Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[CH3:21][N:22]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:41]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:41])[N:22]([CH3:21])[CH:31]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Product: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 149, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 149, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 7.68 (s, 3H), 7.59-7.56 (m, 1H), 7.14-7.08 (m, 1H), 7.05-7.00 (m, 1H), 6.96-6.92 (m, 1H), 3.72 (s, 3H), 3.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+].[Cl-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([NH2:27])=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(N)=O)n(C)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.36 mmol) in DMF (8.3 mL) was added 1,1′-carbonyldiimidazole (60.6 mg, 0.36 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (465 μL, 3.0 mmol) and stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (79 mg, 79%) as a white solid. MS: m/e=331.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 102-104° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.99-4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.9 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (CI) calcd for C18H22N3O3BrCl (M+H)+: 442.0533; found m/z 442.0532.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:33])([CH3:32])[CH2:25][N:26]2[C:29](=[O:31])[CH3:30])=[CH:22][CH:21]=1.C(#N)C.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:28]=[C:27]5[C:23]([C:24]([CH3:33])([CH3:32])[CH2:25][N:26]5[C:29](=[O:31])[CH3:30])=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(C)(C)c2ccc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)cc21
Temperature: 180 °C
Yield: 79.6 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (40 mg, 0.14 mmol), 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (60 mg, 0.29 mmol), and acetonitrile (3 mL) was heated in a sealed tube via microwave at 180° C. for 60 min. The mixture was treated with EtOAc (50 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica gel to give an off-white solid (50 mg).
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]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[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 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.185, m/z=459.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.57 (d, 3H), 2.20 (s, 2H), 2.22-2.35 (m, 2H), 2.38-2.49 (m, 1H), 2.72 (s, 6H), 2.91 (m, 1H), 5.70 (m, 1H), 7.08 (d, 2H), 7.31 (m, 3H), 7.37 (m, 4H), 7.43 (s, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][C:13]([OH:15])=O)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH2:52][C:53]1[CH:54]=[CH:55][C:56]([Cl:63])=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:63][C:56]1[CH:55]=[CH:54][C:53]([NH:52][C:13](=[O:15])[CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([N:6]3[CH:7]=[C:3]([Si:2]([CH3:1])([CH3:20])[CH3:19])[N:4]=[N:5]3)[CH:9]=2)=[CH:58][C:57]=1[C:59]([F:60])([F:61])[F:62]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)c1cn(-c2cccc(OCC(=O)O)c2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cn(-c2cccc(OCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL recovery flask was added [3-(4-Trimethylsilanyl-[1,2,3]triazol-1-yl)-phenoxy]-acetic acid 6 (483 mg, 1.66 mmol, 1.0 eq.) and a stirbar. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g, 3.3 mmol, 2.0 eq.), DMF (8 mL), and N-methylmorpholine (503 μL, 4.98 mmol, 3.0 eq.) were added. The mixture was stirred at room temperature for 30 min. 5-amino-2-chlorobenzotrifluoride (649 mg, 3.3 mmol, 2.0 eq.) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a succession of 10% aq. LiCl (3×50 mL), H2O (50 mL), and sat'd aq. NaCl (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a grayish solid. The solid was recrystallized in hot MeOH to give a light gray solid, which by LC/MS was a mixture of product and the corresponding de-silylated material (200 mg). The mixture was taken on to the next step without further purification. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 469.1 (M+H)+1
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:29]1[C:30]2[C@H:38]([CH3:39])[CH2:37][C:36](=[O:40])[NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.N12CCCN=C1CCCCC2.C>C(O)CC.C(OCCCC)(=O)C>[CH3:39][C@H:38]1[C:30]2[C:29]([N:25]3[CH2:24][CH2:23][CH:22]([C:12]4[N:11]([CH2:10][CH2:9][N:4]5[CH2:5][CH2:6][CH2:7][CH2:8]5)[CH:15]=[C:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[N:13]=4)[CH2:27][CH2:26]3)=[N:34][CH:33]=[N:32][C:31]=2[NH:35][C:36](=[O:40])[CH2:37]1
Reactant: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Agent: Cl
Solvent: CCCO
Solvent: CCCCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C5CCOCC5)cn4CCN4CCCC4)CC3)c21
Temperature: 25 °C
Yield: 109 %

