Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]4[CH:25]=[CH:24]C([N+]([O-])=O)=C[CH:21]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[O:29]1CC[C@H](O)C1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]4[CH2:25][CH2:24][O:29][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: O[C@H]1CCOC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 151.9 %

Procedure:
To 224 mg (0.50 mmol) of 4-nitrophenyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate dissolved in 18 mL of THF, was added (S)-tetrahydrofuran-3-ol (88 mg, 1.0 mmol), followed by 60% NaH (80 mg, 2.0 mmol) and stirred at RT for 2 hr. After 2 hr it was diluted with 30 mL of EtOAc and slowly quench with brine. The organic layer was dried over MgSO4 and concentrated, it was purified using a 40 g silica gel column eluting with 0-10% MeOH/DCM to obtain 301 mg (76% yield) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.01-2.13 (m, 1 H) 2.17-2.29 (m, 1 H) 3.57-3.70 (m, 4 H) 3.74-3.84 (m, 4 H) 3.86-4.01 (m, 4 H) 5.27-5.38 (m, 1 H) 6.37 (d, J=7.83 Hz, 1 H) 7.87 (s, 1 H) 8.28 (d, J=7.83 Hz, 1 H)
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([OH:13])[CH3:12]>>[C:5]1([N:4]2[CH:3]=[CH:2][CH:12]=[CH:11][O:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCNc1ccccc1
Reactant: CCO
Product: C1=CON(c2ccccc2)C=C1
Temperature: 80 °C

Procedure:
0.271 g of P-(2-phenyl-2-chloro acetyl) dimethylamino-benzene (1 mmole) and 0.274 g of N-(2 hydroxy ethyl) aniline (2.0 mmole) were dissolved in 3 ml of dry ethanol and heated in a sealed tube at 80° C. for 8 hours. On cooling the product crystallized out as pale yellow needles, which was filtered and dried to yield 0.2 g of N-phenyl oxazine Compound 15.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14](=[O:23])[NH2:15])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.56 mmol) in ethanol (15 ml) was added 2 ml 10 N aqueous sodium hydroxide. The resulting solution was warmed to reflux for 2 hours, cooled to room temperature, poured into 1 N aqueous hydrochloric acid, and extracted into ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Recovered yellow oil was purified by silica gel chromatography, eluting with dichloromethane-methanol (9.6:0.4) to give the title compound (306 mg, 58%). MS m/z: 339 (M+1)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:30]([O:29][C:27]([N:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14]1[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of ethyl (2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (5.45 g) in toluene (55 ml) was added 1-chloroethyl chloroformate (2.59 g) at room temperature and stirred at 20° C. for 1 hour. 1-Chloroethyl chloroformate (795 mg) and N,N-diisopropylethylamine (0.736 ml) was added to the mixture, and the solution was stirred at 20° C. for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH (70 ml). The mixture was stirred at 65° C. for 30 minutes, and concentrated under reduced pressure. The residue was poured into a mixture of aq NaHCO3 solution (80 ml) and dichloromethane (100 ml). The organic layer was separated and dried over sodium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography (silica gel 125 g, dichloromethane/MeOH (60/1 to 15/1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as oil (2.0 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:40][C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)[N:23]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:40]([C:41]3[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=3)=[O:9])[N:23]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C)cc3)n(Cc3ccccc3)c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C)cc3)n(Cc3ccccc3)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A solution of 1.08 g of 3-chloroperbenzoic acid (80%) in 100 ml of dichloromethane is added dropwise to a solution of 2.46 g of 4,5-bis(4-methoxyphenyl)-1-benzyl-2-(4-methylphenylthio)imidazole in 50 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with ethyl acetate/hexane 2:3, thus producing 2.17 g of 4,5-bis-(4-methoxyphenyl)-1-benzyl-2-(4-methylphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.C(O)(C)C.[N:16]#[C:17]Br.C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:16][C:17]1[N:7]2[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([O:10][CH3:11])[C:6]2=[N:8][N:9]=1
Reactant: COc1cnc(Cl)nc1NN
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cnc(Cl)n2c(N)nnc12
Temperature: 42 °C
Reaction time: 3.5 h
Yield: 173.2 %

