Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][C:18](=[O:20])[CH3:19])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2',5-dichlorobenzophenone, acetyl chloride and pyridine were reacted in ether to give 2'-(o-chlorobenzoyl)-4'-chloroacetanilide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:14]([CH3:16])[NH2:15])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18]>Cl.CO>[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:15][N:14]([C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)[CH3:16])=[CH:21][CH:20]=1)#[N:18]
Reactant: Cc1nc(N(C)N)nnc1-c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Product: Cc1nc(N(C)N=Cc2ccc(C#N)cc2)nnc1-c1ccccc1
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
6N-Hydrochloric acid (1 drop) was added to a stirred solution of 5-methyl-3-(1-methylhydrazino)-6-phenyl-1,2,4-triazine (0.71 g) and 4-cyanobenzaldehyde (0.44 g) in methanol (5 ml) at room temperature and then the stirring was continued for 5 minutes. The mixture was evaporated under reduced pressure, the residue was triturated with diethyl ether, and the precipitates were collected by filtration to give 3-[2-(4-cyanobenzylidene)-1-methylhydrazino]-5-methyl-6phenyl-1,2,4-triazine (0.95 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(Br)cc1
Yield: 102.3 %

Procedure:
A solution of 20.02 g of 4-bromophenol (0.116 mol) in 100 mL of dry THF was treated with 15.0 mL of pivaloyl chloride (0.126 mol), followed by 35.5 mL of triethylamine (0.255 mol). A large amount of white solid precipitated so 50 mL of additional THF was added to the mixture to afford a free-flowing slurry. The reaction mixture was filtered and the precipitate was washed with 200 mL THF and then discarded. The filtrate was concentrated in vacuo to a liquid which solidified when dried under reduced pressure to yield 30.5 g (100%) of 4-bromophenyl pivalate.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[CH3:9].C(O[C@@H]1CCNC[C@H]1C)(=O)C(C)(C)C>>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[CH3:9]
Reactant: CO[C@H]1CCNC[C@@H]1C
Agent: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C
Product: CO[C@@H]1CCNC[C@H]1C

Procedure:
The same procedures employed to synthesize (3S,4S)-4-methoxy-3-methylpiperidine Examples 9-C were utilized, however the starting material used was (3R,4R)-3-methylpiperidin-4-yl pivalate (CAS#863249-35-8, prepared as described in WO 2005077932). 1H NMR (400 MHz, CD2Cl2) δ ppm 0.92 (d, J=6.6 Hz, 3 H) 1.22 (tdd, J=12.3, 12.3, 10.4, 4.3 Hz, 1 H) 1.39-1.55 (m, 1 H) 2.04 (dq, J=12.4, 3.5 Hz, 1 H) 2.23 (dd, J=12.6, 10.6 Hz, 1 H) 2.55 (td, J=12.4, 2.8 Hz, 1 H) 2.75 (td, J=9.7, 4.2 Hz, 1 H) 2.96 (ddd, J=12.6, 4.2, 1.4 Hz, 1 H) 3.02-3.11 (m, 1 H) 3.31 (s, 3 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl.O>[N:11]1([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O[C@H]1CCCC[C@@H]1N1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCCC1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.8 %

Procedure:
To a chilled (−70° C.) solution of oxalyl chloride (20 mL, 0.23 mol) in dichloromethane (500 mL) was added dropwise a solution of anhydrous dimethylsulfoxide (34 mL, 0.48 mol) in dichloromethane (50 mL) and the resulting mixture was stirred for 5 min. at a temperature below −60° C. Then a solution of (1R,2R)/(1S,2S)-2-(4-morpholinyl)cyclohexanol (37.05 g, 0.2 mol) in dichloromethane (50 mL) was added dropwise in order to maintain the reaction temperature below −60° C. and the reaction mixture was stirred for 15 min. Triethylamine (140 mL) was added dropwise to the reaction mixture, keeping the reaction temperature below −50° C., and then the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured into water (600 mL) and the aqueous layer was separated and extracted with dichloromethane (2×500 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. Vacuum distillation yielded 35.1 g (96% yield) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH:20]([CH3:22])[CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Br[C:33]1[S:34][C:35]2[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:33]3[S:34][C:35]4[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:15][C@H:14]2[O:19][CH:20]([CH3:21])[CH3:22])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC(C)C)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC(C)C)C3)sc12
Yield: 63 %

