Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:5]=1[CH3:19])(=[O:3])[CH3:2].Cl[C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]([C:8]1[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:19])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[C:7]=1[CH3:9])=[O:29]
Reactant: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1
Reactant: COC(=O)CCCC(=O)Cl
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(=O)CCCC(=O)OC)c2C)cc1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) and methyl 5-chloro-5-oxovalerate (0.63 mL, 4.5 mmol) reacted to give 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.05 (d, 2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.65 (s, 3H), 2.75 (t, 2H), 2.41 (s, 3H), 2.40 (t, 2H), 2.11 (s, 3H), 2.01 (s, 3H), 2.00 (quintet, 2H), 1.45 (t, 3H); MS (ESI) 386 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C:30]1=[O:38].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][C:30]4=[O:38])[CH2:10][CH2:9]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Reactant: O=C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)Cc5ccccc54)CC3)C(=O)C2(C)C)cc1OC

Procedure:
0.5 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1), 0.16 g 1,3-dihydro-2H-indol-2-one and 0.7 g K2CO3 in 20 ml of acetonitrile is heated to reflux for 10 h. The acetonitrile is removed in vacuo and the residue dissolved in 70 ml of ethyl acetate and washed four times with 30 ml of water. The organic layer is dried over MgSO4 and concentrated in vacuo. The title product is isolated by column chromatography (silica gel, eluent: ethyl acetate to ethyl acetate/methanol 4:1).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C>[CH3:4][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][CH2:22][N:23]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:28]([F:30])([F:31])[F:29])[CH3:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C(F)(F)F
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
7-{5-[4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 19) (160 mg, 0.353 mmol), DIPEA (0.234 ml, 1.342 mmol) and ethyl 4-bromobutanoate (0.110 ml, 0.767 mmol) were stirred at room temperature in DMF (10 ml) for 5 hours. The reaction mixture was then heated to 60° C. for 5 h, and allowed to stand overnight at room temperature. Further ethyl 4-bromobutanoate (0.055 ml, 0.383 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (183 mg, 0.310 mmol) as an orange solid. MS (ES): C28H32F3N3O4 requires 531; found 532 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([F:30])=[CH:18][N:17]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]2[C:19]([F:30])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=4[CH:14]=3)[N:21]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cc1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave (±)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.29 (bs, 1H), 9.89 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.69 (m, 2H), 7.38 (m, 3H), 7.13 (bd, 1H, J=8.1 Hz), 6.83 (d, 1H, J=8.4 Hz), 5.36 (dd, 1H, J=6.3 and 5.7 Hz), 3.70 (s, 3H), 3.52 (dd, 1H, J=10.5 Hz), 3.20 (dd, 1H, J=5.4 and 5.7 Hz); LCMS: purity: 98%; MS (m/e): 415 (MH+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[CH3:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 57b (1.9 g, 3.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:15]1[S:16][C:17]([CH:21](O)[C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:1]([O:5][C:6](=[O:42])[N:7]([C:15]1[S:16][C:17]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccncc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(Cc2c[nH]c3ncccc23)s1
Temperature: 40 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A mixture of {4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519, 0.397 g, 0.57 mmol), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40° C. for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (520, 126 mg, 49%). MS (ESI) [M+H+]+=456.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](I)[CH2:16][CH3:17]>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][C:8]([CH2:15][CH2:16][CH3:17])=[C:4]2[CH2:3]1
Reactant: CCCI
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 8.3 %

