Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11]([CH3:14])([CH3:12])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(C)(O)CCCc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CCCc2cc(Br)ccc21
Reaction time: 2.5 h

Procedure:
15.0 g (58.3 mmol) of 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) was cooled to 0° C. and then 2.8 ml of conc. H2SO4 was added. The mixture was stirred for 2.5 hours, diluted with water (20 ml) and extracted with Et2O (3×40 ml). The combined organic layers were washed with water, sat. aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. Purification by Kugelrohr distillation gave the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH2:13][F:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:11][C:10](=[O:12])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:15])[CH2:13][F:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(CF)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(CF)C(=O)OC(C)(C)C
Yield: 106.3 %

Procedure:
The N-Boc acid 2 (767 mg, 3.46 mmol) in 10 mL of dry CH2Cl2 was stirred overnight with 3 eq of tert-butyl-2,2,2-tricholoracetimdate (2.27 g). After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (5% EtOAc in hexane) to provide 3 (510 mg, 53%) as a white solid: mp 41-42 EC (EtOAc/hexane); 1H NMR (CDCl3) δ 1.44 (9H, s), 1.47 (3H, d, J=2.4), 1.48 (9H, s), 4.57-4.85 (2H, m), 5.34 (1H, broad s). Anal. (C13H24FNO4) C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[N:18][CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)nc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and ethyl 6-chloro-nicotinate. MS (ESI) 352.4 (M+H)+.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[C:17](=[O:25])[C:16]([C:26]([OH:28])=[O:27])=[CH:15]1>N1C=CC=CC=1>[CH:1]([O:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[C:17](=[O:25])[C:16]([C:26]([OH:28])=[O:27])=[CH:15]1)=[O:2]
Reactant: O=CO
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Temperature: 25 °C

Procedure:
Formic acid (1.1 ml) was added to acetic anhydride (2.2 ml) which was cooled to 0°-5°. The mixture was heated at 50° for 15 minutes, cooled to 0° and added to 1,4-dihydro-1(2-hydroxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.5 g) in pyridine (12 ml), also cooled to 0°. The mixture warmed to room temperature and after 1 hour the solid was collected, washed with pyridine and dried, m.p. 213°-214° (85%).
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[C:15]([O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(OC(=O)C)(=O)C>>[C:15]([O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[CH:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:31][CH:32]=2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(C=O)cc2)cc1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)c2ccc(C=Cc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (376 mg) and 4-(4-acetoxybenzoyl)benzaldehyde (537 mg) was added acetic anhydride (0.5 ml) and the mixture was stirred at 140° C for 2 hours. This reaction mixture was concentrated and the residue was washed with n-hexane-diethyl ether and dried to provide 653 mg of yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1.[ClH:44]>O1CCOCC1>[ClH:44].[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCNCC4)cc3)cc12
Yield: 23.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (80 mg, 0.137 mmol) was deprotected in dioxane (1 ml), HCl in dioxane (3 ml). This afforded 5 mg (23.5% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 9.14-9.0 (b, 1H), 8.54 (d, 1H), 7.92 (s, 1H), 7.63-7.60 (s 2H), 7.54-7.53 (s, 1H), 7.5 (m, 1H), 7.10-7.04 (m, 5H), 5.34 (s, 2H), 3.41 (m, 4H), 3.25 (m, 4H), 2.17-2.14 (d, 4H). MS: m/z=481.2 (M+1), HPLC: 90.3% in Method B.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][CH2:32][CH2:33][CH:34]=O.C([BH3-])#N.[Na+].Cl>CO.C(OCC)C>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:31][CH2:32][CH2:33][CH3:34])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.7 g, 1.7 mmol) was dissolved in dry methanol. Butyric aldehyde (0.153 ml, 1.7 mmol) and sodium cyanoborohydride (0.107 g, 1.7 mmol) was added. A solution of anhydrous hydrogen chloride in diethylether (2 M) was added dropwise until pH 6. The resulting mixture was stirred for 24 hours at room temperature under a nitrogen atmosphere and evaporated in vacuo. Addition of 1M sodium hydroxide (50 ml), extraction of the product with diethylether (2×50 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo gave the title compound as a crude oil (0.644 g). Purification of the crude product on a silica gel column (Eluent: methylene chloride/methanol (19:1)) afforded (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-butylpyrrolidine (0.243 g, yield: 30%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[CH:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (19 mg, 9%). MS (ISP) 447.9 [(M+H)+]; mp 177° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Nc3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Nc3ccccc3)[C@H]1S2
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(3-phenylureido)penam-3-carboxylate (1.12 g.) in dimethylformamide (7.5 ml.) were added acetic acid (2.3 ml.) and then zinc powder (1.8 g.) under ice-cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 and residue obtained by distilling off ethyl acetate was crystallized by adding a small amount of acetonitrile to give colorless crystals of 2-methyl-2,3-methylene-6-(3-phenylureido)penam-3-carboxylic acid (0.72 g.), mp 108° to 110°C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH2:12])=O)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>N1C=CC=CC=1>[C:1]([O:4][CH:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][NH:9][C:10]#[N:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCNC(N)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(CCCNC#N)OC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4-acetoxynonylurea (2.4 g., 0.01 mole) in pyridine (10 ml.) is added p-toluene-sulfonyl chloride (2.0 g., excess) in one portion. The reaction is stirred at room temperature for six hours then poured into water (150 ml.). The aqueous mixture is extracted with ether (3 × 75 ml.), the ether is washed with 5% hydrochloric acid, brine, and dried over sodium sulfate. The solvent is removed in vacuo to give 4-acetoxynonylcyanamide as a residual oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C)nc(Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Oc2ccc(N)cc2)n1
Yield: 94.8 %

