Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)=[CH:8][C:7]=1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4].[N-:32]=[N+:33]=[N-:34].[Na+]>CO>[N:32]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)=[CH:8][C:7]=1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4])=[N+:33]=[N-:34]
Reactant: O=C(CBr)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of intermediate (25) (0.105 mol) and sodium azide (6.84 g) in methanol (160 ml) was stirred and refluxed for 6 h. The mixture was cooled, poured into ice water and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 2-azido-N-[2-benzoyl-4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]acetamide (intermediate 26).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:7]([CH:8]=[N:12][OH:13])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ccnc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(Cl)ccnc1Cl
Temperature: 65 °C
Yield: 79.8 %

Procedure:
A solution of 2,4-dichloro-3-pyridinecarbaldehyde (2.15 g, 12.4 mmol) in ethanol (18 mL) was added to a solution of hydroxylamine hydrochloride (1.01 g, 14.5 mmol) and sodium hydroxide (0.58 g, 14.5 mL) in water (9 mL). The resulting solution was heated in a 65° C. oil bath for 3 hours. The mixture was filtered to yield a white solid which was dried in a vacuum oven at 45° C. with P2O5 to yield 2,4-dichloro-3-pyridinecarbaldehyde oxime (1.89 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.35 (d, J=5 Hz, 1H), 8.19 (s, 1H), 7.68 (d, J=5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccc2cccc(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cc2c3c(cccc3c1)NCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15175.5 %

Procedure:
A solution of the above aldehyde (1.17 g, 4 mmol), distilled 1,8-diamino naphthalene (0.63 g, 4 mmol), p-toluenesulfonic acid (10 mg), and tetrahydrofuran (6 mL) was stirred for 0.5 h at room temperature. The mixture was basified with 1 mL saturated sodium carbonate, diluted with THF-ether (1:1) and washed with water. The extract was concentrated and the residual solid was recrystallized from THF-ether (1:1, 30 mL) to give the 2,3-dihydroperimidine (1.50 g, 87%): mp 165-167° C.; 1H NMR (CDCl3) 7.59(s, 4H), 7.45 and 6.9(2d, 4H), 7.1(m, 4H), 6.4(d, 2H), 4.7(bs, 2H), 4.45(t, 1H), 4.0(t, 2H), 2.0-1.5(m, 8H); IR 3385, 3360, 2225, 1601 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10][C:11]#[N:12].[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]=1
Reactant: N#CSCC(=O)c1ccccc1F
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccccc1-c1csc(Br)n1
Temperature: 130 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-oxoethyl thiocyanate (4.20 g, 21.5 mmol) in acetic acid (40 ml) was added a solution of 25% hydrogen bromide/acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (3.41 g, 61.4%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.OC1C=CC(CC(O)=O)=CC=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:64][C:65]([O:68][C:69]([NH:71][C@H:72]([C:76]1[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][CH:77]=1)[C:73](O)=[O:74])=[O:70])([CH3:67])[CH3:66]>C(Cl)Cl.CN(C)C=O>[OH:82][C:79]1[CH:80]=[CH:81][C:76]([C@@H:72]([NH:71][C:69](=[O:70])[O:68][C:65]([CH3:66])([CH3:64])[CH3:67])[C:73](=[O:74])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:77][CH:78]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Yield: 91 %

Procedure:
Preparation of example 153 from the title compound of Example 7 (hydrochloride) (42 mg, 0.134 mmol), (2R)-({[(1,1-dimethylethyl)oxy]carbonyl)}amino)(4-hydroxyphenyl)ethanoic acid (54 mg, 0.202 mmol), triethylamine (0.056 mL, 0.402 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (77 mg, 0.202 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (27 mg, 0.10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were added after 24 hours to drive the reaction to completion. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (48 mg, 0.091 mmol) as a yellow powder in 68% yield.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([CH2:24][CH2:25][C:26](O)=[O:27])=O)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:32][NH2:33]>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]4[CH2:24][CH2:25][C:26](=[O:27])[NH:32][N:33]=4)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCN2CCC(c3ccccc3)CC2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)=NN1

