Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54][NH2:55]>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54][NH:55][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1F
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (200 mg, 1.28 mmol) in DMF (3 ml) at ambient temperature were added HATU (536 mg, 1.41 mmol) and DIEA (268 μL, 1.54 mmol). The reaction was stirred for 30 minutes and then 2-(2,4-dichlorophenyl)ethanamine (193 μL, 1.28 mmol) was added. The reaction was stirred overnight, then concentrated and diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography) to give N-(2,4-dichlorophenethyl)-2-fluoro-4-hydroxybenzamide (0.420 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[OH:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C:27](=[O:33])[NH:28]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:26]3[C:25]4[C:29](=[CH:30][CH:31]=[CH:32][C:24]=4[CH2:23][CH2:22][OH:21])[NH:28][C:27]3=[O:33])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(CCO)c43)c(C)c2C1=O
Yield: 35 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (prepared according to US2004186160) as starting materials to give 5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 35.0%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].CS(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][C@@H:31]([C:33]2[CH:44]=[CH:43][C:36]3[O:37][C:38]([CH3:42])([CH3:41])[O:39][CH2:40][C:35]=3[CH:34]=2)[O:30][C:29]1=[O:45])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][O:7][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][C@@H:31]([C:33]2[CH:44]=[CH:43][C:36]3[O:37][C:38]([CH3:41])([CH3:42])[O:39][CH2:40][C:35]=3[CH:34]=2)[O:30][C:29]1=[O:45]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Reactant: CN(C)c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc(COCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of 3-dimethylaminobenzyl alcohol (641 mg) in DMF (3 ml) under nitrogen was treated with sodium hydride (220 mg, 60% in oil) and the mixture stirred at 20° for 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (2.00 g) in DMF (5 ml) was added and the mixture was stirred at 20° for 21 h. Phosphate buffer solution (15 ml, pH6.5) was added, the mixture stirred for 15 min and then extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by Biotage (40 g). Elution with EtOAc-PE (1:2) gave the title compound (2.125 g). LCMS RT=3.47 min.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]([O:34]C(C)(C)C)=[O:33]>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C:32]([OH:34])=[O:33])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
[(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from [(5Z)-5-({1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 5) and tert-butyl bromoacetate following General Procedure I.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:17](=[O:19])[O:15][CH2:14][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CN(Cc2ccccc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C1OCC2CN(Cc3ccccc3)CCN12
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a stirred solution of (4-benzyl-piperazin-2-yl)methanol (250 mg, 1.21 mmol) in anhydrous DCE (8.0 mL) was added triphosgene (133 mg, 0.45 mmol, 0.37 eq) followed by diisopropylethylamine (0.25 mL, 1.45 mmol, 1.2 eq). The mixture was stirred at 50° C. under N2 for 16 h. The mixture was cooled to rt, quenched with aqueous, saturated NH4Cl solution (2.0 mL), and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 80 to 100% EtOAc/hexane) to give the product (91.2 mg, 32%) as a clear oil, 1H-NMR (300 MHz, CD3OD) 7.35 to 7.24 (m, 5H), 4.38 (t, 1H), 3.96 to 3.87 (m, 2H), 3.71 to 3.66 (m, 1H), 3.57 (q, 2H), 3.14 to 3.07 (m, 1H), 2.97 to 2.93 (m, 2H), 2.04 (dt, 1H), 1.93 (t, 1H); ES-MS m/z 233.2 [M+H]+, RT (min) 0.29.
Reaction SMILES: ClC[C:3]1[N:4]([C@@H:16]([CH3:26])[CH2:17][NH:18][C:19](=O)OC(C)(C)C)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.C(Cl)(Cl)Cl>Cl.CCO>[CH3:26][C@@H:16]1[N:4]2[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[CH:7][C:6]=3[N:15]=[C:3]2[CH2:19][NH:18][CH2:17]1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@H]1CNCc2nc3cnc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
tert-Butyl (2S)-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (2.54 g, 6.77 mmol) was dissolved in 2.2 M HCl in EtOH (50 mL) and the solution was heated to reflux for 15 minutes. N2 was bubbled through the reaction for 15 minutes, and the remaining volatiles were removed under reduced pressure. The resulting material was partitioned between dichloromethane and water. The organic layer was discarded and the aqueous layer was treated with concentrated NH4OH solution to adjust to pH 11. The aqueous layer was extracted with dichloromethane (3×100 mL), and the combined organic layers were washed with brine. Triethylamine (4 mL) was then added to the solution and it was stirred at ambient temperature overnight. The reaction was washed successively with water (2×100 mL) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give an orange foam. Chromatography (SiO2, 20-50% CMA/CHCl3) gave (11S)-11-methyl-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline (1.06 g) as an orange foam.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([Br:20])=[CH:13]3)[C:5]([NH2:21])=[N:4][CH:3]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:20][C:14]1[CH:15]=[N:16][C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:9][N:8]1[C:6]3=[N:7][C:2]([Br:1])=[CH:3][N:4]=[C:5]3[N:21]=[N:22]1)=[CH:19][CH:18]=2
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2ccc(Cn3nnc4ncc(Br)nc43)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 6-bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (300 mg, 0.73 mmol) in 5 mL of acetic acid was added dropwise a solution of NaNO2 (150 mg, 2.17 mmol) in 0.5 mL of water at 20° C. The mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound (130 mg, 42%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.84 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.01 (d, 1H), 7.74 (s, 2H), 5.99 (s, 2H). LCMS (method E): [MH]+=421, tR=5.50 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.C(OC([NH:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1)=O)(C)(C)C.C(N(CC)CC)C.Cl>ClCCl.CCOCC.CCOC(C)=O.O>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:19]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:24][CH2:25]3)[N:18]=[CH:8][C:7]=12
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.089 g, 6.15 mmol) and benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate from Example 12A (2.15 g, 6.15 mmol) in dichloromethane (25 mL) was added triethylamine (2.144 mL, 15.38 mmol). The resulting solution was allowed to stir at ambient temperature for 3 h. The reaction flask was placed in a bath of cold water, then there was added 2N HCl in ether slowly and directly to the reaction mixture. Stirred 5 minutes and then diluted with EtOAc and washed with 1N HCl, sat'd aq sodium bicarbonate and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford Example 12B, benzyl 4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate, as an oil (2.26 g) which was pure enough to be used without purification. LRMS (ESI): 372.2 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:36])[C@@H:10]([NH:24][C:25]1[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:28]([C:34]#[N:35])=[CH:27][CH:26]=1)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:13]2[O:12][C:11]([C@H:10]([NH:24][C:25]3[C:33]4[CH:32]=[CH:31][S:30][C:29]=4[C:28]([C:34]#[N:35])=[CH:27][CH:26]=3)[C@@H:9]([OH:8])[CH3:36])=[N:15][N:14]=2)=[CH:17][CH:18]=1)#[N:23]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Reaction time: 2 h