Procedure:
24.5 g (0.1 mole) of 2-(4-nitro-phenoxy)-4,6-dimethyl-pyrimidine were dissolved in 150 ml of dioxane and subjected to exhaustive hydrogenation with hydrogen in the presence of Raney nickel under a pressure of 50 bar at a temperature between 20° and 50° C. The catalyst was then filtered off with suction and the filtrate was evaporated under reduced pressure. 20.4 g (95% of theory) of 2-(4-amino-phenoxy)-4,6-dimethylpyrimidine were obtained in the form of a solid substance.
Reaction SMILES: [C:1]([C:3]([CH3:14])([CH3:13])[CH:4]([NH:6][S@@](C(C)(C)C)=O)[CH3:5])#[N:2].[ClH:15]>CO>[ClH:15].[NH2:6][C@@H:4]([CH3:5])[C:3]([CH3:14])([CH3:13])[C:1]#[N:2]
Reactant: CC(N[S@](=O)C(C)(C)C)C(C)(C)C#N
Agent: Cl
Solvent: CO
Product: C[C@H](N)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
(R)-2-Methyl-propane-2-sulfinic acid (2-cyano-1,2,2-trimethyl-ethyl)-amide (2.93 g, 13.6 mmol) was dissolved in MeOH and HCl (4.0 M in 1,4-dioxane, 6.8 mL, 27.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then concentrated to give 1.90 g (94%) of (S)-3-amino-2,2-dimethyl-butyronitrile hydrochloride as a white solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].[CH2:15]=[O:16]>C(#N)C>[CH:15]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:16]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
Methyl 4-hydroxybenzoate (3.00 g, 19.7 mmol) and magnesium chloride (2.81 g, 29.5 mmol) were stirred in 100 mL of acetonitrile. TEA (10.3 mL, 73.9 mmol) was added via syringe. Paraformaldehyde (12.0 g, 133 mmol) was added in a single portion and the reaction was heated to reflux. The reaction was stirred at reflux for 24 hours and cooled to rt. The reaction was quenched by the addition of approximately 100 mL of 1N HCl and poured into EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 2.06 g (58%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 10.27 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.03 (dd, J=8.8, 2.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 3.79 (s, 3H).
Reaction SMILES: CC1C=C2C(=CC=1C)C(=O)CC2.[Br:13]C1CC2C(=CC(C)=C(C)C=2)C1=O.C(N)(=S)C.Br.[CH3:31][C:32]1[S:33][CH:34]2[CH2:43][C:42]3[CH:41]=[C:40]([CH3:44])[C:39]([CH3:45])=[CH:38][C:37]=3[C:35]2(O)[N:36]=1>CC(C)=O.C(O)(=O)C>[BrH:13].[CH3:31][C:32]1[S:33][C:34]2[CH2:43][C:42]3[CH:41]=[C:40]([CH3:44])[C:39]([CH3:45])=[CH:38][C:37]=3[C:35]=2[N:36]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)C2
Reactant: CC1=NC2(O)c3cc(C)c(C)cc3CC2S1
Agent: Br
Agent: CC(N)=S
Agent: Cc1cc2c(cc1C)C(=O)CC2
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1nc2c(s1)Cc1cc(C)c(C)cc1-2

