Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>COC(O)C>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: COC(C)O
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc2C1
Temperature: 95 °C

Procedure:
To a solution of 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5one (22.0 g, 0.0944 mol) in dioxane (400 mL) was added borane dimethyl sulfide complex solution (2 M in THF, 118 mL, 0.236 mol) and heated at 75° C. for 4 hr. The reaction was quenched with ethanol (100 mL) and stirred at room temperature for 18 hr., then evaporated. To the residue was added hydrazine hydrate (100 mL) and heated at 95° C. for 4 hr. After evaporation, toluene (50 mL) and ethanol (50 mL) were added, distilled and the reaction evaporated. The residue was extracted with DCM, evaporated, dissolved in ether, filtered and evaporated to give 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine as an oil (16.0 g, 84%). LCMS (m/e) 220 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.79-6.71 (d, 1H, J=7.83 Hz), 6.49 (br, 1H), 6.01-5.99 (d, 1H, J=7.83 Hz), 4.79 (s, 2H), 3.07-3.02 (q, 2H, J=6.82 Hz), 2.85-2.83 (t, 2H, J=8.08 Hz), 2.70-2.68 (t, 2H, J=8.09 Hz), 1.13-1.10 (t, 3H, J=7.07 Hz), 1.00-0.97 (t, 3H, J=7.32 Hz), 712d) 5-Chloro-N*2*-(1,4-diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidin-2,4-diamine was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (0.068 g, 0.00023 mol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (0.081 g, 0.00023 mol), camphorsulfonic acid (0.0187 g, 0.0008 mol) and methoxyethanol (10 mL). The mixture was heated at 95° C. for 18 hr. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with THF/methanol (10-1) giving the product as a tan solid (0.053 g, 43%). Mp 165-166° C. LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 9.07 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.65 (d, 1H), 7.15-7.13 (d, 1H, J=8.33 Hz), 7.01 (s, 1H), 6.84-6.82 (d, 1H, J=8.08 Hz), 6.69 (s, 1H), 6.49-6.47 (d, 1H, J=8.59 Hz), 3.80 (s, 3H), 3.76 (t, 2H, J=4.05), 3.54 (s, 2H), 3.14 (t, 3H), 3.01-2.99 (q, 2H, J=7.07 Hz), 2.90-2.84 (m, 2H), 2.78-2.69 (m, 2H), 2.40-2.30 (m, 2H), 1.11-1.08 (t, 3H, J=6.57 Hz), 1.03-1.00 (t, 3H, J=7.33).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:22][NH2:23]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4]([NH:22][NH2:23])[N:3]=1
Reactant: NN
Reactant: Fc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(Nc2ccc(F)c(C(F)(F)F)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a stirred solution of (2,6-dichloropyrimidin-4-yl)-(4-fluoro-3-trifluoro-methylphenyl)amine (XXII) (2.5 g, 7.66 mmol) in dioxane (15 mL) was added hydrazine monohydrate (1 mL) and the mixture stirred at ambient temperature for 24 h. The mixture was diluted with water and the resulting slurry was stirred for 10 min then filtered under vacuum. The white precipitate was rinsed with water and dried under vacuum to give (2-chloro-6-hydrazinopyrimidin-4-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XXIV) as a white solid (2.1 g, 85% yield): m.p. 102-103° C., 1H NMR (CDCl3) δ 7.7 (m. 1H), 7.59 (m, 1H), 7.21 (m, 1H), 5.95 (s, 1H), 3.77 (s, 3H); ESI/MS 325 (M−H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH2:35]Br>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][C:34]3[CH:37]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: FC(F)(F)c1ccc(Cl)cc1CBr
Product: FC(F)(F)c1ccc(Cl)cc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 5-chloro-2-trifluoromethylbenzyl bromide as in the procedure of Example 43. MS (ESI) m/z 572.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3,4-dichlorophenyl)propan-1-ol (10.9 g) and triethylamine (4.00 mL) in THF (100 mL) was added chloroacetyl chloride (1.91 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (12.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(C(=O)Oc3ccc(C=O)cc3)cc2)cc1
Reaction time: 18 h
