Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][C@H:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:10](=[O:30])[N:11]([CH2:13][C:14]3[CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[CH:17]=[CH:18][C:19]=3[CH2:20][OH:21])[N:12]=2)=[CH:4][CH:3]=1.ClS([N:42]=[C:43]=[O:44])(=O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[C:43](=[O:44])([O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])=[CH:15][C:14]=1[CH2:13][N:11]1[C:10](=[O:30])[N:9]([CH2:31][C@H:32]([OH:37])[C:33]([F:34])([F:36])[F:35])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1)[NH2:42]
Reactant: O=c1n(Cc2cc(-c3cccc(Cl)c3Cl)ccc2CO)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)OCc1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
65 mg (0.11 mmol) of the compound from Example 137 were dissolved in 3 ml of dichloromethane, and the mixture was cooled to 0° C. 14 μl (0.16 mmol) of chlorosulfonyl isocyanate were added, and the mixture was stirred at RT for 18 h. 1.5 ml of water were then added, and the mixture was stirred at 60° C. for a further 18 h. For work-up, 3 ml of saturated aqueous sodium bicarbonate solution were added, and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 30 mg (43% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.CN(C)C(=O)C.[H-].[Na+].Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43]>O>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(CCN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reactant: Fc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccccc3F)CC2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
To a stirred mixture of 3.5 parts of 2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole and 18 parts of N,N-dimethylacetamide were added portionwise 0.5 parts of a sodium hydride dispersion 59.4% at room temperature. After stirring for 35 minutes at room temperature and for 10 minutes at 60° C., a solution of 1.7 parts of 1-(chloromethyl)-2-fluorobenzene in 9 parts of N,N-dimethylacetamide was added dropwise at 60° C. After stirring for 10 minutes, the reaction mixture was cooled and poured into 150 parts of water. The product was extracted twice with 4-methyl-2-pentanone. The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 3.0 parts (65.5%) of 1-[(2-fluorophenyl)methyl]-2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 109.3° C. (515).
Reaction SMILES: [CH2:1]([C:3]1[CH:50]=[CH:49][C:6]2[CH:7]([C:17]3[C:18]([S:47]C)=[N:19][C:20](=[O:46])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([CH3:45])[CH2:30][C:31]([NH:33][C:34]5[S:35][CH:36]=[C:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:38]=5)=[O:32])[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([C:3]1[CH:50]=[CH:49][C:6]2[CH:7]([C:17]3[C:18](=[S:47])[NH:19][C:20](=[O:46])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([CH3:45])[CH2:30][C:31]([NH:33][C:34]5[S:35][CH:36]=[C:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:38]=5)=[O:32])[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(SC)nc3=O)n2)n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(=S)[nH]c3=O)n2)n1

Procedure:
The product from step (v) (0.61 g) was dissolved in dry pyridine (20 ml) and triethylamine (1.0 ml). Hydrogen sulphide gas was slowly bubbled through the solution for 15 minutes. The solvents were evaporated under reduced pressure and the residue azeotroped twice with toluene. The residue was purified by chromatography eluting with ethyl acetate in toluene. Yield 0.41 g.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>CC(N(C)C)=O>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[OH:29])[S:3][C:4]=2[CH:10]=1
Reactant: OCc1ccc2nc(Br)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: OCc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of (2-bromobenzo[d]thiazol-6-yl)methanol (400 mg, 1.6 mmol) from Step 2 of Example 2 in DMA (6 mL) were added DIEA (258 mg, 2.0 mmol) and (1R,2R)-2-aminocyclohexanol (226 mg, 2.0 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure to give crude (1R,2R)-2-((6-(hydroxymethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown oil (445 mg, 100%), which was used for the next step without any further purification. LCMS (ESI) m/z 279 (M+H)+.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)=[N:7][N:6]=1)(=O)=O.CS(C1SC(C2C=C3C(=CC=2)C=NC=C3)=NN=1)=O.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH2:44]>CCOC(C)=O>[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH:44][C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)=[N:7][N:6]=1
Reactant: NCc1ccco1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3cnccc3c2)s1
Agent: CS(=O)c1nnc(-c2ccc3cnccc3c2)s1
Solvent: CCOC(C)=O
Product: c1coc(CNc2nnc(-c3ccc4cnccc4c3)s2)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A stirred mixture of 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)isoquinoline and 6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)isoquinoline (44 mg, 0.16 mmol) and furan-2-ylmethanamine (78 mg, 0.8 mmol) (commercially available from Acros Organics (Order Number 11980)) was heated at 80-100° C. for 3 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc and washed with 2M aqueous Na2CO3 solution and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with gradients of EtOAc in hexanes) to provide N-(furan-2-ylmethyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine as an amphorous solid (32 mg, 65%). LCMS (M+H) 309.3 calc for C16H13N4OS 309.1. 1H NMR (300 MHz, DMSO-d6): δ ppm 9.34 (s, 1H), 8.54 (m, 2H), 8.29 (s, 1H), 8.17 (m, 2H), 7.92 (d, J=5.8 Hz, 1H), 7.64 (s, 1H), 6.43 (m, 2H), 4.58 (d, J=5.2 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:27][CH2:26][CH2:25][CH2:24][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCO)cc1)N(C)C
Reaction time: 12 h

