Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>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.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
A mixture of 4-bromobenzotrifluoride (10.0 g), 4-formylphenylboronic acid (7.33 g), tetrakis(triphenylphosphine)palladium(0) (308 mg), potassium carbonate (30.7 g), tetrahydrofuran (300 mL) and water (100 mL) was stirred at 85° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added to it, which was then extracted with ethyl acetate twice and the combined organic layers were washed with saturated brine. After adding anhydrous magnesium sulfate to the organic layers, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in n-hexane (60 mL) with heating and thereafter cooled to 0° C. The resulting precipitate was recovered by filtration to give the titled compound as a gray solid (12.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:23])=[C:18]([CH2:20][CH2:21][OH:22])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]([Si:35](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:23])=[C:18]([CH2:20][CH2:21][O:22][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a mixture of 2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [CAS 403611-91-6] (4.04 g, 13.0 mmol), triethylamine (3.6 mL, 25 mmol, and DMAP (0.16 g, 1.3 mmol) in CH2Cl2 (80 mL) at 0° C. is added a solution of tert-butylchlorodiphenylsilane (3.95 g, 14.4 mmol) in CH2Cl2 (10 mL) drop wise. The mixture is warmed to room temperature and stirred for 6 h. The mixture is washed with 0.5 N HCl (80 mL), and the organic phase is dried (MgSO4). After the solvent is removed in vacuo, the residue is purified by flash chromatography (elute 2:1 hexanes:EtOAc) to yield 7.09 g of the title compound as a white solid. MS (ES+) 548
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:45](O)=[O:46])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:45]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:46]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: COC1CCN(c2c(NC(=O)c3nc(-c4ncccc4F)sc3N)cnn2C)CCC1N

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(3-fluoro-pyridin-2-yl)thiazole-4-carboxylic acid gave racemic 323 (35.8 mg, 24% over two steps). 1H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.43 (d, J=4.6 Hz, 1H), 7.89-7.78 (m, 1H), 7.66 (s, 2H), 7.62 (s, 1H), 7.48 (dt, J=8.3, 4.1 Hz, 1H), 3.65 (s, 3H), 3.28 (d, J=7.5 Hz, 5H), 3.26-2.95 (m, 8H), 2.07 (dd, J=10.6, 4.4 Hz, 1H), 1.92 (dd, J=10.6, 7.4 Hz, 1H), 1.79-1.55 (m, 2H). LCMS (ES+) m/z 461 (M+1)
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH2:29][OH:30]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: NC(CO)CO
Product: Cc1ccc(-c2cc(CNC(CO)CO)c(=O)n(CC(C)C)n2)cc1
Yield: 83.7 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 2-amino-1,3-propanediol were reacted to yield the title compound as colorless needles (yield: 83.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:19]=[O:20])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Fc1ccc(C2CNc3ccccc3C2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=NN1CC(c2ccc(F)cc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline (0.25 g, 0.0011 mol) in ethanol (1.2 mL) was added 1N hydrochloric acid (1.2 mL). The reaction mixture was cooled to 0° C., and to this a cold solution of sodium nitrite (0.151 g, 0.0022 mol) in water (3.0 mL) was added at the same temperature. The reaction mixture was warmed to RT and stirred for 1 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure to obtain product as a brown colored oil (0.27 g).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=C.[O:26]=[O+][O-]>CO>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]2=[C:5]3[C:4]=1[CH2:1][CH:2]([OH:26])[N:18]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:6]3=[N:7][CH:8]=[N:9]2
Reactant: O=[O+][O-]
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Solvent: CO
Product: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine (0.14 g, 0.39 mmol) (from Example 16, Step E, supra), in methanol (50 mL) at −78° C. was passed a continuous stream of O3 until the color of the solution became blue. The reaction solution was then purged with argon, and methyl sulfide (5 mL) (Aldrich) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The solution was concentrated, the residue was dried in vacuo to give the desired 7,8-dimethoxy-4-(4-chloro-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol as a crude yellow solid. (Yield 0.14 g, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O>CC(C)=O.C(OCC)(=O)C>[Cl:8][CH2:9][C:10]1[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: CC(=O)NC(N)=S
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C

Procedure:
A mixture of acetylthiourea (591 mg, 5 mmol) and 1,3-dichloroacetone (667 mg, 5.25 mmol) in acetone (15 mL) was heated at reflux for 7 hours, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography to give the title compound. MS (DCI) m/e 191 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 12.21 (s, 1H), 7.22 (s, 1H), 4.70 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1cnc(N)s1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ncc(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-thiazol-2-ylamine (22.8 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (9.29 mg, 0.400, 20.0%). ESI-MS m/z calc. 232.1, found 233.2 (M+1)+ Retention time 2.65 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(N(CC)CC)C.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>C1C=CC=CC=1>[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)[C:18](=[O:19])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CSc1ccc(N(C)C(=O)Cl)cc1
Reactant: OCc1cccnc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CSc1ccc(N(C)C(=O)OCc2cccnc2)cc1
Yield: 40.5 %