Procedure:
5,6-Dimethylindan-1-one is converted as described above for the other indan-1-ones into 2-bromo-5,6-dimethylindan-1-one. This is reacted with an equivalent amount of thioacetamide in acetone. The precipitate consisting of the hydrobromide of 2,5,6-trimethyl-8,8a-dihydroindeno-[1,2-d]thiazol-3a-ol is heated in glacial acetic acid and affords, after removal of the solvent and treatment with diisopropyl ether, 2,5,6-trimethyl-8H-indeno[1,2-d]thiazole hydrobromide with a melting point of 290° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](OCC)=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[S:4][N:3]=1.O1CCCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[S:4][N:3]=1
Reactant: CCOC(=O)c1c(Cl)nsc1-c1ccccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1snc(Cl)c1CO
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 3-chloro-5-(2-methylphenyl)-1,2-thiazole-4-carboxylate (730 mg, 2.59 mmol, 1.00 equiv), tetrahydrofuran (10 mg, 0.14 mmol, 0.05 equiv). This was followed by the addition of LiAlH4 (296 mg, 7.80 mmol, 3.01 equiv), in portions at 0° C. The resulting solution was stirred for 2 h at 30° C. The reaction was then quenched by the addition of 1.5 g of ice/salt. The solids were filtered out. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (25:75). This resulted in 260 mg (42%) of [3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methanol as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C11H10ClNOS, 240.0 (M+H). found 240.0.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[S:13][C:14]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=O)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=2)=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[N:16]=1.O>O1CCCC1>[NH2:11][C:12]1[S:13][C:14]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=2)=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[N:16]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(NCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Aluminum lithium hydride (0.16 g, 4.1 mmol) was added to a suspension of aluminum chloride (0.55 g, 4.1 mmol) in anhydrous tetrahydrofuran (30 mL) and the mixture was stirred at room temperature for 15 minutes. A solution of N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.40 g, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the mixture and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain 0.20 g (0.51 mmol, yield 51%) of the title compound.
Reaction SMILES: [CH2:1]([C:7]1[S:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[CH:13]=2)=[N:10][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)CCC>[CH2:1]([C:7]1[S:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:18]=3)[CH:13]=2)=[N:10][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nnc(-c2ccc3cc(O)ccc3c2)s1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCOc1ccc2cc(-c3nnc(CCCCCC)s3)ccc2c1
Yield: 35.5 %

Procedure:
In a 50 ml-round-bottomed flask, 0.60 g (1.92 mM) of 2-hexyl-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole prepared in Step ii) of Example 24, 0.18 g (2.73 mM) of potassium hydroxide and 15 ml of butanol were placed and dissolved under heating. To the mixture, 0.53 g (2.50 mM) of hexyl iodide was added at about 100° C. under stirring, followed by refluxing for 6 hours under stirring. After the reaction, butanol was distilled off under reduced pressure, and water and ethyl acetate were added to the residue, followed by stirring. The resultant organic layer was washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a solid. The solid was purified by silica gel column chromatography (eluent: benzene) and recrystallized from a mixture solvent (ethyl acetate-ethanol) to obtain 0.27 g of 2-hexyl-5-(6-hexyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 35.5 %). ##STR141##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1

Procedure:
4-Bromo-1-fluoro-2-nitro-benzene (5 gms.), 3.85 gms. 3-methoxyphenylboronic acid and 22 mL of a 2M aqueous solution of sodium carbonate are suspended in 100 mL of a 1:1 (v:v) mix of toluene and ethanol. The resulting suspension is then treated with 0.8 gms. tetrakis(triphenylphosphine)palladium (0) at room temperature. The reaction mixture is then heated at reflux for 12 h. The reaction mixture is subsequently concentrated in vacuo, and the resulting residue is taken up in ethyl acetate (200 mL). The ethyl acetate solution is then washed successively with water (2×200 mL), and brine (2×200 mL). The organic layer is then dried by filtering through phase separator paper and concentrated in vacuo to yield 7.19 gms. of crude product. The crude product is then recrystallized from hot ethanol yielding 4-fluoro-3′-methoxy-3-nitro-biphenyl as a yellow-white solid in the amount of 4.767 gms.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:28](C)=[CH:27][S:26][C:25]=2[C:30]([NH:32][CH3:33])=[O:31])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:28]=[CH:27][S:26][C:25]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)NC3(C)C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1826d, 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one and 3-(2,5-dichloropyrimidin-4-ylamino)-N,4-dimethylthiophene-2-carboxamide were converted to 3-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N-methylthiophene-2-carboxamide, TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.2 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 7.25 (d, 1H), 7.1 (dd, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.6 (m, 2H), 2.1 (s, 3H) 1.7 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:26][C@H:27]1[C:35]2[C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=[N:31][C:30]=2[C@H:29]([OH:42])[CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:14]([N:39]2[CH2:40][CH2:41][N:36]([C:34]3[C:35]4[C@H:27]([CH3:26])[CH2:28][C@@H:29]([OH:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:37][CH2:38]2)=[O:15])=[CH:22][CH:21]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c21
Yield: 88.6 %

Procedure:
(S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.1765 g, 0.5194 mmol) was combined with (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1596 g, 0.5194 mmol) and then slurried in methylene chloride (4.5 mL). The suspension was treated with diisopropylethylamine (0.2714 mL, 1.558 mmol) then with HBTU (0.1970 g, 0.5194 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with 10% Na2CO3 and then separated. The aqueous portion was washed twice with dichloromethane. The combined organic portions were dried with Na2SO4 and concentrated in vacuo. The residue was subjected to chromatography on SiO2 eluting with 4% MeOH/dichloromethane to yield (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (0.256 g, 89%). MS (ESI+) [M+H] 556.1/558.1.