Procedure:
To a cooled (−75° C.) solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.0 g, 9.51 mmol) in THF (40 mL) tert.-butyllithium (15 mL, 1.5 N in pentane) is slowly added. The mixture is stirred at −78° C. for 15 min before n-propyliodide (5.22 g, 30.7 mmol) is added. Stirring is continued at −78° C. for 45 min before the reaction is quenched by adding water/methanol 1:1 (10 mL). The mixture is allowed to warm to rt, diluted with tert.-butyl methylether and 10% aq. citric acid solution. The mixture is extracted twice with EA, the combined organic extracts are washed with brine, dried over Na2SO4 and concentrated. The crude product is purified by prep. HPLC to give 5,5-dimethyl-3-propyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (200 mg) as a colourless resin; LC-MS: tR=1.04 min, [M+1]=253.31; 1H NMR (CDCl3): δ 2.98 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.36 (s br, 1H), 2.26 (s, 2H), 1.63 (hex, J=7.6 Hz, 2H), 1.51 (t, J=7.0 Hz, 2H), 0.95 (t, J=7.6 Hz, 3H), 0.94 (s, 6H).
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]([OH:16])=O)[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.C[ClH]N.[CH2:32]([N:34](CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:32][NH:34][C:14]([C:4]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:2][N:7]=[N:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of methyl 3,5-diphenylpyridazine-4-carboxylic acid (compound 6) (200 mg, 0.72 mmol) in CH2Cl2 (10 mL), oxalyl chloride (230 mg, 1.81 mmol), catalytical DMF were added and stirred at 0° C. for 1 h. After the complete consumption of the acid shown by TLC, the volatiles were removed under reduced pressure and the crude acid chloride obtained was taken up in dry CH2Cl2 (5 mL). A solution of methyl amino hydrochloride (238 mg, 3.62 mmol) in CH2Cl2 (5 mL) cooled to 0° C., triethylamine (219 mg, 2.17 mmol) and acid chloride were added dropwise at 5° C. After the completion of the starting material, the reaction mixture was diluted with CH2Cl2 (20 mL), washed with aq NaHCO3 (5 mL×1), brine (5 mL×1) and dried over anhydrous Na2SO4. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 30% EtOAc in hexane) to furnish N-methyl-3,5-diphenylpyridazine-4-carboxamide (compound 1) (100 mg, 47%) as a light orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11](O)(=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:11](=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=CCCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-nitroaniline (0.433 mmol)) and pent-4-enoic acid (1.30 mmol) in CH2Cl2 (4 mL) at ambient temperature was added HOBt (0.234 g, 1.73 mmol) and EDC (0.332 g, 1.73 mmol). The resulting mixture was stirred for 4 hours. The reaction mixture was cooled to 0° C. and quenched with H2O. The aqueous layer was extracted with CH2Cl2 thrice and the combined organic extracts were washed with saturated NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure to give (viC1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ncccc3o2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A mixture of 700mg. of 2-(3-nitrophenyl)oxazolo[4,5-b]pyridine in 50 ml. of ethanol was hydrogenated over 150 mg. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration and the solvent was concentrated to dryness. The residue was recrystallized from chloroformpetroleum ether to give 2-(3-aminophenyl)oxazolo[4,5-b]pyridine, m.p. 179°-180.5° C.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N(C(C)C)C(C)C.[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:5]1[C:4]([F:20])=[C:3]([F:21])[C:2]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To an oven dried flask charged with a solution of methyl 5-bromo-2-(2-fluorophenylamino)-3,4-difluorobenzoate (21.68 mmol, 8.1 g) in THF (116 ml), was added CuI (2.16 mmol, 0.4 g) and iPr2NH (43.36 mmol, 6.1 ml). After addition is completed, reaction was purged with Argon and Pd(PPh3)2Cl2 (3.73 mmol, 2.62 g) and TMS-acetylene (26.88 mmol, 3.7 ml) are added. The reaction mixture was stirred at room temperature for 16 h, concentrated and taken up in EtOAc. The organic fraction was washed with sat NH4Cl, brine, dried over MgSO4 and conc. The crude was purified by flash chromatography using 5% to 20% EtOAc in Hexane to afford the desired product 6.96 g (85%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:23])([CH3:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[N:5]=[CH:6]1)([CH3:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.05 g) was reacted with benzenesulphonyl chloride (1.15 g) in a similar manner to Example 55 to give N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-4-yl}ethyl]benzenesulphonamide, as an oil. The compound contained 7% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl]benzenesulphonamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(=O)O[CH2:11][CH2:10][O:9]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1(=O)OCCO1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][CH2:10][OH:9])[CH:3]=1
Reactant: Oc1cccnc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1cccnc1
Temperature: 86 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
3-hydroxypyridine (20.0 kg), ethylene carbonate (19.4 kg), K2CO3 (18.9 kg), and DMF (75.5 kg) were charged to a 400 L reactor and heated to 86° C. After 13H, an aliquot was taken. There was still some 3-hydroxypyridine left by GC so more ethylene carbonate (1.0 kg) was added. After 20H, the reaction was deemed complete. The reaction was cooled to 20° C., H2O (85 L) was slowly added to the 400 L reactor, and stirring continued for 30 min. The title compound was extracted with 35° C. CH2Cl2 (4×170 L) sending the CH2Cl2 extractions into the 1000 L portable tank. The aqueous layer was discarded, and the 400 L reactor was cleaned. The solution of the title compound in the 1000 L portable tank was transferred to the 400 L and distilled in the 400 L reactor sending the distillate to the 400 L receiver. Toluene (200 L) was added so the 400 L reactor and distilled sending the distillate to the 400 L receiver. The resulting oil was transferred to a 20 L glass bottle to produce 21.0 kg (72%) of the title compound of 100.0% GC purity.
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([NH:47]C(OC(C)(C)C)=O)[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[ClH:55]>C(#N)C>[ClH:55].[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]([NH2:47])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C:41]([CH3:43])([CH3:42])[CH3:44])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:19][CH:20]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C(C)(C)C