Procedure:
A 5 liter (L) 3-neck round bottom flask with thermowell was fitted with a condenser/N2 inlet, mechanical stirrer and an addition funnel. The pot was charged with 2-chloro-4-hydrazino-5-methoxypyrimidine (136 g of 70.7 wt. %, 96 g active, 0.55 mol) and isopropyl alcohol (IPA; 1100 mL). Cyanogen bromide (185 g of 34.6 wt. % in CH3CN, 64 g active, 0.6 mol) was added rapidly causing a slow endotherm from 22 to 15° C. and then a slow exotherm to 27° C. During the exotherm the mixture goes through a very thick stage which lasts several minutes. The slurry was then warmed to 42° C. and held there for 3.5 h at which time high pressure liquid chromatography (HPLC) analysis indicated the reaction was complete. The slurry was cooled to room temperature and treated with a solution of Na2CO3 (64 g, 0.6 mol) in water (1100 mL) over a 30 minute (min) period causing the temperature to exotherm 4° C. The mixture was stirred at ambient temperature for 2 h and then the solid was collected by filtration. The filter cake was washed with water (400 mL) and then pressed as dry as possible under aspirator pressure. This provided the title compound (190.1 g of wet cake, 51 wt % by HPLC, 97 g active, 88%) as a brown solid. Drying a sample to a constant weight resulted in the following data: MS(GC, 70eV) 201(15%), 200 (30%), 199 (70%), 198 (100%); 1 H NMR (300 MHz, DMSO-d6) 3.92 (s, 3H), 6.51 (br s, 2H), 7.11 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:32]([F:31])=[CH:39][CH:38]=[CH:37][C:36]=3[F:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1cccc(F)c1CBr
Product: Cc1nc2c(ccn2Cc2c(F)cccc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,6-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.39 (m, 1 H), 7.34-7.28 (m, 1 H), 7.23-7.16 (m, 1 H), 7.11-7.06 (m, 1 H), 6.98-6.87 (m, 3 H), 6.22-6.16 (m, 1 H), 5.62-5.49 (m, 3 H), 4.31-4.24 (m, 2 H), 2.93-2.77 (m, 2 H), 2.73 (s, 3 H), 2.09-2.06 (m, 2 H), 1.00-0.93 (s, 9 H); LC/MS (m/z) ES+=521.36 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[O:15][CH3:16]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[CH:9][C:8]=1[O:15][CH3:16]
Reactant: [Li]CCCC
Reactant: COc1cc(C=O)ccc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(F)c(OC)c1
Temperature: -40 °C
Yield: 89.7 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (68.20 g, 0.191 mol) in anhydrous THF (400 mL) cooled to −40° C. was added n-butyllithium (2.5 M in hexanes, 71.2 mL, 0.178 mol) via syringe over 15 min, at which point the characteristic yellow color of the phosphorus ylide persisted. The reaction mixture was warmed to −10° C. over 1 h to complete the reaction. The mixture was subsequently cooled to −30° C. and a solution of 4-fluoro-3-methoxybenzaldehyde (10.00 g, 63.64 mmol) in anhydrous THF (40 mL) was added via a cannula over 10 min. The resultant mixture was warmed to ambient temperature over 16 h. The reaction was quenched by gradual addition of water (200 mL) and the aqueous extracted with diethyl ether (3×200 mL). The combined organic layers were washed with water (2×200 mL), brine (200 mL), dried (MgSO4) and concentrated under reduced pressure to give 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE II.1) (8.69 g, 57.1 mmol, 90%) as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25](Cl)=[CH:24][N:23]=3)=[C:17](OC)[CH:16]=2)(=[O:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH:44]([O-])=[O:45].[NH4+]>[Pd]>[CH3:44][O:45][C:15]1([P:11]2(=[O:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:16]=[CH:17][C:18]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:25]=[CH:24][N:23]=2)=[CH:19][CH2:20]1
Reactant: O=C[O-]
Reactant: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Agent: [Pd]
Agent: [NH4+]
Product: COC1(P2(=O)CCNCC2)C=CC(Nc2nccc(Nc3ccccc3S(=O)(=O)C(C)C)n2)=CC1
Yield: 42 %