Procedure:
15.0 g (0.050 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one and 26.3 g (0.35 mol) of 3-amino-1-propanol are dissolved in 30 ml of dry dimethylacetamide, and the solution is heated up to 150° C. together with 13.8 g (0.1 mol) of potassium carbonate, and stirred overnight (about 12 h). After the solution is cooled down, it is poured into 300 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:1) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.52 (br, 1H), 1.82-1.94 (m, 3H), 2.00-2.07 (m, 1H), 2.35 (s, 6H), 3.17 (d, 1H), 3.20 (d, 1H), 3.32-3.37 (m, 2H), 3.81-3.85 (m, 2H), 4.42 (br, 1H), 6.52 (d, 2H), 7.14-7.28 (m, 5H), 8.32 (d, 2H).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([CH3:37])([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:28])([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:16]([O:18]CC)=[O:17])C.[OH-].[K+]>O.C(O)C>[CH3:28][C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:29])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:37])([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[C:4]([OH:38])=[O:3])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(C)cc2)C(=O)O)cc1
Yield: 38.6 %

Procedure:
According to the procedure given for 210f, 209e (9.0 g, 17.2 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in water (10 mL) and ethanol (30 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/10, 1/6, 1/2) to give 210e (3.1 g, 39%) as a white solid. Mp 48-50° C. 1H NMR (CDCl3): δ 10.8-8.8 (br., 2H), 7.22 (d, 4H, J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H), 1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m, 4H). 13C NMR (CDCl3): δ 211.63, 183.07, 140.40, 137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82, 21.39. HRMS (LSIMS, gly): Calcd for C29H39O5 (MH+): 467.2797, found: 467.2785. HPLC: 92.4% pure. Anal. (C29H38O5) C, H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([NH:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
80 mg (0.29 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.26 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA in 1.5 mL DMF were stirred at 150° C. After the reaction of the reactants the reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down. The residue was dried.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:28][CH2:27][C:26]([C:38]([OH:40])=O)=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:28][CH2:27][C:26]([C:38]([NH:29][C:23]4[CH:24]=[CH:41][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:40])=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2F)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2F)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (146 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (108 mg) and triethylamine (496 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8) to give 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 66) (139 mg) as yellow amorphous.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1.[H-].[Na+]>CN(C)C=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:14]3[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1[N+](=O)[O-]
Yield: 83.8 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-(imidazol-1-yl)phenol (4.1 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (7.85 g), sodium hydride (55 wt. %, 1.25 g) and anhydrous N,N-dimethylformamide (45 ml) and the reaction mixture was purified to give the title compound (8.8 g).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1>C1COCC1.C(O)C>[O:9]([CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(COc2ccccc2)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of sodium hydride (55 mg, 60% dispersion in mineral oil, 1.38 mmol) in THF (1 ml) at 0° C. was added phenol (100 mg, 1.06 mmol). After stirred at 0° C. for 10 minutes, the reaction solution was warmed to room temperature and stirred for 10 minutes. The reaction solution was cooled to 0° C. again, and was added a solution of N-(4-(chloromethyl)thiazol-2-yl)acetamide in ethanol (1 ml). The reaction was stirred at room temperature overnight and then was heated at 70° C. for 5 hours. The reaction solution was concentrated and the residue was purified via preparative HPLC to afford N-(4-phenoxymethyl-thiazol-2-yl)-acetamide as a tan amorphous solid (50 mg, 20%). LC/MS m/z 249.15 (M-1)+; HPLC Rt: 2.875 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([NH:12][C@@H:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])([O:10][CH3:11])=[O:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:19])[CH2:18][C@@H:13]([NH:12][C:8]([O:10][CH3:11])=[O:9])[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@@H]1CC(=O)OC1=O
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N[C@H](CC(=O)c1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of bromobenzene (373 g) and (R)-2-carbomethoxyaminosuccinic anhydride (1) (90.51 g) in dichloromethane (260 ml) was cooled in ice, and aluminum chloride (174.34 g) was added over 1 minute (exothermic!). The dark red mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was poured onto crushed ice, and concentrated hydrochloric acid was added slowly with stirring. Diethylether was added and the mixture was stirred until all of the red-brown material disappeared. The layers were separated, and the aqueous was extracted twice more with diethylether. The combined ether extracts were washed with water and extracted with aqueous sodium carbonate. The combined extracts were washed with diethylether, cooled in ice, and acidified with conc. hydrochloric acid. The acid was extracted 3 times with diethylether. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave the title compound as a foam, 149.6 g. [α]D =-41° (25° C., CH3OH, c=1.0352).
Reaction SMILES: [C:1]([C:4]1([NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[N:20]4[C@@:21]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=5)([CH3:33])[C:22](=[O:32])[N:23]([C:24]5[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=5)[C:19]4=[N:18][CH:17]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].[CH2:43](OC(OCC)CBr)[CH3:44].Cl.O1CCOCC1>CC(C)=O>[S:3]1[CH:44]=[CH:43][N:2]=[C:1]1[C:4]1([NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[N:20]4[C@@:21]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=5)([CH3:33])[C:22](=[O:32])[N:23]([C:24]5[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=5)[C:19]4=[N:18][CH:17]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(N)=S)CC4)CC3)n21
Reactant: CCOC(CBr)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5nccs5)CC4)CC3)n21
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-thiocarbamoyl-cyclo-propylcarbamoyl)-cyclopropyl]-amide (92 mg, 0.15 mmol) in 1.5 mL of acetone was added bromoacetaldehyde diethyl acetal (0.089 mL, 0.59 mmol) and HCl in dioxane (4 M, 0.002 mL, 0.01 mmol). The reaction mixture was heated at reflux for 15 h, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 25 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The organic phase was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated in vacuo to yield a pale brown oil. The crude product was purified by flash chromatography on silica gel (1-5% MeOH in CH2Cl2), to furnish 30 mg (31%) of the title compound as a pale brown foam, m/z 646.7 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>[H-].[Na+].CN(C)C=O>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cccc(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cccc(OCc3ccccc3)n2)c1
Yield: 78.8 %

