Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([N:19]([CH3:25])[CH2:20][C:21](OC)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C>CO>[CH2:10]([CH:9]1[C:17](=[O:18])[N:19]([CH3:25])[CH2:20][C:21](=[O:22])[NH:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CC(=O)NC(Cc2ccccc2)C1=O

Procedure:
The compound obtained in Step (i) was treated with trifluoroacetic acid (30 ml), and then the resultant was heated under reflux in methanol in the presence of triethylamine to give the subtitle compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>C(Cl)Cl>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)=[O:10]
Reactant: O=C=Nc1cccc(I)c1
Reactant: COC(CN)OC
Solvent: ClCCl
Product: COC(CNC(=O)Nc1cccc(I)c1)OC
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A suspension of 3-iodophenylisocyanate (1.1 g) in DCM (10 ml) was treated with aminoacetaldehyde dimethyl acetal (0.49 ml) and stirred under nitrogen at 20° C. for 24 h. The reaction mixture was quenched by adding MeOH. The solvents were removed under reduced pressure to give the title compound (1.35 g) LCMS RT=2.92 min.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.C(OCC)(=[O:34])C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:5][C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:4])[CH:1]=[O:34]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (8.60 g, 45.5 mmol) in toluene (60 mL)/tetrahydrofuran (40 mL) was added dropwise a 1.0M solution of diisobutylaluminum hydride in hexane (100 mL, 100 mmol) at −78° C. over 1 hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr and at 0° C. for 1 hr. The reaction mixture was poured into a mixture of ethyl acetate (200 mL) and 3N hydrochloric acid (300 mL), and the organic layer and the aqueous layer were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (6.39 g, 73%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:10][C:11]([S@@:14](/[N:16]=[CH:8]/[C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:15])([CH3:13])[CH3:12]
Reactant: Cc1cccnc1C=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Cc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-methyl-2-pyridinecarboxaldehyde (3.243 g, 26.8 mmol) in DCM (18 mL) was added (S)-2-methylpropane-2-sulfinamide (6.55 g, 54.0 mmol) and copper(II) sulfate (8.72 g, 54.6 mmol). The suspension was stirred at rt for 17 hours, filtered, and the solid was washed with DCM (2×35 mL). The filtrates were concentrated, and the resulting product was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using DCM/MeOH gradient to yield the desired product (S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide as a yellow solid.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[C:27]1([CH:33]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](O)([C:43]3[C:44]([OH:52])=[CH:45][C:46]4[O:50][CH2:49][CH2:48][C:47]=4[CH:51]=3)[C:35]2=[O:54])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:55]1([CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]([C:43]3[C:44]([OH:52])=[CH:45][C:46]4[O:50][CH2:49][CH2:48][C:47]=4[CH:51]=3)[C:35]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1C(c2cc3c(cc2O)OCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (67%) as a white solid: MS (ES+) m/z 434.3 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[S:20][C:21]([CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:22]([CH3:24])[CH:23]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)C.Cl>[Li+].[OH-].CO>[CH2:27]([N:26]([CH2:25][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])=[O:31])=[CH:9][CH:10]=3)[N:18]=2)=[CH:23][C:22]=1[CH3:24])[CH2:29][CH3:30])[CH3:28]
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)NCC(=O)O)cc3)no2)cc1C
Yield: 30.4 %

Procedure:
A solution of {4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoylamino}-acetic acid ethyl ester (105 mg, 230 μmol) in 2 M LiOH in methanol (10 mL) is stirred at rt for 20 h. The mixture is acidified by adding aq. HCl before it is extracted twice with EA. The aq. solution is neutralised by adding sat. aq. NaHCO3 solution and concentrated. The remaining solid is suspended in methanol, filtered and the filtrate is concentrated. The remaining residue is again suspended in a small volume of methanol, filtered and the filtrate is again concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 20% of methanol to give the title compound (30 mg) as a white solid; LC-MS: tR=0.48 min; [M+1]+=429.09; 1H NMR (D6-DMSO): δ1.04 (t, J=7.0 Hz, 6H), 2.23 (s, 3H), 2.58 (q, J=7.3 Hz, 4H), 3.60 (d, J=4.8 Hz, 2H), 3.74 (s, 2H), 7.84 (s, 1H), 8.02-8.07 (m, 2H), 8.10-8.15 (m, 2H), 8.17 (t, J=4.5 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][CH:28](C(O)=O)[C:29]([OH:31])=[O:30])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC(C(=O)O)C(=O)O)ccc3o2)n1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCC(=O)O)ccc3o2)n1
Reaction time: 7 h
Yield: 72.8 %