Procedure:
A flask was charged with N2-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-chloro-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (40.0 mg, 0.0625 mmol) and 10% Pd—C (40.0 mg). The flask was evacuated and filled with nitrogen. Anhydrous methanol (2 mL) was added to the flask and the flask was equipped with a reflux condenser with a nitrogen inlet. Ammonium formate (31.5 mg, 0.500 mmol) was added in one portion at room temperature. The resulting mixture was stirred at reflux for 3 h. The reaction was filtered through a Celite pad and the Celite was washed with 2×5 mL methanol. The combined filtrate and washing was evaporated in vacuo. The crude residue was purified by prep-HPLC to afford the final compound (13.6 mg, 42% yield). MS/ES+: m/z=516.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12]([N:14]1[CH2:18][CH:17]([OH:19])[CH:16]([NH:20][C:21](OCC2C=CC=CC=2)=O)[CH2:15]1)=O)(C)(C)C>C1COCC1>[CH3:12][N:14]1[CH2:15][CH:16]([NH:20][CH3:21])[CH:17]([OH:19])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(NC(=O)OCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CN(C)CC1O
Temperature: 0 °C
Yield: 18 %

Procedure:
LAH (1.40 g, 35.0 mmol) is slowly added to a stirred solution of 3-benzyloxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in THF (15 ml) at room temperature. The reaction mixture is heated to reflux under N2 for 2 hours and then cooled to 0° C. The reaction mixture is quenched by the slow addition of Na2SO4.10H2O, warmed to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate is concentrated and purified on a silica gel column (10:1:0.5 methylene chloride, MeOH, 30% NH4OH solution) to yield 0.21 g (18% for two steps) 1-methyl-4-methylamino-pyrrolidin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]1[C:35]([Cl:45])=[CH:36][C:37]([F:44])=[C:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=1>CC(C)=O>[Cl:45][C:35]1[C:34]([CH2:33][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[CH:39][C:38]([S:40]([NH2:43])(=[O:41])=[O:42])=[C:37]([F:44])[CH:36]=1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: NS(=O)(=O)c1cc(CBr)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3cc(S(N)(=O)=O)c(F)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (0.94 g, 2.49 mmol) and K2CO3 in acetone (5 mL) was added 5-(bromomethyl)-4-chloro-2-fluorobenzenesulfonamide (0.83 g, 2.73 mmol). After stirring 3 h, the reaction mixture was filtered. The filtrate was concentrated and purified by chromatography (silica, EtOAc-Hex) to afford the title compound (1.21 g). 1H-NMR (DMSO-d6, 400 MHz) δ 7.81 (d, J=7.8 Hz, 1H), 7.77 (s, 2H), 7.70 (d, J=9.7 Hz, 1H), 7.22-7.19 (m, 1H), 7.16 (s, 1H), 7.01-6.97 (m, 2H), 6.56-6.49 (m, 4H), 4.26 (s, 2H), 3.64 (s, 3H), 1.46 (s, 6H); MS (EI) m/z 598 [M]+.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:5]2=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)CCC>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.O1CCOCC1>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[C:5]2[N:6]([C:2]([C:30]3[CH:35]=[N:34][CH:33]=[CH:32][N:31]=3)=[CH:3][N:4]=2)[N:7]=[CH:8][CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1ccncc1-c1ccnn2c(I)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1ccnn2c(-c3cnccn3)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A microwave vial was charged with a mixture of 3-iodo-8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, TFA (66 mg, 0.147 mmol), 2-(tributylstannyl)pyrazine (162 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol), and dioxane (4 mL) was stirred at RT for 5 min. under nitrogen. The resulting mixture was heated to 114° C. for 15 h in microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep. HPLC to give 18.2 mg (30%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.86 (1H, d, J=1.76 Hz), 8.97 (1H, s), 8.86 (2H, dd, J=16.12, 5.29 Hz), 8.66-8.79 (1H, m), 8.59 (1H, d, J=2.52 Hz), 8.56 (1H, s), 8.10 (1H, d, J=6.04 Hz), 7.54 (1H, d, J=4.78 Hz), 2.57 (3H, s); LC (Conditions B & C): >95% purity. LC/MS: Rt=1.05 min. LC/MS (Condition A): 289.12.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25]CC)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of the compound (3.96 g, 10.22 mmol) obtained in step 5 and 1N aqueous sodium hydroxide solution (15.33 mL, 15.33 mmol) in ethanol (50 mL) was stirred at room temperature for 2 hr. To the reaction mixture was further added 1N aqueous sodium hydroxide solution (5.0 mL, 5.0 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration, and crystallized from ethyl acetate and hexane to give 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (2.52 g, 7.01 mmol, 69%) as a pale-yellow powder.
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][N:7]=1>O1CCCC1.COCCOC>[Cl:5][C:6]1[NH:7][CH:8]([CH2:3][CH3:4])[C:9]([F:13])=[C:10]([Cl:12])[N:11]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCBr
Agent: [Mg]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCC1NC(Cl)=NC(Cl)=C1F