Procedure:
To a solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (355 mg, 0.69 mmol) in THF (33 mL) was added TBAF (0.70 mL, 0.70 mmol, 1 M solution in THF) at −50° C. After addition, the reaction mixture was stirred between −30° C. to −50° C. for 2 h, then quenched by adding saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried over Na2SO4. The solvent was removed to provide a residue, which was subjected to flash chromatography purification to give the title compound 4-(1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-O-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (173 mg, 63%) and some dehydration product 4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (70 mg, 27%). Title compound: 1H NMR (400 MHz, Acetone-db, δ in ppm) 8.16 (d, J=8.8 Hz, 2H), 7.95 (d, J=8.8 Hz, 2H), 7.87 (d, J=5.7 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.6 Hz, 1H), 5.25 (dd, J=4.3, 8.6 Hz, 1H), 4.79 (b, 1H), 4.66 (m, 1H), 1.42 (d, J=6.3 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, 5 in ppm) 8.25 (d, J=8.2 Hz, 2H), 8.01 (d, J=8.2 Hz, 2H), 7.96 (d, J=5.5 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.09 (q, J=7.0 Hz, 1H), 6.58 (d, J=8.2 Hz, 1H), 1.95 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([O:14][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]3)=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Oc1cnc(-c2ccc(Br)cc2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3ccc(Br)cc3)nc2)CC1

Procedure:
1,1-Dimethylethyl 4-({[2-(4-bromophenyl)-5-pyrimidinyl]oxy}methyl)-1-piperidinecarboxylate was prepared (0.387 g, 76%) as a white solid from 2-(4-bromophenyl)-pyrimidine-5-ol (0.30 g, 1.19 mmol), N-Boc-4-piperidinemethanol (0.27 g, 1.19 mmol) and Ph3P (0.32 g, 1.19 mmol) in THF (8 mL) followed by diisopropyl azodicarboxylate (0.26 g, 94%, 1.19 mmol) in THF (3 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 2H), 8.22 (d, 2H, J=8.3 Hz), 7.59 (d, 2H, J=8.3 Hz), 4.25-4.10 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 448/450 (M+H).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[N:29]2[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=S)[CH2:36][C:37]3[N:38]=[CH:39][N:40]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:41]=3)[C:30]2=[O:62])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.CO.[Ni]>[Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[N:29]2[CH2:33][CH2:32][C@H:31]([NH:34][CH2:35][CH2:36][C:37]3[N:38]=[CH:39][N:40]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:41]=3)[C:30]2=[O:62])=[CH:21][CH:20]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=S)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of (S)-N-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidin-3-yl}-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]thioacetamide, as described above in Step E, (1.85 g, 2.18 mmol) and Raney Ni (3.7 g of a slurry in EtOH) was stirred in MeOH (80 mL) at 35° C. for 5 hours. The mixture was filtered through a pad of celite, washing with MeOH, and the filtrate was concentrated to provide the titled product as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)[CH3:13]>C(O)(=O)C.CCO>[CH2:12]([C:14]1[S:18][C:17]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCc1ccc(C=O)s1
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccc(C=NNC(=O)c2ccc(O)cc2)s1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-ethyl-2-thiophenecarboxaldehyde (0.28 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.53 g, in 96% yield, mp: 194.5° C. 1H NMR (CD3OD) δ 8.39 (s, 1H), 7.79 (d, 2H), 7.19 (s, 1H), 6.86 (d, 2H), 6.80 (s, 1H), 2.86 (q, 2H), 1.31 (t, 3H). 13C NMR (CDCl3) δ 166.5, 162.7, 153.1, 144.9, 137.7, 132.3, 130.8, 125.3, 124.8, 116.3, 24.7, 16.2. Anal. Calcd for C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21. Found: C, 61.00; H, 5.18; N, 10.00.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]1N(C)C.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:6]([CH2:4][CH2:5][C:2]([CH3:13])([CH3:1])[CH:3]=[CH:15][C:14]([OH:17])=[O:16])([O:8][CH3:9])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1CC(C)(C)C1N(C)C
Product: COC(=O)CCC(C)(C)C=CC(=O)O