Procedure:
Charge 4-(1-(2-(Pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride (300 g, 1.0 equiv), (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (146.2 g, 1.0 equiv) and n-propanol (3.0 L) to a 12-L reaction flask. Stir the reaction mixture and add 1,8-diazabicyclo[5.4.0]undec-7-ene (394.3 g, 3.5 equiv) over ten minutes. Heat the reaction to 90° C. for 8 hours, and allow to cool to room temperature over 12 hours. Displace the n-propanol with n-butyl acetate to a total volume of 3-L and a residual n-propanol content of 11% (w/w). Heat the organic solution to 50-60° C. and wash with brine (2.25 L). Back-extract the aqueous phase with nButyl acetate (1.5 L) and combine the organic layers. Wash the combined organic layers with water (2×450 mL) at 50-60° C. Separate the organic layer and add activated charcoal (75 g, 0.25 equiv) and stir at 50-60° C. for 30 min. Filter the slurry and rinse the solids with n butyl acetate (1.5 L). Wash with water (1 L), separate the organic phase and azeotropically dry the organic phase to remove water. At 50-60° C., add heptanes (3.0 L) cool to 40° C. and add seed crystals. Allow the slurry to cool to room temperature over ˜12 h. Cool to 0-5° C., filter the slurry and wash with heptanes (2×900 mL). Dry in vacuo and isolate (R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (365.3 g, 64%). MS (ES) m/z=494 [M]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[CH2:30]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
6.5 g (180 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 22) are suspended in 80 ml acetone added to 9.9 g (72.0 mmol) potassium carbonate. A solution of 3.4 g (19.8 mmol) benzyl bromide in 10 ml acetone is added dropwise to this mixture at RT and stirred overnight. Subsequently, the suspension is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 100 ml CHCl3 and washed with 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5 to 90/10) and crystallized from 15 ml acetonitrile after drawing off the solvent. Beige colored crystals with a MP of 88-90° C. were recovered; yield: 1.1 g (16%).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:43]=[C:44]2[CH:50]=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])([CH3:9])([CH3:8])[CH3:7].[NH:48]1[C:45]2=[N:46][CH:47]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Pd+2]
Agent: C=CC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]ccc2c1

Procedure:
tert-Butyl acrylate (5.9 mL, 40.6 mmol), diisopropylethylamine (3.5 mL, 20.3 mmol) and P(o-tolyl)3 (618 mg, 2.0 mmol) were successively added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.15 mmol) in propionitrile (40 mL) and dimethylformamide (10 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (227 mg, 1.0 mmol). The mixture was then purged with argon a second time and refluxed overnight. The reaction mixture was filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in ethyl acetate (3×100 mL). The organic layers were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (1:0 to 7:3) as eluent. The title compound was obtained as a yellow solid (465 mg, 28%)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.[CH:29]([NH2:31])=O>CCOC(C)=O.O>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[CH:5]=[N:4][C:3]4[C:2]3=[N:1][CH:29]=[N:31][C:20]=4[C:21]3[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccc(S)cc2)c1N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(S)cc3)ncnc21
Temperature: 180 °C
Yield: 59 %