Procedure:
A solution of 3-pyridylcarbinol (2.4 g., 0.0222 mole) in triethylamine (2.24 g., 0.0222 mole) was added dropwise to a solution of N-methyl-(4-methylthiophenyl)carbamoyl chloride in 150 ml. of benzene. The reaction mixture was heated to reflux temperature for about 1 hr. then allowed to stand over night at room temperature. The reaction mixture was washed with water and the benzene layer separated, dried over magnesium sulfate and concentrated in vacuo to give an oil which solidified. The product was recrystallized from methylcyclohexane to give 2.6 g. of solid melting at 100°-102° C. This was a 40.5% yield of 3-pyridylmethyl N-methyl-N-(4-methylthiophenyl)carbamate.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)Cc1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)c1ccccc1

Procedure:
A stirred mixture of benzyl methyl ketone (26.8 ml) and dimethylformamide dimethyl acetal (30.0 ml) was heated in a distillation apparatus on an oil bath at 95°-100° C. for 11/2 hours. Methanol slowly distilled off. The residual volatiles were removed under vacuum and the resulting oil was crystallised from ether-petroleum spirit (40°-60° C.) to yield the title compound (mp 66° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(=O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1ccccc1CBr

Procedure:
A mixture of 2-methylbenzophenone (9.8 g), N-bromosuccinimide (8.9 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (150 ml) was refluxed for 1 hour with light irradiation. The mixture was cooled, and then filtered to remove insoluble substances. The filtrate was concentrated to afford quantitatively the above-titled compound as an oily susbstance.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11](Cl)([O:13][C:14](=[O:20])OC(Cl)(Cl)Cl)Cl.[F:22][C:23]1[CH:30]=[C:29]([C:31]2[N:32]=[C:33]([NH:36][C:37](C)([CH3:40])[CH2:38]O)[S:34][CH:35]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(Cl)Cl>[CH3:38][C:37]1([CH3:40])[CH2:11][O:13][C:14](=[O:20])[N:36]1[C:33]1[S:34][CH:35]=[C:31]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:22])[CH:30]=2)[N:32]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)c(F)c2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)c(F)c2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
N,N-diisopropylethylamine (1.4 mL, 7.9 mmol) and triphosgene (1.2 g, 3.9 mmol) in 20 mL of dry methylene chloride were added to a solution of 2-fluoro-4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (955 mg, 3.3 mmol), prepared in the previous step, in 50 mL of dry methylene chloride at 0° C. The reaction was stirred at 0° C. for 3 h and then allowed to warm to room temperature. The reaction was washed with 1×100 mL of 2N HCl. The aqueous layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 1.0 g of a yellow solid. Purification of the solid on silica gel using a stepwise gradient of 5% to 40% ethyl acetate-hexane gave the title compound (450 mg, 43%) as a yellow solid, mp 204-206° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1
Reactant: Nc1cc(Br)cc(OCc2ccccc2)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
Ethylsulfonyl chloride (113 uL, 1.2 mmol) was added dropwise to a stirred solution of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) and pyridine (247 uL, 3.1 mmol) in DCM (5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 14 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 95%) in hexanes to afford the title compound (345 mg, 94%) as an amber oil that solidified upon standing. LCMS (M+H)+=371.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+].CCOCC>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][CH2:7][CH2:6][C:5]1[S:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1
Reactant: OCCc1cc2ccccc2s1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCc1cc2ccccc2s1

Procedure:
2-Benzo[b]thiopheneethanol (2.20 g), 1,6-dibromohexane (2.59 ml), TAB (0.25 g), aqueous 12.5M sodium hydroxide (9 ml), and ether (20 ml) were stirred overnight at room temperature. The mixture was diluted with water (50 ml), extracted with ether (3×50 ml), and the combined, dried extracts were evaporated. The residual oil was purified by FCC eluting with cyclohexane-diethyl ether (100:0→98:2) to give the title compound as a colourless oil (2.73 g).
Reaction SMILES: [N:1]1[C:2](=O)[NH:3][CH:4]=[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.O(Cl)[Cl:15].[P+3]>>[Cl:15][C:2]1[N:3]=[CH:4][C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=1
Reactant: O=c1nc2c(c[nH]1)CCCCCC2
Reactant: ClOCl
Agent: [P+3]
Product: Clc1ncc2c(n1)CCCCCC2