Procedure:
The same operation as in Example (1h) was performed using cis(±)-4-chloro-N-(3-isopropoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (148a) (0.150 g, 0.427 mmol), diisopropylethylamine (0.186 mL, 1.07 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (0.147 g, 0.514 mmol), to obtain 0.140 g of the title compound as a yellow foamy solid (63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCC1C=C[C:30]([S:33](C)(=[O:35])=[O:34])=CC=1>>[CH3:20][O:19][C:18]1[C:17]2[N:16]=[C:15]([NH2:21])[N:14]3[CH2:22][CH2:23][N:24]=[C:13]3[C:12]=2[CH:11]=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:33]([CH3:30])(=[O:35])=[O:34])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bistrifluoroacetate salt (Intermediate A) and 1-(chloromethyl)-4-(methylsulfonyl)benzene. High vacuum drying gave the title compound (970 mg, 56%): HPLC MS RT=1.59 min, MH+=401.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.21 (3H, s), 3.85 (3H, s), 4.16-4.19 (2H, m), 4.32-4.35 (2H, m), 5.47 (2H, s), 7.36 (1H, d), 7.74 (2H, d), 7.88 (1H, d), 7.97 (2H, d).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.[CH3:24][N:25](C)C=O.O.[C-]#N.[Na+]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:24]#[N:25])[CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CN1CCC(=C2c3ccccc3CCc3ccc(Br)cc32)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC(=C2c3ccccc3CCc3ccc(C#N)cc32)CC1

Procedure:
A mixture of 9.17 gm. (0.0249 mol) of 1-methyl-4-(3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4.58 gm. (0.0498 mol) of cuprous cyanide, and 30 ml. of dry dimethylformamide is stirred and heated under reflux for 6.5 hr. To the cooled solution (25° C.) is added 54 ml. of water, 27 ml. of a saturated aqueous solution of sodium cyanide, and 75 ml. of benzene. The mixture is stirred until a two phase system is obtained. The benzene phase is removed and the aqueous phase is extracted with two 75 ml. portions of benzene. The combined benzene phases are washed with 100 ml. of aqueous 0.1M sodium cyanide, three 100 ml. portions of water, and dried over magnesium sulfate. After filtering, evaporation of the benzene gives 7.40 gm. of a crystalline residue. This material is dissolved in the minimum volume of chloroform and passed over an alumina column (15" × 1") packed in chloroform. The column is eluted with chloroform. Evaporation of the chloroform gives a crystalline product that is recrystallized from isopropyl alcohol to give pure 1-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ylidene)piperidine, m.p. 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]([CH3:31])([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[NH2:25]>>[CH3:23][C:24]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:20][C:19]([F:21])([F:22])[CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:15])([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[CH3:31]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140 a) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=449.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1C(C)CC(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(=O)O)[C@@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1O[C@@H](CCCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.5 %

Procedure:
To an ice bath cooled solution of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)butanoic acid (5.2 g, 10.3 mmol) in anhydrous THF (100 mL) was added slowly borane-tetrahydrofuran complex (12.3 mL of a 1M soln in THF, 12.3 mmol) and the resulting mixture allowed to warm to room temperature and stirred for 3 days. Mixture quenched by the addition of methanol (5 mL) and diluted with sat. NaCl (200 mL) and extracted with EtOAc (2×150 mL); combined EtOAc layers dried over Na2SO4, filtered and evaporated. Residue purified by silca gel column chromatography (Teledyne Isco: 120 g) eluent: gradient 0-100% EtOAc in Hexanes to give the title compound (1.73 g, 34%) as a clear oil. 1H NMR (CDCl3) δ 7.40-7.28 (15H, m), 4.79 (2H, m), 4.71 (1H, d, J=12.1 Hz), 4.66 (2H, m), 4.54 (1H, d, J=11.9 Hz), 3.99 (1H, m), 3.93 (1H, m), 3.80 (3H, m), 3.65 (2H, t, J=6.5 Hz), 1.67 (2H, m), 1.60-1.41 (4H, m), 1.30 (3H, d, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:1]=[CH:23][C:21]2[O:22][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:25])([F:10])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Product: Oc1ccc(Cl)cc1N=Cc1ccc(-c2ccccc2C(F)(F)F)o1

