (8.9 g, 27.33 mmol). The reaction stirred at 0° C. for 3.5 hours. The mixture was diluted with sat. NH4Cl and extracted with CH2Cl12 (2×). The combined organic solutions were washed with water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by normal phase chromatography (10% EtOAc/hexanes—20%) to give a light brown oil (7.36 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[F:13][C:14]([F:27])([F:26])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.S(=O)(=O)(O)O>C(O)C(F)(F)F.O.C([O-])(O)=O.[Na+]>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([N:1]2[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:15]([C:14]([F:13])([F:26])[F:27])=[N:2]2)=[N:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: OCC(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine (456 mg, 2.04 mmol) and 4,4,4-trifluoro-1-phenyl-1,3-butanedione (441 mg, 2.04 mmol) in dry trifluoroethanol (30 ml) was added a catalytic amount of concentrated sulfuric acid (-0.5 ml) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and diluted with water 50 ml and neutralized with saturated NaHCO3 to PH˜7 and then extracted with EtOAc (50 ml×3). The organic layer was washed with brine (25 ml), dried (MgSO4) and concentrated to give the crude solid. The crude solid was recrystallized in ethanol to provide a desired product as a crystalline white solid (337 mg, 45% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C#N)cc1
Yield: 94.3 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.502 g, 1.83 mmol), α-bromo-p-tolunitrile (0.538 g, 2.75 mmol), KI (65 mg, 0.40 mmol), and DIPEA (0.72 mL, 4.13 mmol) in DMF (9 mL) was heated at 60° C. for 16 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.66 g (94%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a white solid. 1H NMR (CDCl3) δ 1.60-1.73 (m, 3H), 2.02-2.12 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.56 (s, 2H), 4.14 (d, 2H, J=10.5 Hz), 6.64 (d, 2H, J=8.1 Hz), 6.95 (dd, 2H, J=7.5, 4.8 Hz), 7.10 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.2 Hz), 8.37 (d, 2H, J=3.9 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc(-c2cccc(Cl)c2)on1
Temperature: 0 °C

Procedure:
In a screw cap vial equipped with stir bar was added 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (110 mg, 0.49 mmol), dichloromethane (3 ml) and triethylamine (0.34 ml, 2.46 mmol). Cooled the mixture down to 0° C. and to it added methane sulfonyl chloride (0.08 ml, 0.98 mmol). Left the reaction mixture stirring at room temperature for 30 min. Reaction was quenched with saturated sodium bicarbonate (aqueous, 40 ml) and extracted with dichloromethane (3×30 ml). Combined organic phase was washed with brine (40 ml), dried (sodium sulfate), filtered and concentrated, in-vacuo to isolate the desired compound as brown oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:34]2[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30][C:29]=2[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.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.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[CH2:30][CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][C:34]=4[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC(C)(C)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 69.9 %

Procedure:
2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (107 mg, 259 μmol) and 1,6,6-trimethyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (see Example 70, 188 mg, 414 μmol.6) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (15.0 mg, 12.9 μmol) and CuI (4.64 mg, 51.8 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (silica, 40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 15 min) to give N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 181 μmol, 70.0%) as a light yellow solid and of approximately 75% purity. MS (M+H)+=497.1; 1H NMR (CDCl3) δ: 9.10 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 5.68 (s, 2H), 4.34-4.60 (m, 1H), 3.82 (s, 3H), 3.48-3.61 (m, 2H), 3.03 (t, J=6.2 Hz, 2H), 2.41 (s, 2H), 1.61 (t, J=6.4 Hz, 2H), 1.33 (d, J=6.8 Hz, 6H), 1.09 (s, 6H), 0.83-0.97 (m, 2H), −0.06 (s, 9H). NMR and LCMS showed an impurity that was identified as the dimer of the tetrahydroindazole (MW 326.49) linked at the 3-position.
Reaction SMILES: CO[C:3](=[O:19])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:5].[CH3:20][N:21]=[C:22]=[S:23].N>C(O)C>[C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:22](=[S:23])[N:21]([CH3:20])[C:3]1=[O:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)c1ccccc1
Agent: N
Solvent: CCO
Product: CN1C(=O)C(CCCCNC(=O)c2ccccc2)NC1=S
Temperature: 40 °C

Procedure:
A solution of Nε-benzoyl-L-lysine methyl ester (26 g) and methyl isothiocyanate (6.75 g) in ethanol (250) was heated under reflux for 12 hours. The solution was saturated with ammonia at 0°C and heated in a bomb at 40°C for 3 days. Evaporation of the solvent gave a gum which was crystallised from isopropyl alcohol. Recrystallisation from iso-propyl alcohol gave the title compound as the quarter isopropyl alcohol solvate 10 g (m.p. 137-8°C). Found: C, 59.4; H, 6.25; N, 13.1. C15H19N3O2S.1/4C3H8O requires C, 59.0; H, 6.6; N, 13.1%.