Procedure:
10 g (23.7 millimoles) of 3-{p-[3-(4-phenylpiperidino)-propionylamino]-benzoyl}-propionic acid were stirred with 1.2 g (23.7 millimoles) of hydrazine hydrate in 200 ml of ethanol for 5 hours at 80° C. The product was filtered off under suction and recrystallized from dimethylformamide/water. 7.6 g (78%) of 6-{p-[3-(4-phenylpiperidino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.1/4H2O were obtained as colorless crystals of melting point 238°-240° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:35])[NH:17][C:18]1[S:19][C:20](C2C=CC=C(C(=O)NC3CC3)C=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]([C:40]1[O:41][C:42](C2N=C(N)SC=2)=[CH:43][CH:44]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC(N1CCC[C@H]1C(O)=O)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:35])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:42]2[O:41][C:40]([C:38]([O:37][CH3:36])=[O:39])=[CH:44][CH:43]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2csc(N)n2)o1
Reactant: O=C(NC1CC1)c1cccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1

Procedure:
In a similar procedure as described for the synthesis of Compound 5312 (Example 312), 5-(2-amino-thiazol-4-yl)-furan-2-carboxylic acid methyl ester was treated with HATU (0.98 g, 2.38 mmol), DIEA (0.7 mL, 5.36 mmol), and (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.61 g, 2.45 mmol) to furnish (S)-2-[4-(5-Methoxycarbonyl-furan-2-yl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester; MS: 169.1 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[CH:4]=[C:3]([NH2:11])[CH:2]=1.[C:12]([O-])(=[O:14])[CH3:13].[Na+:16].C(OC(=O)C)(=O)C>>[Na+:16].[C:12]([NH:11][C:3]1[CH:4]=[C:5]([S:7]([O-:10])(=[O:8])=[O:9])[CH:6]=[CH:1][CH:2]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(S(=O)(=O)[O-])c1
Yield: 95 %