Procedure:
Using 2-amino-4-chlorophenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.76 g of 4-chloro-2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 86%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].C([Si](C)(C)[O:27][C@H:28]1[CH2:33][C@H:32]([O:34][Si](C(C)(C)C)(C)C)[CH2:31]/[C:30](=[CH:42]/[CH:43]=[CH:44]/[CH2:45][CH2:46][CH2:47][C:48]([CH3:63])([CH3:62])[CH2:49]/[CH:50]=[CH:51]/[C:52]([C:58]([F:61])([F:60])[F:59])([OH:57])[C:53]([F:56])([F:55])[F:54])/[C:29]1=[CH2:64])(C)(C)C>O1CCCC1>[F:54][C:53]([F:55])([F:56])[C:52]([C:58]([F:59])([F:60])[F:61])([OH:57])/[CH:51]=[CH:50]/[CH2:49][C:48]([CH3:63])([CH3:62])[CH2:47][CH2:46][CH2:45]/[CH:44]=[CH:43]/[CH:42]=[C:30]1\[C:29](=[CH2:64])[C@@H:28]([OH:27])[CH2:33][C@H:32]([OH:34])[CH2:31]\1
Reactant: C=C1/C(=C\C=C\CCCC(C)(C)C/C=C/C(O)(C(F)(F)F)C(F)(F)F)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1/C(=C\C=C\CCCC(C)(C)C/C=C/C(O)(C(F)(F)F)C(F)(F)F)C[C@@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
0.83 g of tetrabutylammoniumfluoride trihydrate (2.60 mmol) in 3.5 ml of tetrahydrofuran was carefully dried by stirring during 2 h at room temperature over 1.05 g of 3 Å molecular sieve. This solution was then added to the above prepared 151 mg of (3E,10E)-12-[(Z)-(3S,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene-cyclohexylidene]-1,1,1-trifluoro-6,6-dimethyl-2-trifluoromethyl-dodeca-3,10-dien-2-ol and kept for 1.5 h at 45°. The reaction mixture was then poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/ethylacetate=4/6) yielded 76 mg of the title compound as colourless oil.
Reaction SMILES: C(C1C=C2C(=CC=1)/C(=[N:12]/[OH:13])/CC2)=C.[I:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH2:20][CH2:19][CH2:18]2>>[I:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)/[C:21](=[N:12]/[OH:13])/[CH2:20][CH2:19][CH2:18]2
Reactant: C=Cc1ccc2c(c1)CC/C2=N\O
Reactant: O=C1CCCc2cc(I)ccc21
Product: O/N=C1\CCCc2cc(I)ccc21

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 87B employing 6-iodo-3,4-dihydronaphthalen-1(2H)-one as a starting material. The compound had an HPLC retention time=3.28 min. (condition C); LC/MS M+1=288.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:19](NC1C=CC(N)=CN=1)(=[O:21])[CH3:20]>C(O)C>[CH2:19]([O:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1)[CH3:20]
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CC(=O)Nc1ccc(N)cn1
Solvent: CCO
Product: CCOC1=C/C(=C2/C(=O)NN=C2C)Nc2ccccc21
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one (0.033 g, 0.13 mmol) and 2-acetamido-5-aminopyridine (Matrix) (0.058 g, 0.38 mmol) were dissolved in ethanol (1.5 mL). The reaction mixture was heated to 180° C. using a microwave reactor for 6 hrs. The mixture was concentrated and purified by LC-MS to give the title compounds of Example 4 and Example 5.
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[CH2:8][CH:7]([CH2:9]O)[CH2:6]1)([CH3:4])[CH3:3].S(Cl)([Cl:13])=O>ClCCl>[ClH:13].[Cl:1][CH2:9][CH:7]1[CH2:8][N:5]([CH:2]([CH3:4])[CH3:3])[CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N1CC(CO)C1
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CC(CCl)C1
Temperature: 0 °C

Procedure:
(1-isopropylazetidin-3-yl)methanol hydrochloride (2.6 g, 15.7 mmol) was dissolved in dichloromethane (50 ml) and cooled to 0° C. Thionyl chloride (1.4 ml, 19.2 mmol) was added dropwise over 5 min. The reaction mixture was then stirred whilst warming to ambient temperature. Stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (40 ml) to give the title compound as a beige hygroscopic powder (2.8 g, 99%). LRMS ESI+ m/z 148/150 [M+H]+ (CI isotopes).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17]CC3C=CC=CC=3)[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2ccc(O)cc2o1
Yield: 97.3 %

Procedure:
A solution of 6-benzyloxy-benzofuran-2-carboxylic acid tert-butyl ester (5.68 g, 17.5 mmol) in THF (50 mL) and MeOH (20 mL) is added to Pd/C (5%, 200 mg). The mixture is stirred under a balloon of hydrogen for 16 hours at room temperature. The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (3.99 g, 97%). LC-ES/MS m/e 233.0 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[C:5]([N+:13]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16]>C(O)C.[Pd]>[NH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:16])[N:2]([CH3:1])[C:10]2([CH3:12])[CH3:11]
Reactant: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)c2c(N)cccc2C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
20 mg of 5% Pd/C was cautiously added to a solution of 2,3,3-trimethyl-7-nitroisoindolin-1-one (Compound 148B, 0.15 g, 0.68 mmol) in ethanol (5 mL), and stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture was and concentrated to remove ethanol to provide 80 mg of pure the title compound (62%). 1H NMR (CDCl3, 500 MHz): δ 1.36 (s, 6H), 3.58 (s, 3H), 3.60 (brs, 2H), 6.58 (d, J=8.0 Hz, 1H), 6.69 (d, J=7.0 Hz, 1H), 6.84 (dd, J=7.0, 8.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10]([OH:12])=O)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:27][CH:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>C(Cl)Cl.CN(C=O)C.O>[CH3:27][CH:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:10]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:12]
Reactant: COC(=O)C1(C(=O)O)CCCC1
Reactant: CC(C)CCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C1(C(=O)NCCC(C)C)CCCC1
Reaction time: 0.17 h

