Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[N:16]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)nc(NC(C)C)c1[N+](=O)[O-]
Yield: 86.8 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylpyrimidine (10.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (10.2 g) in a yield of 86.8%. 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 4.48 (m, J=4.1, 1H), 2.72 (s, 3H), 1.32 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:30]1[CH2:36][CH2:35][CH2:34][NH+:33]([CH2:37][B-](F)(F)F)[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:37][N:33]5[CH2:34][CH2:35][CH2:36][O:30][CH2:31][CH2:32]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)C[NH+]1CCCOCC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCCOCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and ([1,4]oxazepanium-4-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.94 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5](=[N:7][OH:8])[NH2:6].Cl.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.N>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1ccc(F)c(F)c1
Agent: Cl
Agent: N
Product: Fc1ccc(-c2noc(-c3cccnc3)n2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 1 using 3,4-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J=7.5, 4.4 Hz, 1 H), 8.60 (dt, J=7.8, 2.1 Hz, 1 H), 8.93 (dd, J=4.8, 1.6 Hz, 1 H), 9.38 (dd, J=2.2, 1.0 Hz, 1 H), 9.44-9.48 (m, 3 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Si:13]([CH3:15])([CH3:14])[CH3:16])=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)c1cc(N)ccc1[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc(NC(=O)c2ccccc2)ccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the compound of Example 217 (0.118 g, 0.5 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.14 mL, 1.0 mmol), benzoyl chloride (70 L, 0.6 mmol) and 4-dimethylaminopyridine (12 mg). The reaction was stirred at RT for 16 h, diluted with water, and extracted with ethyl acetate. The extracts were washed with 0.04 N HCl, sat NaHCO3, brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by recrystallization from ethyl acetate/hexanes to afford the title compound as fluffy white crystals (0.129 g, 76%). m.p. 185-187° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[OH:19])=[O:8].[CH3:20]COCC.B(F)(F)F.P(Cl)(Cl)(Cl)(Cl)Cl>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7](=[O:8])[C:9]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[O:19][CH:20]=1
Reactant: COc1cc(O)c(C(=O)CCCCCBr)cc1OC
Reactant: CCOCC
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CN(C)C=O
Product: COc1cc2occ(CCCCBr)c(=O)c2cc1OC
Temperature: 10 °C
Yield: 58.6 %

Procedure:
1st method: A solution A is prepared from 500 mg of the compound of the above Step, 6-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexan-1-one (1.5 mmol), dissolved in 0.60 ml (4.5 mmol) of Et2O—BF3, and the solution is cooled to 10° C. 2.3 ml of DMF are then added. There is prepared, in addition, a solution B of 4 ml of DMF and there is added thereto in small portions at 10° C. 470 mg (2.25 mmol) of PCl5. Solution B is heated at 55° C. for 20 min, and is then introduced dropwise into solution A, referred to at the beginning, with a return to ambient temperature. The mixture turns orangey yellow and precipitates. 50 ml of 0.1N HCl are introduced and the mixture is extracted with AcOEt, the organic phases are washed with saturated NaCl solution, separated, dried over MgSO4, filtered and evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 70-30. The purified fractions crystallise after evaporation. 300 mg of 3-(4-bromobutyl)-6,7-dimethoxychromen-4-one are obtained in the form of crystals (yield=59%); TLC SiO2hept-AcOEt 50-50 Rf=0.4.
Reaction SMILES: C([C@H]1CO1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Mg]Br)=C.[C:21]1([CH:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:28]([OH:32])[CH2:29][CH:30]=[CH2:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:33]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:28]([OH:32])[CH2:29][CH:30]=[CH2:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C=CC[C@H](O)C(c1ccccc1)c1ccccc1
Agent: C=C[Mg]Br
Agent: c1ccc(C(c2ccccc2)[C@H]2CO2)cc1
Product: C=CC[C@@H](O)C(c1ccccc1)c1ccccc1
Yield: 694.5 %

Procedure:
(2S)-2-benzhydryl-oxirane (0.61 g, 2.91 mmol) was reacted with vinylmagnesium bromide (7.26 ml of 1.0M solution in THF, 7.26 mmol) in the presence of CuI (0.055 g, 0.29 mmol) (Procedure A) to yield (2R)-1,1-diphenyl-pent-4-ene-2-ol 0.48 g (70%, [α]D=(+)26, c=1, MeOH). The 1HNMR and 13CNMR were identical with (2S)-1,1-diphenyl-pent-4-ene-2-ol.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1[CH2:12][C:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13](F)(F)F)[O:10][N:9]=1)=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([CH3:13])[O:10][N:9]=[C:8]([CH2:6][OH:5])[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: CCOC(=O)C1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(c2cc(Cl)cc(Cl)c2)CC(CO)=NO1
Temperature: 40 °C
Reaction time: 2 h
Yield: 123.7 %