Procedure:
A mixture of 4-tert-butyl-2-[5-{2-(2,2-dicarboxyethyl)phenylmethoxy}benzofuran-2-yl]thiazole (1.30 g) in xylene (20 ml) was refluxed with stirring for 7 hours. After being cooled, the mixture was subjected to column chromatography on silica gel (45 g) and eluted with a mixture of methanol and chloroform. The fractions containing object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of diethyl ether and petroleum ether to give 4-tert-butyl-2-[5-{2-(2-carboxyethyl)phenylmethoxy}benzofuran-2-yl]thiazole (0.86 g).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26]C1C=CC=CC=1S(Cl)(=O)=O>>[CH3:25][O:26][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[S:7]([NH:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8]
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2OC)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxlyate and 2-methoxybenzene-sulphonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.BrCC1C=CC=CC=1[Cl:28]>>[Cl:28][C:17]1[CH:18]=[CH:19][CH:2]=[CH:3][C:4]=1[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1
Reactant: Clc1ccccc1CBr
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Product: COc1cc(SCc2ccccc2Cl)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-2-chlorobenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:46])[C:29]([C:31]1[N:40]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:34]2[N:35]=[C:36](Cl)[N:37]=[CH:38][C:33]=2[CH:32]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:36]4[N:37]=[CH:38][C:33]5[CH:32]=[C:31]([C:29](=[O:30])[N:28]([CH3:27])[CH3:46])[N:40]([CH:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)[C:34]=5[N:35]=4)=[CH:22][CH:23]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(c3ccc(N)nc3)C2=O)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCCC5(CCN(C(=O)OC(C)(C)C)CC5)C4=O)cn3)nc2n1C1CCCC1
Yield: 93.1 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-amino-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylic acid tert-butyl ester (98 mg, 0.27 mmol) was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (80 mg, 0.27 mmol) which gave 2[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylic acid tert-butyl ester (155 mg) in 92% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.92-8.70 (m, 1H), 8.63-8.53 (m, 1H), 8.25-8.13 (m, 1H), 7.75-7.36 (m, 1H), 6.59-6.46 (m, 1H), 4.93-4.70 (m, 1H), 3.93-3.78 (m 2H), 3.74-3.65 (m, 2H), 3.28-3.18 (m, 2H), 3.14 (s, 6H), 2.65-2.49 (m, 2H), 2.24-1.88 (m, 9H), 1.85-1.71 (m, 2H), 1.65-1.50 (m, 3H), 1.47 (s, 9H); HR-MS m/z 617.3583 (M+H)+
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24]>>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: CCCCN1C(=O)COc2ccc(C=O)cc21
Product: CCCCN1C(=O)COc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (intermediate 65) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.BrCC1CCCCO1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:12]4=[O:20]
Reactant: BrCC1CCOCC1
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 4-(bromomethyl)tetrahydropyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 2-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 186-187° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.66-7.60 (m, 1H), 7.34-7.27 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.91 (m, 3H), 5.04-4.97 (m, 1H), 4.78-4.72 (m, 1H), 4.07-3.93 (m, 3H), 3.52-3.35 (m, 3H), 2.52 (s, 3H), 2.32-2.15 (m, 1H), 2.07-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.57-1.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 169.3, 160.6, 149.2, 143.1, 132.7, 129.1, 128.7, 123.7, 123.0, 122.3, 119.9, 108.7, 108.5, 81.5, 67.9, 62.4, 58.1, 46.6, 34.3, 30.9, 20.2, 14.6; MS (ES+) m/z 407.0 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H][H].[ClH:20]>C(O)C.[Pd]>[ClH:20].[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: OCc1ccc(-c2cccc3cncn23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 0.36 g of 5-(p-hydroxymethylphenyl)imidazo[1,5-a]pyridine in 25 ml of ethanol and 6.4 ml of concentrated hydrochloric acid is hydrogenated with 0.15 g of 10% palladium on charcoal at 40 psi of hydrogen and 60° for 4 h. The reaction mixture is filtered and evaporated and the residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated to an oil which is purified by preparative layer chromatography on silica with ethyl acetate. The hydrochloride salt is prepared in acetone with 1.1 molar equivalents of ethereal hydrogen chloride to yield the title compound, m.p. 173°-175°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([O-])=O.[Na+].O>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([F:9])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
Alternatively, 4-chloro-2-fluorophenyl hydrazine is prepared by the following method. 43.7 parts of 4-chloro-2-fluoroaniline was dissolved in 735 parts of concentrated hydrochloric acid. The solution was cooled to 0°-5° C. and a solution of 22.8 parts of sodium nitrite in 187 parts water was added dropwise maintaining the temperature of the reaction between 0°-5°. The excess nitrite was destroyed by the addition of small amounts of sulfamic acid until a negative test with sulfone reagent was obtained. To the solution of the diazonium salt was added, as rapidly as possible, a solution of 170 parts stannous chloride dihydrate in 275 parts of concentrated hydrochloric acid, precooled to -50°. When the addition was complete, a heavy white precipitate formed. The reaction mixture was allowed to warm to ambient temperature over one hour. The precipitate was collected by filtration, then suspended in 750 parts ice-water. The pH of the solution was adjusted to 11 by the addition of 50% aqueous sodium hydroxide. The resulting aqueous suspension was extracted three times; 200 parts of methylene chloride was used for each extraction. The combined organic extracts were dried with anhydrous magnesium sulfate, and the solvent removed under reduced pressure of 300 mm Hg to leave 38.5 parts of pinkish-tan crystalline 4-chloro-2-fluoro-phenylhydrazine, mp 51°-63°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH3:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH3:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: CCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (64 mg, 0.112 mmol) in DCM (5 ml) was added TFA (2.0 ml) and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (28 mg, 0.063 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 12.83-13.43 (m, 1H), 8.20 (d, 1H), 7.73 (s, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 6.66 (s, 1H), 4.48 (d, 2H), 2.53 (q, 2H), 1.08 (t, 3H). LC-MS (ES+) m/z 441.59, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]2)=[N:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:6].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([N:33]3[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]3)=[O:24])[CH2:18][CH2:17]2)=[N:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:6]
Reactant: OC1CCNCC1
Reactant: N#Cc1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cnc(N2CCC(CC(=O)N3CCC(O)CC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A mixture of 0.015 g (0.038 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.019 g (0.19 mmol) of 4-hydroxypiperdine, 0.016 g (0.049 mmol) of 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.016 mL (0.11 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is allowed to stir at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is diluted with water which results in a solid precipitating. The light red solid is collected by filtration and washed with water. The collected material is purified using preparative reverse phase HPLC to give 0.011 g (61%) of the title compound (145) as a colorless solid. [M+H]+=482.2
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: C(N[C@@H]1C(=O)N2[C@H](C(O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1.[C:26]([NH:34][CH:35]1[C:41](=[O:42])[N:40]2[CH:43]([C:47]([NH:49][CH:50]3[CH2:54][C:53](=[O:55])[O:52][CH:51]3[O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:48])[CH2:44][CH2:45][CH2:46][N:39]2[C:38](=[O:64])[CH2:37][CH2:36]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(N[C@H]1CC(=O)OC1OCC1C=CC([Cl:86])=CC=1)=O)C=C>>[C:26]([NH:34][CH:35]1[C:41](=[O:42])[N:40]2[CH:43]([C:47]([NH:49][CH:50]3[CH2:54][C:53](=[O:55])[O:52][CH:51]3[O:56][CH2:57][C:58]3[CH:59]=[CH:60][C:61]([Cl:86])=[CH:62][CH:63]=3)=[O:48])[CH2:44][CH2:45][CH2:46][N:39]2[C:38](=[O:64])[CH2:37][CH2:36]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccc(Cl)cc1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Agent: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Product: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccc(Cl)cc2)O1