Procedure:
To 1-(methoxycarbonyl)cyclopentanecarboxylic acid (630 mg, 3.7 mmol) in CH2Cl2/DMF (5:1, 37 mL) at 0° C. was added HOBT (730 mg, 4.8 mmol) and EDC (920 mg, 4.8 mmol). The mixture was stirred for 10 min then 3-methylbutylamine (640 mg, 7.4 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid (800 mg, 90%). MS [M+H]+ 243.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([Cl:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[CH2:22]([Mg]Br)[CH3:23]>>[Cl:18][C:16]1[C:15]2[CH2:14][CH2:13][CH:12]([CH2:22][CH3:23])[C:11]=2[C:10]2[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=2[CH:17]=1
Reactant: CCOC(=O)N1CCc2cc(Cl)c3c(c2CC1)C(=O)CC3
Reactant: CC[Mg]Br
Product: CCC1CCc2c(Cl)cc3c(c21)CCNCC3

Procedure:
Example 6 was prepared in a similar fashion to Example 4, except Intermediate 4 was used as the starting material and ethylmagnesium bromide (3M in diethyl ether) was used instead of cyclopropylmagnesium bromide (Example 4, step (a)). 1H NMR (300 MHz, CDCl3) δ 6.92 (s, 1H); 3.16-3.09 (m, 1H); 2.98-2.84 (m, 10H); 2.37-2.32 (br s, 1H); 2.17-1.94 (m, 2H); 1.47-1.25 (m, 2H); 0.95 (t, J=7.5 Hz, 3H); MS: ESI (positive): 250, (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
Indole-5-carboxylic acid (5.02 g, 31.3 mmol) in tetrahydrofuran (40 mL) was added slowly to the lithium aluminium hydride (1.88 g, 49.5 mmol) stirred in tetrahydrofuran (125 mL) under nitrogen with external heating so as to maintain a gently reflux. The mixture was heated at reflux for 2 hours and cooled to room temperature. 2 N sodium hydroxide (10 mL) was then added dropwise to the reaction mixture. The precipitate was removed by filtration and the filtrate was concentrated. It was dissolved in dichloromethane (80 mL), washed with 2 N sodium hydroxide (10 mL), water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give about 5 g of (1H-indol-5-yl)-methanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[O:13])[S:8][C:6]=2[N:7]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:5]3[N:10]=[C:9]([CH2:11][C:12]([N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:21])[CH3:22])[CH2:16][CH2:15]4)=[O:13])[S:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CC(C)(O)C1CCN(C(=O)Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC(=O)N3CCC(C(C)(C)O)CC3)sc2n1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
A mixture of 2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-[4-(1-hydroxy-1-methylethyl)piperidin-1-yl]ethanone (40 mg, 0.09 mmol), 2-ethylbenzimidazole (15 mg, 0.10 mmol), Pd2(dba)3 (2.1 mg, 2.5 mol %), Xphos (4.3 mg, 10 mol %) and Cs2CO3 (44 mg, 0.14 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 20 h, in a sealed tube. The reaction mixture diluted with EtOAc, filtered through Celite® and evaporated. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give 549 as a pale beige solid (19 mg, 38%). LCMS (Method I): RT=3.47 min, [M+H]+ 550.2. 1H NMR (400 MHz, CHCl3-d): δ 8.02-7.98 (m, 1 H), 7.81-7.76 (m, 1 H), 7.33-7.29 (m, 2 H), 4.81-4.75 (m, 1 H), 4.52-4.29 (m, 4 H), 4.19 (s, 2 H), 4.07 (m, 1 H), 3.89-3.84 (m, 4 H), 3.38 (q, J=7.5 Hz, 2 H), 3.15-3.06 (m, 1 H), 2.63-2.54 (m, 1 H), 1.90-1.92 (m, 2 H), 1.92-1.80 (m, 2 H), 1.61-1.50 (m, 1 H), 1.44 (t, J=7.5 Hz, 3 H), 1.36-1.23 (m, 1 H), 1.20 (d, J=11.0 Hz, 6 H)