Yield: 40.4 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (0.5 g, 2.35 mmol) in DCM (10 mL) was added DMF (3 drops) then oxalyl chloride (0.262 mL, 3.1 mmol) and left for 2 h. The reaction mixture was added to a solution of 4-hydroxybenzaldehyde (0.31 g, 2.6 mmol) and TEA (0.4 mL, 2.82 mmol) in DCM (10 mL) and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and washed with NaHCO3 (100 mL). The organic layer was pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 300 mg (40%) 4-formylphenyl 4′-methyl-[1,1′-biphenyl]-4-carboxylate INT-27 as a white solid. LCMS-ESI (m/z) calculated for C21H16O3: 316; no m/z observed, tR=4.25 min (Method 1).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[N:7]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]2)=[O:10])[N:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[CH:4]=1.N(CCO)CCO>CN(C)C=O>[CH3:2][C:3]1[N:7]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[S:1])[NH2:18])[CH2:13][CH2:12]2)=[O:10])[N:6]=[C:5]([C:19]([F:22])([F:20])[F:21])[CH:4]=1
Reactant: S
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Solvent: CN(C)C=O
Solvent: OCCNCCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Hydrogen sulfide gas was passed into a solution of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile (i.e. the product of Example 8, Step B) (9.0 g, 30 mmol) and diethanolamine (3.15 g, 30 mmol) in N,N-dimethylformamide (15 mL) at 50° C. in a flask equipped with dry-ice condenser. The hydrogen sulfide feed was stopped when the reaction mixture became saturated with hydrogen sulfide, as indicated by condensation on the cold-finger. The reaction mixture was stirred for an additional 30 minutes at 50° C. Then excess hydrogen sulfide gas was sparged into the scrubber by a subsurface nitrogen flow, and water (70 mL) was gradually added.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.CCCCCC.[Cl-].Cl[CH2:20]/[CH:21]=[C:22](/[F:31])\[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>O1CCCC1>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:20][CH:21]=[C:22]([F:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: C1CSCSC1
Reactant: F/C(=C/CCl)COC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(=CCC1SCCCS1)COC1CCCCO1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of 1,3-dithiane (1.55 g, 12.9 mmole) in tetrahydrofuran (60 ml) cooled to -30° C. was added dropwise a 1.32M solution of n-butyllithium in hexane (9.77 ml, 12.9 mmoles), the mixture was stirred at -30° C. for 30 min. Then the mixture was cooled to -40° C. and the chloride prepared in 1C (2.69 g, 12.9 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The reaction was stirred 30 min at -40° C. and 2 hrs at 0° C. The reaction was quenched with saturated aqueous ammonium chloride and the tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silicagel and elution with a 8:2 mixture of hexane and ethyl acetate afforded the title dithialane as an oil (3.34 g, 90%). NMR (H1, CDCl3, 60 MHz) characetristic peaks: 4.00 (t, JHH =7 Hz, 1), 4.21 (d, JHF =20 Hz, 2), 4.7 (broad peak, 1), 5.40 (dt, JHF =20 Hz, JHH =8 Hz, 1).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1(C(O)=O)CCCCC1.S(Cl)([Cl:27])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>C(N(CC)CC)C>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:27])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C1CCCCC1
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 100 μL triethylamine (0.72 mmol=0.005 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 22 minutes at a temperature of 41-51° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 54-55° C. After 10 minutes the reaction was almost complete (0.13% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 0.13% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After 1.5 hr the reaction was complete (0.04% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 3.5-4.3 mbar followed by 120° C. bath, 10-11 mbar) 26.19 g of residue was obtained (assay 92.9% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cccc(CF)n1