Procedure:
Metanilic acid (3-aminobenzenesulfonic acid) in an amount of 37.5 parts, and 18.7 parts of sodium acetate are charged into the kneader and the procedure described and 32 parts of acetic anhydride are added to the reaction mixture. The powdery reaction mass is mixed for one hour and then dried at 85° C. in a stream of air to give a 95% yield of 3-acetylaminobenzenesulfonic acid sodium salt. Liquid chromatography and titration analysis indicated a purity of greater than 97% and the presence of about 0.5% metanilic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([C@H:15]1[O:17][CH2:16]1)[Cl:14]>CC#N>[Cl:14][CH2:13][C@@H:15]([OH:17])[CH2:16][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: ClC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CC#N
Product: O=C1CSc2ccc(NC[C@H](O)CCl)cc2N1
Temperature: 45 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
A suspension of 6-amino-4H-benzo[1,4]thiazin-3-one (18.0 g, 100 mmol; commercial) and Ca(OTf)2 (0.5 eq.) in MeCN (800 mL) was heated at 50° for 1 h. (S)-epichlorohydrin (18.5 g, 200 mmol) was added and the mixture was stirred at rt for 72 h and at 45° C. for 24 h. The volatiles were removed under reduced pressure. After aqueous workup and extraction with EA, the title intermediate crystallised from EA to afford a beige solid (17.38 g, 64% yield).
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].[OH-].[K+]>C(O)C>[CH:1]([C:3]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCCOc1cccc(OCc2ccccc2)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1c(OCCCCC(=O)O)cccc1OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of ethyl 5-(2-formyl-3-benzyloxyphenoxy)pentanoate (3.61 g, 0.01 M), potassium hydroxide (1.19 g, 0.021 M) and ethanol (40 ml) were stirred at 50°-60° C. for 5 hours. The ethanol was then removed in vacuo, the residue dissolved in water (50 ml) and the solution extracted with ether (2×80 ml). The aqueous layer was then acidified by the addition of 2N aqueous hydrochloric acid and the product extracted with ether (3×50 ml), and the combined extracts washed with water to neutrality, dried, and concentrated in vacuo to give 5-(2-formyl-3-benzyloxyphenoxy) pentanoic acid, 3.0 g, 91% as a yellow oil which crystallised on standing. The crude solid was crystallised from benzene/petroleum spirit 30°-40° C. to give pale cream crystals m.p. 110° C.
Reaction SMILES: [K+].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10](=[O:24])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O-:23])=O)=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C1COCC1.CN(C=O)C>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10](=[O:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[O:23])=[CH:17][CH:18]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
A mixture of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid potassium salt (1.25 g, 3.6 mmol), EDC (828 mg, 4.32 mmol), HOBT (584 mg, 4.32 mmol), TEA (1.0 ml, 7.2 mmol), NH2OTHP (421 mg, 3.60 mmol) in THF (20 ml) and DMF (20 ml) was stirred at room temperature for 12 h and then partitioned between water and AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 2:8) to give 1.2 g of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C:9](C)([CH2:11]C#N)[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].[OH-:19].[K+].[CH2:21]([OH:24])[CH2:22]O.Cl>O>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C:9]([CH2:22][C:21]([OH:24])=[O:19])([CH3:11])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16]
Reactant: [OH-]
Reactant: OCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of the rac.-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile from Example 7 (14.8 g), 10.2 g (155 mmoles) of 85% KOH, 9 ml of water and 83 ml of ethylene glycol was stirred and refluxed for 17.5 hr. The resulting solution was cooled to room temperature and diluted with 250 ml of water. The pH of the solution was adjusted to 8 with 3 N aqueous HCl and the resulting mixture was extracted with three portions of ether (the ether extracts were discarded). The aqueous phase was further diluted with water and acidified by the dropwise addition of 3 N aqueous HCl. The resulting precipitate was filtered off and washed with water, then dried under high vacuum at room temperature for 24 hr to give 8.05 g (75%) of rac.-(6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)acetic acid as a tan solid m.p. 169°-172° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].CCN(C(C)C)C(C)C.Cl[C:31]1[N:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:31]1[N:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1)=[O:20]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cn1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-aminocyclopentyl]-2,6-m dimethoxybenzamide hydrochloride (Intermediate 5; 80 mg, 0.27 mmol), DIPEA (0.139 ml, 0.80 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 0.058 mg, 0.32 mmol) and dry NMP (0.9 ml). The resulting mixture was subjected to microwave irradiation at 250° C. for 20 minutes. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:10][CH2:11][CH2:12][Cl:13])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][NH:22][CH2:21]2>>[ClH:13].[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:10][CH2:11][CH2:12][N:22]2[CH2:23][CH:24]3[CH2:27][CH2:28][CH:20]([CH2:26][CH2:25]3)[CH2:21]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCCCl)(c1ccccc1)c1ccccc1
Reactant: C1CC2CCC1CNC2
Product: Cl
Product: N#CC(CCCN1CC2CCC(CC2)C1)(c1ccccc1)c1ccccc1

Procedure:
Using an equivalent quantity of 2,2-diphenyl-5-chlorovaleronitrile in place of the 2,2-diphenyl-4-bromobutyronitrile, and 3-azabicyclo[3.2.2]nonane in place of the piperidine used in Example 22, and substantially repeating the procedure detailed therein, affords 2,2-diphenyl-5-(3-azabicyclo[3.2.2]non-3-yl)valeronitrile hydrochloride, melting at about 272° - 273° C. This compound is represented by the following structural formula. ##STR17##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](F)[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2].CS(C1C=CC(C2SC(N)=NC=2C)=CC=1[C:47]([F:50])([F:49])[F:48])(=O)=O>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([C:47]([F:50])([F:49])[F:48])[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl-].[CH3:11][O:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH2+:16]1)=[O:14].Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(#N)C>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[C:13]([O:12][CH3:11])=[O:14]
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyldiisopropylamine (6.52 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidinium chloride (3.057 g) [see Preparation 1] and 2-chlorobenzoxazole (2.13 ml) in acetonitrile (50 ml). The reaction mixture was stirred at room temperature for 18 hours and then at 50° C. for a further 2 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:10:0, changing to 0:100:0, followed by 0:95:5, by volume, hexane:ethyl acetate:methanol, to afford methyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.18 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(-c2ccncc2)c1
Reaction time: 0.58 h
Yield: 82.1 %