Procedure:
To magnesium turnings (4.27 g) in tetrahydrofuran (56 ml) was added a solution of bromoethane (19 g) in THF (19 ml) over 5 hours. To this slurry at 0° C. was added a solution of the product of part (i) (24 g) in 1,2-dimethoxyethane (70 ml) over 1 hour. The reaction was quenched at 10° C. using glacial acetic acid (10 g) to give a solution of the title compound which was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH:18]1[CH2:19][O:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: ClCC1CO1
Product: CC(C)(C)c1ccc(OCC2CO2)c(C(C)(C)C)c1

Procedure:
The title compound was prepared from 2,4-di-tert-butyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(=O)C4CC4)c23)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (145.7 mg, 0.365 mmol) in dimethylsulfoxide (3.0 mL) was added Dess-Martin reagent (170.4 mg, 0.402 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium thiosulfate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (137.0 mg, 0.345 mmol, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[C:26]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]1)=[O:14])=[CH:7]2)([O-])=O>CN(C)C=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[C:26]([NH:27][C:28]([CH3:31])([CH3:32])[CH2:29][CH3:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]1)=[O:14])=[CH:7]2
Reactant: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reaction time: 4 h

Procedure:
To a solution of 1-[5-nitroindole-2-carbonyl]-4-[3-(1,1-dimethylpropylamino)-2-pyridinyl]piperazine (PREPARATION 67, 1.00 g) in dimethylformamide/methanol (200 ml, 50/50) under nitrogen is added palladium on carbon (10%, 250 mg). The mixture is put under hydrogen (balloon) for 4 hr and nitrogen for 17 hr, filtered through a pad of celite, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 9.25, 7.66, 7.24, 7.06, 6.88, 6.76, 6.63, 4.58, 4.05, 3.35, 3.14, 1.73, 1.35 and 0.91.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N(C(=O)COCCCCO)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(CCOCCCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 2-(4-hydroxybut-1-oxy)acetamide (4.7 g, 13 mmol) in THF (30 mL) was slowly added 1 M lithium aluminum hydride in THF (20 mL, 19.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and then quenched by slow addition of 15% aqueous sodium hydroxide at 0° C. until no gas formation was observed. After stirring for 10 minutes at room temperature, a solid formed and the reaction mixture was filtered and the precipitate washed with THF three times. The filtrate was then concentrated and the residue was dissolved in dichloromethane and this solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 3.71 g of the title intermediate (82% yield).