Procedure:
was synthesized from 212e by the methods used to prepare 213e from 212e using 2101a to afford 380 mg of 2100f, 1H NMR (CDCl3) δ1.8-2.0(m, 10H), 2.30(d, 1H), 2.31-2.5(m, 3H), 2.7-2.9(m, 3H), 3.05(m, 2H), 3.1-3.2(m, 4H), 4.45(q, 1H), 4.5-4.6(m, 3H), 4.7(d, 2H), 4.85(d, 1H), 4.9(t, 1H), 5.2(t, 1H), 5.15(m, 2H), 5.25(s, 1H), 5.55(d, 1H), 6.5(d, 1H), 6.9(d, 1H), 6.95(d, 1H), 7.25(m, 3H), 7.35(t, 2H), 7.45(m, 2H), 7.55(1H), 7.8(m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][CH2:31][N:30](C(OCC3C=CC=CC=3)=O)[CH2:29][CH2:28]2)[NH:24][C:23]1=[O:43])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[NH:24][C:23]1=[O:43])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCNCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Yield: 101.1 %

Procedure:
A solution of 1.01 g of benzyl 3-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleramido]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate in 15 ml of methanol was treated with 0.432 g of 10% palladium-on-charcoal catalyst. The mixture was shaken in a hydrogen atmosphere for 18 hours. The catalyst was filtered off and the methanol evaporated. The residue was triturated with ether and there was obtained 0.81 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide in the form of a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[CH2:7]1)C.[BH4-].[Na+]>>[Br:16][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:7][CH:6]([CH2:5][CH2:4][OH:3])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Agent: [BH4-]
Agent: [Na+]
Product: OCCC1CC(c2cccc(Br)c2)C1
Temperature: 67 °C
Yield: 30.3 %

Procedure:
[3-(3-Bromo-phenyl)-cyclobutylidene]-acetic acid ethyl ester (1.96 gm, 6.63 mmol) was suspended in poly(ethylene glycol) (Average MW 400, 40 mL) and sodium borohydride (1.00 g, 26.4 mmol) was added portionwise. The slurry was warmed at 67° C. overnight, then cooled to room temperature and partitioned between 2N hydrochloric acid and diethylether. The ether extracts were dried with sodium sulfate and purified by column chromatography (50% EtOAc/hexanes) to afford 512 mg of an oil (30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.29 (m, 1H) 1.31-1.38 (m, 1H) 1.47-1.52 (m, 1H) 1.59-1.68 (m, 1H) 1.97-2.32 (m, 2H) 2.34-2.41 (m, 1H) 4.22-4.31 (m, 1H) 3.23-3.39 (m, 3H) 7.15-7.24 (m, 2H) 7.29-7.38 (m, 2H); MS (EI) m/z 254 [M+·].