Procedure:
To a solution of 4-(2-fluoro-5-nitrophenyl)pyridine (1.0 g, 5.58 mmol) in ethanol (30 ml) and ethyl acetate (10 ml) was added platinum(IV) oxide (52 mg) and the mixture stirred for 35 min under hydrogen (40 psi). The reaction was filtered through glass microfibre filter paper and the filtrate evaporated to dryness to give 4-fluoro-3-(pyridin-4-yl)phenylamine (862 mg, 100%) as a white solid: 1H NMR (360 MHz, CDCl3) δ 3.49 (2H, s), 6.66-6.70 (1H, m), 6.71-6.76 (1H, m), 6.99 (1H, t, J 9 Hz), 7.44-7.46 (2H, m), 8.66 (2H, d, J 5 Hz).
Reaction SMILES: Cl[C:2]1C=C[CH:5]=[CH:4][C:3]=1C.[CH2:9]([CH:11]1[O:13][CH2:12]1)[Cl:10].[O:14]=O>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2]>[Cl:10][C:9]1[CH:5]=[CH:4][CH:3]=[CH:2][C:11]=1[C:12]([OH:13])=[O:14]
Reactant: O=O
Reactant: Cc1ccccc1Cl
Reactant: ClCC1CO1
Agent: [Co+2]
Agent: CCCCC(CC)C(=O)[O-]
Product: O=C(O)c1ccccc1Cl
Temperature: 155 °C

Procedure:
Into the column were charged 453 grams (3.58 moles) of o-chlorotoluene, 2.25 grams of cobalt octoate (6% Co), and 1.0 gram of epichlorohydrin. The reaction mixture was heated to 155° C. and maintained at that temperature while oxygen was bubbled through it at the rate of 300 ml./min. An additional 1.0 gram of epichlorohydrin was added to the reaction mixture every two hours during the oxidation. Throughout the reaction period, the gases leaving the column remained non-acidic. At the end of 14 hours, when 35 grams of water had been collected, the reaction mixture was removed from the column, cooled to 75° C. and extracted with 600 grams of 10 percent aqueous sodium hydroxide solution. The layers that formed were separated. The aqueous layer was diluted with water to a volume of 1500 ml. and then acidified with hydrochloric acid. The o-chlorobenzoic acid that precipitated was collected, washed with water, and dried. There was obtained 177 grams (1.135 moles) of o-chlorobenzoic acid. The conversion of o-chlorotoluene to o-chlorobenzoic acid was 43 percent. The yield of o-chlorobenzoic acid, based on o-chlorotoluene reacted, was 73.8 percent.
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][NH:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO>[CH2:25]([N:23]1[CH2:24][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH2:22]1)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1CC(c2ccccc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (735 mg, 2.21 mmol) in methanol (10 mL) was added acetaldehyde (107 mg, 136 μL, 2.43 mmol), then sodium cyanoborohydride (195 mg, 1.5 mL, 3.10 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with DCM (50 mL), washed with 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was extracted with DCM (2×25 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography using (0-75% EtOAc/DCM) as eluent to give tert-butyl 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540 mg, 68%) as a viscous yellow oil. ESI-MS m/z calc. 360.5. found 361.7 (M+1)+; Retention time: 1.15 minutes (3 min run).