Procedure:
The mixture of 3-[5-Amino-4-(4-mercapto-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide (33 mg, 0.09 mmol), formamide (0.5 mL, excess), and p-tolunesolfonic acid (10 mg) was heated in the microwave at 180° C. for 30 min. After cooling, the mixture was diluted with EtOAc and water, and the EtOAc layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparatory HPLC to provide the title compound (20 mg, 59%) as a white solid: HPLC tR=2.47 min; MS m/z 416.27 [M+H]+.
Reaction SMILES: [H-].[Li+].C(S)CC.C[O:8][C:9]1[CH:26]=[C:25]2[C:12]([C@@:13]3([CH3:30])[C@H:22]([CH2:23][S:24]2)[C@:21]2([CH3:27])[C@H:16]([C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)=[C:11]([C:31]#[N:32])[CH:10]=1>CN(P(N(C)C)(N(C)C)=O)C>[OH:8][C:9]1[CH:26]=[C:25]2[C:12]([C@@:13]3([CH3:30])[C@H:22]([CH2:23][S:24]2)[C@:21]2([CH3:27])[C@H:16]([C:17]([CH3:28])([CH3:29])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)=[C:11]([C:31]#[N:32])[CH:10]=1
Reactant: COc1cc(C#N)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)cc(C#N)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
A mixture of LiH (0.127 g, 16.2 mmol), 1-propyl thiol (1.60 mL, 17.6 mmol) in HMPA (2 mL) was stirred at room temperature for 15 minutes under N2. To the mixture, a solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carbonitrile (77) (0.10 g 0.27 mmol) in HMPA (3.0 mL) was added. The mixture was heated at 130° C. for 30 min. The reaction mixture was cooled to room temperature and quenched with water, then extracted with EtOAc. The organic layer was separated and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 10:1) to yield (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carbonitrile (78) (0.06 g, 62%) as a white solid. 1H NMR (CDCl3): δ 6.86 (d, 1H), 6.72 (d, 1H), 4.72 (s, 1H), 3.47 (m, 1H), 2.86 (m, 2H), 1.86-1.56 (m, 4H), 1.52-1.36 (m, 6H), 1.28-0.97 (m, 3H), 0.94 (s, 3H), 0.90 (m, 1H), 0.87 (s, 3H), 0.84 (s, 3H). MS m/z 354 (C22H29NOS−H+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl[CH:6]([C:12]([C:14]([F:17])([F:16])[F:15])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].O>CN(C)C=O>[NH2:1][C:2]1[O:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([C:14]([F:15])([F:17])[F:16])[N:4]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc(N)nc1C(F)(F)F
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mechanically-stirred mixture of 53.2 g (0.885 mol) of urea and 38.6 g (0.177 mol) of ethyl α-chloro-γ,γ,γ-trifluoroacetoacetate was reacted in 50 ml dry dimethylformamide at 100°-110° C. for 71 hours. The reaction mixture was cooled to ambient temperature and the resulting orange slurry was poured into 500 ml of water and then cooled in an ice bath. Suction filtration of the mixture provided a mustard-colored solid material which when dried under an infrared lamp yielded 26.0 g of material. This solid material was slurried in hot chloroform, then cooled in an ice bath to yield 22.1 g of beige plate-like crystal material (m.p. 193-195° C.). A second crystal crop was obtained after concentration of the slurry residue, recrystallization in hot ether and filtration through glass wool. Total yield was 22.4 g of crystal product (m.p.=193°-195° C.) identified in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:33]([NH2:34])=[CH:32][N:31]=[CH:30][N:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:35](=S)=[S:36].CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([SH:36])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Nc1cncnc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: S=C=S
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(CC3CCN(CCn4c(S)nc5cncnc54)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 11.3 parts of N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine, 3.75 parts of carbon disulfide and 117 parts of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5 parts (40%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-9H-purine-8-thiol; mp. 163.7° C. (495).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:6]=1[C:7](OC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:6]=1[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(N)ccc1C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N)cc1CO
Yield: 19.4 %

Procedure:
To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0.72 mmol) in THF (5 mL) was added dropwise LiAlH4 (1.4 mL, 1M in THF, 1.4 mmol) at 0° C. The reaction mixture was refluxed for 2 h, diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated to give (2-tert-butyl-5-aminophenyl)methanol (E-8) (25 mg, 20%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 6.56 (dd, J=8.4, 2.7 Hz, 1H), 4.83 (s, 2H), 1.36 (s, 9H).
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH:14]1[CH2:20][CH2:19][CH2:18]S[C:16]2[CH:21]=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[S:23][C:15]1=2>O.CO>[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH:14]1[CH2:20][CH2:19][CH2:18][S:3](=[O:5])(=[O:4])[C:16]2[CH:21]=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[S:23][C:15]1=2
Reactant: COCCOCOC1CCCSc2cc(S(N)(=O)=O)sc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCOC1CCCS(=O)(=O)c2cc(S(N)(=O)=O)sc21
Temperature: 25 °C
Reaction time: 41 h

Procedure:
A solution of OXONE® (28.9 g, 0.047 mole) in water (200 ml) was added to a stirred suspension of 8-(2-methoxyethoxymethoxy)-5,6,7,8-tetrahydrothieno[3,2-b]thiepin-2-sulfonamide (14.0 g, 0.040 mole) in methanol (250 ml) and the mixture was stirred at ambient temperature for 41 hours. Methanol was evaporated under reduced pressure and the aqueous suspension was extracted with ethyl acetate (3×250 ml). The combined extracts were washed twice with water, dried over sodium sulfate and evaporated under reduced pressure to give 16.62 g (theory 15.42 g) of solvated oily product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccccc1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.