Procedure:
The procedure of Example 4a) was also used to introduce the 3-trifluoromethyl phenoxy group by reaction of 2-benzyloxy-6-chloropyridine (5 g; 23 mmols) from a) above with 3-trifluoromethylphenol (3.3 g; 0.018 mols) using dry sodium hydride (0.55 g) and dry dimethylformamide (200 ml) as solvent, with a 1 hour reflux stage. 2-(3-Trifluoromethylphenoxy)-6-benzyloxypyridine (4.9 g; 51%) was obtained as a yellow oil following solvent extraction (chloroform/water--500 ml; 50/50), and chromatography plus distillation of the organic layer.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C.Cl>C1(C)C=CC=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]3[N:22]=[N:21][NH:20][N:2]=3)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 moles) in toluene (2.3 L) was added trimethyltin azide (525 g, 2.55 moles) at room temperature. The mixture was refluxed for 24 hours, cooled to room temperature, filtered, washed with toluene and sucked dry in a funnel. The precipitate was resuspended in toluene (3.5 L) and THF (250 mL) was added. Anhydrous HCl was bubbled in at a moderate rate at room temperature to give a clear solution (45 minutes). Addition of HCl gas was continued for another 20 minutes with stirring whereupon a white precipitate formed. The reaction mixture was stirred overnight. The solid product was filtered, washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrazole. m.p. 152°-154° C.; 1H-NMR (CDCl3): 2.40 (s, 3H), 7.19 (dd, 1H), 7.55 (m, 2H), 8.25 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2cccc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cccc(Cl)c2)c1
Yield: 92.9 %

Procedure:
Methyl 5-(3-chlorophenylthio)pyrrole-3-carboxylate (1.5 g.) was refluxed with 10 ml. of 1 N sodium hydroxide and 20 ml. of methanol, at which time thin layer chromatography (silica gel with hexane-5/ethyl acetate-1/5% acetic acid as eluant) indicated hydrolysis was complete. The methanol was allowed to evaporate. The aqueous residue was diluted with approximately one volume of water and extracted twice with ether. The aqueous phase was acidified with 6 N hydrochloric acid and product extracted multiply into ethyl acetate. The combined ethyl acetate extracts were back-washed with water and then with saturated brine, dried over anhydrous sodium sulfate and evaporated to an oil. Trituration of the oil with hexane gave 5-(3-chlorophenylthio)pyrrole-3-carboxylic acid (1.32 g., m.p. 134°-137° C., m/e 253).