Procedure:
Under a nitrogen atmosphere, 1.37 g (1.84 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane are stirred in 64 ml of acetonitrile and 64 ml of aqueous 2N HCl at room temperature for 6 days. The reaction mixture is filtered, and the filtrate is concentrated by evaporation under a high vacuum at room temperature and is finally lyophilised from dioxane to yield the title compound: HPLC20-100 : tRet =14.2; 1H-NMR (CD3OD) inter alia δ 8.1 0 (d, J=8, 2Harom), 7.8 (m, 1Harom), 7.53 (m, 2Harom), 7.32 (m, 3Harom), 7.17 (m, 6Harom), 2.23(S, 2 H3Ctetrazole-protecting group).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:5].[C:32](OC(=O)C)(=[O:34])[CH3:33].[OH-].[NH4+]>O>[C:32]([NH:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:15][NH:14][C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:5])(=[O:34])[CH3:33]
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9 parts of 2-amino-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro [4,5]dec-8-yl]ethyl}-benzamide, 8.5 parts of acetic acid anhydride and 85 parts of water is stirred for 30 minutes in a water-bath at about 80° C. The reaction mixture is cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane. The combined organic phases are washed three times with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 5.2 parts of 2-(acetylamino)-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro-[4,5]dec-8-yl]ethyl}benzamide; mp. 195.1° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]([O:9]C2C=CC=CC=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:19][N:20]1[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([NH:19][N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25]2)=[O:9])=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(F)cc1)Oc1ccccc1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Yield: 45.1 %

Procedure:
A solution of 4-fluoro-N-phenoxycarbonylaniline (2.29 g), N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.02 g) in chloroform (25 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) using chloroform as an eluent to give N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.05 g). mp: 156°-157° C.
Reaction SMILES: O.[ClH:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:10]([O:14][C:15](=[O:18])[NH:16][NH2:17])([CH3:13])([CH3:12])[CH3:11]>CO>[ClH:2].[C:10]([O:14][C:15]([NH:16][N:17]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 4-piperidone hydrochloride monohydrate (31.2 g, 203 mmol) and tert-butylcarbazate (26.8 g, 203 mmol) in 100 mL MeOH is stirred over weekend at RT and then concentrated in vacuo. The residue is crystallized from ethyl acetate. Yield: 47.5 g.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](=[O:15])[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])(=O)[CH3:2].ClCC[S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.[OH-].[K+].CO>O>[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:7](=[O:15])[CH2:6][CH2:5][S:4][CH2:1][CH2:2][S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)(=[O:14])[CH3:13]
Reactant: ClCCSC1CCCCO1
Reactant: CC(=O)NCCNC(=O)CCSC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NCCNC(=O)CCSCCSC1CCCCO1
Temperature: 75 °C

Procedure:
A quantity of the S-{2-[N-(2-acetylaminoethyl)carbamoyl]ethyl} thioacetate, prepared above, (3.2 g, 23 mmol), 2-(2-chloroethylthio)tetrahydropyran (2 g, 11 mmol), potassium hydroxide (2.5 g, 44 mmol), methanol (10 cm3) and water (5 cm3) were mixed together and heated at 75° C. for 30 min. The mixture was allowed to cool and then partitioned between chloroform (50 cm3) and water (50 cm3). The organic layer was separated and the aqueous layer extracted with a further portion of chloroform. The combined chloroform extracts were then dried (MgSO4) and volatile components removed under reduced pressure to leave the crude product as an oily solid. A quantity of this material was purified firstly by chromatography on silica using a mixture of ethyl acetate, and methanol (95:5) as the eluant and then by reverse phase h.p.l.c. using aqueous methanol as the eluant. The pure N-(2-acetylaminoethyl)-3-[2-(tetrahydropyran-2-ylthio)ethylthio]propionamide was obtained as a white solid (0.3 g).