Yield: 64.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1; from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol, Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 650%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as a white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH:11]1[CH2:21][CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1.N1CCC[C@@H](C(OCC)=O)C1.C([C@@H]([C@H](C([O-])=O)O)O)([O-])=O>C(O)(C)C.O>[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[NH:11]1[CH2:21][CH2:20][CH2:19][C@@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CCOC(=O)C1CCCNC1
Agent: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 62.5 °C
Reaction time: 0.42 h

Procedure:
L-(+)-Tartaric acid (47.74 g, 318 mmol) was suspended in 265 g of isopropyl alcohol and 16.91 g of water. The mixture was heated to 60-65° C. to afford a homogeneous solution. One equivalent of (±)-ethyl nipecotate (50 g, 318 mmol) was added while the temperature was maintained at or below 75° C. The mixture was stirred at 70-75° C. for 20-30 minutes, then cooled to 60° C. over 60 minutes. Seed crystals of (R)-(−)-ethyl nipecotate-L-(+)-tartrate (25 mg, 0.08 mmol) were added and the reaction was cooled to 26-30° C. over three hours. The temperature was maintained at 26-30° C. for 30 minutes until precipitation was complete. The product was isolated (62.0 g, 94.8% de) and washed twice with a mixture of isopropyl alcohol (21.05 g) and water (1.34 g). The crude product was slurried in a mixture of isopropyl alcohol (188 g) and water (12 g) at 73-77° C. After stirring for 10-20 minutes, the suspension was cooled to 26-30° C. Temperatures exceeding 30° C. will result in less yield, while a temperature of less than 25° C. resulted in de<98%. The product was isolated by filtration and washed twice with a mixture of isopropyl alcohol (21.05 g) and water (1.34 g). This afforded the title compound as a white powder in 72% yield, 98.8% de.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:30][N:31]1CCOC[CH2:32]1.CNC.C1COCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:19]
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 87 %

Procedure:
(2S)-1-{[(Phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (2.0 g, 7.595 mmol) and HOBt (1.231 g, 9.114 mmol) were dissolved in CH2Cl2 (40 mL), and 4-methylmorpholine (2.5 mL, 22.78 mmol), 2.0 M solution of dimethyl amine in THF (4.55 mL, 9.114 mmol), and EDCI (1.750 g, 9.114 mmol) were added. This solution was stirred overnight, and was then washed with 1 N HCl (25 mL) and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes) to provide phenylmethyl (2S)-2-[(dimethylamino)carbonyl]-1-piperidinecarboxylate (1.919 g, 87%). LCMS: (M+H)+: 291.1.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[Cl:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16](B(O)O)=[C:15]([F:24])[CH:14]=1.C(=O)([O-])O.[Na+]>O.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>[Cl:8][C:7]1[C:2]([C:16]2[CH:17]=[C:18]([O:19][CH3:20])[C:13]([Cl:12])=[CH:14][C:15]=2[F:24])=[N:3][CH:4]=[C:5]([S:9]([CH3:11])=[O:10])[CH:6]=1
Reactant: CS(=O)c1cnc(Cl)c(Cl)c1
Reactant: COc1cc(B(O)O)c(F)cc1Cl
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: O
Product: COc1cc(-c2ncc(S(C)=O)cc2Cl)c(F)cc1Cl
Yield: 30.1 %

Procedure:
4.6 g of 2,3-dichloro-5-methylsulfinylpyridine, 4.5 g of 4-chloro-2-fluoro-5-methoxybenzeneboronic acid, 5.5 g of sodium hydrogen carbonate and 1.0 g of tetrakis(triphenylphosphine)palladium(0) were refluxed for 180 hours in a mixture of 100 ml of water and 100 ml of tetrahdyrofuran. After the tetrahydrofuran has been evaporated, the residue was extracted four times with in each case 70 ml of MTB. The combined organic phases were then dried over sodium sulfate and finally concentrated. The resulting oil was purified by means of chromatography on silica gel (eluent: cyclohexane/MTB=7:3→1:1 and cyclohexane/ethyl acetate=2:1). Stirring this purified oil with diethyl ether gave 2.2 g (30%) of white crystals.; m.p.: 117-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([O-])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[CH2:16][CH2:17]1)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccncc1C(=O)[O-]