Procedure:
Crude 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2(3H)-one was heated in phosphorus (III) oxychloride (50 mL) for 1.75 h. The solvent was removed under vacuum and the residue was treated with ice water and 1M aqueous potassium carbonate solution, the aqueous layer was extracted with a mixture of diethyl ether and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-chloro-5,6,7,8,9,10-hexahydro-cycloocta[d]pyrimidine as a yellow solid, 1.5 g; 1H NMR (CDCl3, 300 MHz) 8.18 (s, 1H), 2.82 (m, 2H), 2.66 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H), 1.34 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 173.25, 158.66 (2C), 132.74, 34.28, 32.03, 30.20, 28.57, 26.02, 25.90; MS(ES) 197/199 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10]Cl)=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:38]=[CH:37][C:16]([C:17]([NH:19][C@H:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[K+].[Br-]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10][NH:12][C:13]2[CH:38]=[CH:37][C:16]([C:17]([NH:19][C@H:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[O:18])=[CH:15][CH:14]=2)=[CH:4][N:3]=1
Reactant: N#Cc1nc(CCl)cnc1N
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc(N)c(C#N)n2)cc1)C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
2-Amino-5-chloromethylpyrazine-3-carbonitrile (1.68 g, 0.01 mol) was added in small portions over 10 min to a stirred solution of di-tert-butyl N-(4-aminobenzoyl)-L-glutamate (3.78 g, 0.01 mol) and i-Pr2NEt (1.74 mL, 1.29 g, 0.01 mol) in dry DMF (25 mL). After 20 hours at room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between CH2Cl2 and H2O. The organic layer was evaporated and the product purified by column chromatography on a column of neutral Al2O3 (120 g, 3×24 cm) with 50:1 CHCl3 --MeOH as the eluent. Fractions containing the above-specified glutamate (Rf 0.4, silica gel, 9:1 CHCl3 --MeOH) were allowed to evaporate passively in the hood until yellow crystals were formed; yield 3.60 g (59%); mp 71°-78° C; IR (KBr) 3400, 3210, 2990, 2940, 2230 (C≡N), 1730 (ester (C=O), 1635, 1615, 1575, 1515, 1495sh, 1460, 1420, 1395, 1375, 1335, 1315, 1285, 1260 cm-1 ; NMR (CDCl3) δ 1.41 (s, γ-t-OBu), 1.48 (s, α-t-OBu), 2.0-2.4 (m, CH2CH2), 4.37 (m, 2H, CH2NH), 5.35 (m, α-CH and NH), 6.61 (d, J=9 Hz, 3'- and 5'H), 7.67 (d, 9 Hz, 2'- and 4'-H), 8.22 (s, 6--H). Anal. (C26H34N6O5 -0.8 CHCl3) Calcd: C, 53.11; H, 5.79; N, 13.87. Found: C, 53.23; H, 5.94; N, 13.76.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:23][S-:24].[Na+].[OH-].[Li+]>CN(C)C=O>[CH3:23][S:24][C:14]1[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:2])=[O:22])=[CH:12][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: C[S-]
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(F)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (1.97 g, 6.15 mmol) in dry N,N-dimethylformamide (20 mL) at 25° C. under argon was carefully treated with sodium thiomethoxide (0.680 g, 9.27 mmol) and was then heated at 100° C, for 3 h. The reaction mixture was then concentrated in vacuo to remove N,N-dimethylformamide. The remaining residue was suspended in a saturated aqueous ammonium chloride solution (100 mL) and was extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was then dissolved in methanol (40 mL) and was treated with a 0.8M aqueous lithium hydroxide solution (20.60 mL, 16.7 mmol). The reaction mixture was stirred at 25° C. for 16 h and then was concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (1.71 g, 83%) as a light yellow oil: [αC]23589=−23.26° (c=0.49, chloroform); EI-HRMS m/e calcd for C15H17F3O3S (M−H2O)+ 316.0744. found 316.0749.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][Mg]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:4]([C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCCC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.37 g, 5.0 mmol) in THF (10 mL) at −20° C., there was added (4-methoxybutyl)magnesium chloride in THF (1.47 M, 10.2 mL, 15.0 mmol) dropwise such that the temperature remained below −20° C. After addition, the resulting solution was warmed to rt, and quenched with 1 N aq HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3×5 mL). The combined organic layers were washed with satd aq NaHCO3 (10 mL) and brine (5 mL), and dried over Na2SO4. The solvent was then removed in vacuo to give (R)-tert-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.41 g, 93%), which was used for the next step without purification; MS m/s 324 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1cccs1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cccs2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and thiophene-2-carboxylic acid (9 mg, 0.07 mmol). Yield 26 mg (72%).