Procedure:
Lithiumborohydride (0.86 g, 39.7 mmol) was added in portions at ambient temperature to a solution of 5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carboxylic acid ethyl ester (8.8 g, 24.8 mmol) in tetrahydrofuran (100 ml) and a small amount of methanol (1.5 ml). After stirring for 2 h at 40° C. the reaction mixture was cooled to 20° C., made acidic with 2N hydrochloric acid and stirred for 1 h. Solid potassium carbonate was added until the reaction mixture was slightly alkaline. After extraction with ethylacetate the organic phase was separated, dried over sodium sulfate and concentrated to give 7.98 g of a white material which was used in the next step without further purification 1H-NMR (CDCl3, 400 MHz): 7.38-7.48 (m, 3H), 4.47 (d, 2H), 3.82 (d, 1H), 3.43 (d, 1H), 1.93 (t, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.CC(C)([O-])C.[K+].[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][NH:35][C:36](=[O:49])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](OC)=[O:46])=[CH:39][CH:38]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>CN(C=O)C>[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][NH:35][C:36](=[O:49])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](=[O:46])[NH:2][C:3]2[NH:8][CH2:7][CH2:6][CH2:5][N:4]=2)=[CH:39][CH:38]=1)[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.25 g (9.2 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride and 1.03 g (9.2 mmol) of potassium tert-butoxide were dissolved in 3 ml of absol. DMF and the mixture was stirred at RT for 30 min. 740 mg (1.53 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionate (Example 3c) in 1 ml of DMF were then added and the mixture was stirred at RT for 4 h. It was adjusted to pH 4 using glacial acetic acid, the solvent was stripped off in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol/glacial acetic acid/water (9/1/0.1/0.1)). Yield: 190 mg (38%). MS: ES+, m/e=552.3 (M+H+, 100%)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27]O)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:31]#[N:33])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:29][CH:30]=1
Reactant: CCN(CC)CC
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a mixture of [2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (2.00 g), triethylamine (0.97 g) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (1.10 g) under ice-cooling and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) of sodium cyanide (0.59 g) at room temperature and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The obtained crystals were subjected to silica gel column chromatography to give crystals (1.40 g, 68%) of 2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[CH3:14][SH:15].O>CN(C)C(=O)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:15][CH3:14])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSC(C)(C)C1(O)CC=C(C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 100 ml of N,N-dimethylacetamide was added 4.4 g of 60% sodium hydride. The mixture was cooled to 5°-10° C. and saturated with methyl mercaptan. Stirring was continued while heating the reaction mixture to 100° C. over a two and one-half hour period. After an additional hour at 100° C., the reaction mixture was poured into water and extracted twice with p-pentane. The combined extracts was washed with water, dried and Claisen-distilled to give 15.8 g of the desired product, b.p. 83°-85° C. (0.2 mm).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[C:7]([F:27])[CH:6]=1)(=O)C.C1(C)C=CC=CC=1.CN>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:24])([F:25])[F:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[C:7]([F:27])[CH:6]=1
Reactant: CCOCCCCCC(OC(=O)c1ccc(OC(C)=O)cc1F)C(F)(F)F
Agent: CN
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A reactor was charged with 1 g of 4-acetoxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxy-carbonyl)benzene (formula (1); X=F, Y=--CF3, Q=--CH3, m=1, p=5, n=2), 15 ml of toluene and 0.5 g of a methanol solution containing 40 wt% methylamine, and the mixture is stirred at room temperature for 15 minutes. After the reaction, the reaction mixture was washed with a 4 wt% hydrochloric acid aqueous solution and then with water to separate an organic layer from the solution. The organic layer was dried over anhydrous sodium sulfate, and then, the solvent is distilled off to give 4-hydroxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxy-carbonyl)benzene (formula (2); X=F, m=1, p=5, n=2). This product was dissolved in acetone and analyzed by gas chromatography to show no presence of methylacetamide (CH3CONHCH3).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=1)=[O:19])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 3-(trifluoromethyl)benzoyl chloride (33.4 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.91-0.98 (m, 3 H) 1.34-1.47 (m, 2 H) 1.61-1.72 (m, 2 H) 2.30-2.33 (m, 3 H) 4.07-4.16 (m, 2 H) 6.56-6.60 (m, 1 H) 6.66-6.72 (m, 1 H) 7.69 (t, 1 H) 7.80 (d, 1 H) 8.17-8.23 (m, 1 H) 8.27 (d, 1H); MS (ESI) positive ion 342 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[N:23]=[C:24]([N:29]([CH3:31])[CH3:30])[S:25][C:26]=1[CH:27]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[S:25][C:24]([N:29]([CH3:31])[CH3:30])=[N:23][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN(C)c1nc(Cl)c(C=O)s1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)c1nc(Cl)c(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)s1
Yield: 28.4 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Chloro-2-dimethylamino-thiazole-5-carbaldehyde (53.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 36.84 mg (33%) of the title compound. (300 MHz, DMSO-d6) 12.56 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.18 (m, 2H), 6.34 (s, 2H), 5.04 (t, J=17 Hz, 8.5 Hz, 1H), 3.11 (s, 6H), 2.87 (s, 1H), 2.75 (s, 1H), 2.58 (s, 1H), 2.19 (d, J=8 Hz, 1H), 1.36 (d, J=8 Hz, 1H). MS=509 (M+H), HPLC: 2.39 min. (G Method).
Reaction SMILES: IC.[CH2:3]([S:5][C:6]1[NH:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:10]=1)C>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]([S:5][CH3:3])[NH:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Solvent: CI
Product: COc1ccc(-c2nc(SC)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
By substituting iodomethane for the iodoethane of Example 10, one obtains as product 4,5-bis(4-methoxyphenyl)-2-methylthioimidazole, m.p. 157°-158.5°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][C:17](OCC)=[O:18])[N:15]=2)=[CH:5][CH:4]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C1COCC1.C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: OCCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Ethyl [[(E)-2-(4-(trifluoromethyl)phenyl)ethenyl]-1,3-oxazol-4-yl]acetate (1.72 g) was added to a suspension of calcium chloride (2.35 g) and sodium borohydride (1.60 g) in THF-ethanol (10 ml- 10 ml) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was combined with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:1 to ethyl acetate) to give the titled compound (1.27 g) as a colorless crystal powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 165 °C
Yield: 97.6 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 28, 0.33 g, 1.1 mmol), (s)-1-(4-fluoro-phenyl)-ethylamine (0.16 g, 1.2 mmol) and DIEA (0.21 ml, 1.2 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.43 g, 97%). 1H NMR (400 MHz) δ 12.09, 12.05 & 11.64 (s, 1H), 10.94, 10.87 & 10.72 (s, 1H), 8.98, 8.76 & 8.70 (d, J=7.6 Hz, 1H), 8.16 & 8.11 (d, J=9.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.22-7.10 (m, 2H), 6.25 & 6.04 (d, J=9.6 Hz, 1H), 6.23 & 5.86 (d, J=13.6 Hz, 1H), 5.31, 5.21 & 4.89 (m, 1H), 4.71, 4.59 & 4.27 (m, 1H), 1.52 (m, 3H), 1.26 (m, 6H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [N:1]1([C:6]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:6][C:8]2([C:14]3[CH:15]=[CH:16][C:17]([S:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:18][CH:19]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCCC1)C1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1cc(C2(CN3CCCC3)CCOCC2)ccc1SCCCN1CCCC1
Yield: 27 %