Procedure:
The process of claim 1 wherein methyl 3,3-dimethyl-2-dimethylaminocyclobutanecarboxylate is reacted with acetic anhydride to produce 6-carbomethoxy-4,4-dimethyl-2-hexenoic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([Br:18])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=[O:3])[CH3:2].CI.[C:34]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.[Cl-].[Na+].O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:34])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=3)=[C:17]([Br:18])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(Br)c2n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2c(c(Br)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Temperature: 85 °C
Yield: 96.5 %

Procedure:
To a solution of 3-(7-bromo-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (See Compound 36, Step 1, 25 mg, 0.050 mmol) in DMF (1 mL) was added CH3I (14.1 mg, 0.10 mmol) followed by K2CO3 (20.6 mg, 0.15 mmol). The reaction was heated at 85° C. for 1.5 h, cooled to RT then diluted with EA (10 mL) and brine (5 mL). The organic layer was washed with aq. 1N LiCl (3×20 mL), dried over Na2SO4 and concentrated to give 3-(7-bromo-1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (25 mg, 97.3% yield) as an oil. LCMS: MH+ 518 and TR=1.877 min. Used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]#[N:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:11][C:12](O)([CH2:14][CH:15]([OH:17])[CH3:16])[CH3:13]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[O:17][CH:15]([CH3:16])[CH2:14][C:12]([CH3:13])([CH3:11])[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CC1
Reactant: CC(O)CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C2=NC(C)(C)CC(C)O2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61730.3 %

Procedure:
To concentrated sulfuric acid (102 mL) was added 1-cyano-cyclopropanecarboxylic acid ethyl ester (60 g, 0.43 mol) dropwise followed by 2-methylpentan-2,4-diol (52 g, 0.44 mmol) dropwise at 0° C. The mixture was stirred for an additional 1 h at 0° C. then poured onto ice-water. The aqueous phase was washed with AcOEt (3×200 mL) and then basified to pH 12 with 10 M NaOH. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel to give 1-(4,4,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-cyclopropanecarboxylic acid ethyl ester (65 g, yield: 63.2%). 1H NMR (CDCl3 400 MHz): δ4.21-4.06 (m, 3H), 1.73-1.69 (m, 1H), 1.40-1.10 (m, 17H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1>[F:21][C:4]1[CH:3]=[C:2]([NH:30][C:27]2[N:26]=[CH:25][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:29][N:28]=2)[CH:7]=[CH:6][C:5]=1[C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Br)cc2F)C1
Reactant: Nc1ncc(C(F)(F)F)cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2F)C1
Temperature: 100 °C
Yield: 82.5 %

Procedure:
To a 25 ml glass vial was added (+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (300 mg, example 192(f)) and 5-trifluoromethyl-pyrimidin-2-ylamine (156 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (58.3 mg), tris(dibenzylideneacetone)dipalladium(0) (30.5 mg) and sodium tert-butoxide (89.8 mg) were then added. The vial was capped and heated at 100° C. for 2 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to afford (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (304 mg, 83%) as an amorphous yellow solid. MS (ISP): 441.2 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.FC1C=C(C=C(C(F)(F)F)C=1)[C:18]([N:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[O:35][CH3:36])C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)[C:5]([N:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[O:35][CH3:36])[CH3:18])=[O:7]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)cc(C2CC2)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(C2CC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 3-chloro-5-cyclopropylbenzoic acid and 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (0.18 g, 775 μmol, example 129, intermediate) after a reaction time of 41 hours at room temperature. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.012 g; 3%). MS (ESI): m/z=411.13 [M+H]+.