Reactant: CC(C)N(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccncc1CN1CCC(N(C(=O)OC(C)(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.9 %

Procedure:
A solution of 4-(N-tert-butoxycarbonyl-N-isopropylamino)piperidine (118 g, 0.49 mol) in dichloroethane (600 mL) was stirred at room temperature for 1 hour, and then 4-methoxypyridine-3-carboxylate (63.5 g, 0.46 mol) was added. The resulting solution was stirred at room temperature for 2.5 hours and then cooled to 5° C. in an ice/water bath. Sodium triacetoxyborohydride (124 g, 0.58 mol) in dichloroethane (600 mL) was added and the reaction mixture was stirred at 5° C. for 15 minutes. The ice bath was then removed and reaction mixture was stirred for 4 hours at room temperature. Acetic acid (30 mL) was then added to the reaction mixture and the resulting mixture was stirred for 0.5 hours, and then concentrated to half its original volume. This solution was cooled in a dry ice/acetone bath and 10 N aqueous sodium hydroxide (350 mL) was added. This mixture was stirred for 0.5 hours and then the organic layer was separated and washed with 1 N aqueous sodium hydroxide (400 mL). The aqueous layer was then washed three times with dichloromethane (400 mL) and the combined organic layers were dried over sodium sulfate (40 g). The sodium sulfate was filtered off and washed with dichloromethane (100 mL) and the combined organic layers were concentrated in vacuo to give 177 g of the title intermediate as a yellow oil (>99% yield; 74% purity by GC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2[CH:36]=[CH:37][CH:38]=[N:39]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:38]1([NH:39][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:23])[CH2:36][CH2:37]1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reaction time: 43 h
Yield: 77.1 %

Procedure:
To a solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 30.0 mg, 0.092 mmol) and HATU (52.1 mg, 0.137 mmol) in dry DMF (0.5 mL) was added cyclopropylamine (10.5 mg, 0.183 mmol) followed by diisopropylethylamine (35.5 mg, 0.275 mmol). The mixture was stirred under an atmosphere of N2 for 43 hours. The crude mixture was purified by reverse phase chromatography eluting with 0-50% acetonitrile/water to yield the title compound as a white solid (26 mg, 78% yield). MS (apci) m/z=367.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A 500 ml flask was charged with 3-bromophenol (A) (25 g, 144 mmol), THF (200 ml) and triethylamine (14.67 g, 145 mmol). The flask was cooled to 0° C. in an ice bath, and chlorotriethylsilane (21.8 g, 144 mmol) was added dropwise. The mixture was allowed to stir at room temperature to completion over 2 h. The hydrochloride salt was then filtered. Removal of solvents followed by flash chromatography afforded 3-bromo-O-triethylsilylphenol (J) as a clear liquid (30.4 g, 73%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]=[CH:18][C:19]2[S:23][C:22]3=[CH:24][N:25]=[CH:26][N:21]3[CH:20]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].C(OCC)(=O)C>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH:17]=[CH:18][C:19]2[S:23][C:22]3=[CH:24][N:25]=[CH:26][N:21]3[CH:20]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=Cc1cn2cncc2s1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C=Cc1cn2cncc2s1
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
Potassium thioacetate (0.22 g) is added to a solution of 1.07 g of (3R,5S)-1-allyloxycarbonyl-3-methane sulfonyloxy-5-[2-(imidazo[5,1-b]thiazol-2-yl)vinyl]pyrrolidine (a mixture of geometrical isomers) in 5 ml of DMF, and the mixture is stirred at 70° C. for 4 hr. Ethyl acetate is added to the reaction mixture, and the mixture is successively washed with water and a saturated aqueous sodium hydrogencarbonate solution, and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation. The residue is purified by column chromatography on silica gel to give 0.42 g of the title compound.