Procedure:
The title compound (58 mg, 27%) was prepared using 1-[3-({4-[4-(pyrrolidin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenyl}thio)propyl]pyrrolidine and lithium aluminium hydride similarly to the procedure used for example 142. 1H NMR (400 MHz, CDCl3) δ 1.54-1.57 (m, 4H), 1.75-1.79 (m, 4H), 1.84-1.94 (m, 4H), 2.06-2.10 (m, 2H), 2.18-2.22 (m, 4H), 2.47-2.50 (m, 4H), 2.57 (t, 2H), 2.63 (s, 2H), 2.96 (t, 2H), 3.54 (t, 2H), 3.73-3.78 (m, 2H), 7.22 (d, 2H), 7.29 (d, 2H). HRMS ESI+ m/z 389.2615 [MH]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2C(C(OC)=O)=CON=2)C=CC=CC=1>>[C:5]1([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C(O)c1conc1-c1ccc(F)cc1
Agent: COC(=O)c1conc1-c1ccccc1
Product: O=C(O)c1conc1-c1ccccc1

Procedure:
This compound was synthesised following the procedure described for Compound 8D but using Compound 15A instead of Compound 8C (90.2%). M.p. 162.7-164.5° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]2[NH:20][C:19]3[CH:21]=[CH:22][N:23]=[C:24]([C:25]([F:28])([F:27])[F:26])[C:18]=3[C:17](=[O:29])[N:16]2[CH:30]([CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:39][C:34]1[CH:33]=[C:32]([CH2:31][CH:30]([N:16]2[C:17](=[O:29])[C:18]3[C:24]([C:25]([F:26])([F:27])[F:28])=[N:23][CH:22]=[CH:21][C:19]=3[NH:20][CH:15]2[C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:40])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1O
Reaction time: 2.5 h
Yield: 100 %

Procedure:
2-(3-(benzyloxy)pyridin-2-yl)-3-(1-(3,4-difluorophenyl)propan-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (4.61 g, 8.31 mmol) was dissolved in absolute ethanol (150 mL). To this was added 10% palladium on carbon (0.50 g) and the mixture was hydrogenated on a Parr shaker at 45 PSI for 2.5 hours. The reaction was filtered through celite, and the filter cake washed with ethanol. The combined filtrates were concentrated in vacuo to an oil. This oil was purified by silica gel column chromatography using 20%-40% acetone/hexanes as eluant to yield the product diastereomers as a pale yellow foam (3.86 g, 77% yield).