Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[C:10]([CH:12]([CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(C#N)CC(OCC)OCC
Temperature: 145 °C
Yield: 78 %

Procedure:
2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq.) was added to a mixture of ethyl 2 cyanoacetate (11.4 g, 101 mmol, 5.0 eq.), K2CO3 (2.8 g, 20 mmol, 1.0 eq.) and NaI (200 mg, 1.3 mmol, 0.06 eq.), as described in J. Chem. Soc., 1960, 131-138. The reaction mixture was refluxed for 4 h at 145° C. After cooling, the reaction mixture was purified by chromatography on silica gel (eluted with petroleum ether/ethyl acetate (80:1→40:1→10:1) to give 3.57 g of xlii-a as a colorless oil (78%). 1H NMR (400 MHz, CDCl3): δ 4.70 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.78-3.64 (m, 3H), 3.62-3.45 (m, 2H), 2.35-2.14 (m, 2H), 1.34 (q, J=7.2 Hz, 3H), 1.25-1.16 (m, 6H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: COc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1
Reactant: C#CCCO
Product: COc1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 468 (0.22 mmol) and but-3-yn-1-ol (0.28 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.8, 160.8, 148.5, 141.1, 141.0, 138.1, 135.5, 134.8, 133.9, 132.6, 130.4, 127.8, 122.2, 120.7, 119.9, 116.6, 113.6, 113.2, 109.4, 107.3, 61.6, 55.4, 28.7, 19.9
Reaction SMILES: [CH2:1]=[CH:2]C(=O)CCC.[OH:8][C:9]1([CH3:23])[CH2:14][CH:13]([OH:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH:10]1[CH:18]=[CH:19][CH:20]([OH:22])[CH3:21]>>[OH:8][C:9]1([CH3:23])[CH2:14][CH:13]([OH:15])[CH2:12][C:11]([CH3:16])([CH3:17])[CH:10]1[CH:18]=[CH:19][CH:20]([OH:22])[CH2:21][CH2:1][CH3:2]
Reactant: C=CC(=O)CCC
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCCC(O)C=CC1C(C)(C)CC(O)CC1(C)O

Procedure:
The entitled compound was prepared from 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl)]hex-1-en-3-one in the same manner as described in Example 1-(4), (5), and (6).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:13][C:5]2[NH:6][C:7]([C:9]([O:11]C)=[O:10])=[CH:8][C:4]=2[CH2:3]1.O.[OH-].[Li+]>>[F:14][C:2]1([F:1])[CH2:13][C:5]2[NH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CC(F)(F)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CC(F)(F)C2

Procedure:
The title compound was synthesized from methyl 5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide monohydrate according to General Procedure 7. The material was purified by reverse-phase chromatography (MeCN/H2O, 0.05% TFA) to afford 1.6 mg of 5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid in 45.0% yield. 19F NMR (400 MHz, acetone-d6) δ ppm −86.73; LCMS-MS (ESI+) 188.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33](O)=[O:34])=[N:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:24][N:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1noc2ccccc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2noc3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Benzo[d]isoxazole-3-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=473.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][CH:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-amino-N-methylpiperidine according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.41-1.84 (m, 10 H), 2.09 (s, 3 H), 2.54-3.03 (m, 4 H), 2.92 (s, 4 H), 3.63 (s, 1 H), 6.30 (s, 1 H), 6.94-6.98 (m, 2 H), 7.15 (d, J=8.8 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1H), 7.43 (s, 1 H), 7.51-7.61 (m, 3 H), 7.80 (d, J=8.8 Hz, 1 H), 7.97 (d, J=8.4 Hz, 1 H), 8.20 (s, 1 H), 10.42 (s, 1 H).
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.C([NH:15][C@H:16]([C:21](O)=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18])(OC(C)(C)C)=O.Cl>>[ClH:1].[NH2:15][C@@H:16]([CH:17]([CH3:18])[CH2:19][CH3:20])[C:21]([N:5]1[CH2:6][C:3]([F:7])([F:2])[CH2:4]1)=[O:22]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: FC1(F)CNC1
Agent: Cl
Product: CCC(C)[C@H](N)C(=O)N1CC(F)(F)C1

Procedure:
(S)-2-amino-1-(3,3-difluoro-azetidin-1-yl)-3-methyl-pentan-1-one hydrochloride was prepared by coupling 3,3-difluoro-azetidine hydrochloride (WO 0047582) with Boc-(L)-isoleucine followed by HCl deprotection as analogously described in Example 1 (mp 195° C. dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6]C(=O)C(C)C(O)=O.[CH:18]([CH:21]([C:27]([O:29]CC)=O)[C:22]([O:24]CC)=[O:23])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:27](=[O:29])[CH:21]([CH:18]([CH3:19])[CH3:20])[C:22]([OH:24])=[O:23]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Product: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-isopropyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl isopropyl-malonate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1.Cl>C(Cl)Cl>[C:5]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=2[F:22])=[CH:21][CH:20]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A reaction vessel was charged with 113 g of anhydrous aluminum chloride and 600 ml of methylene chloride. To the mixture was added dropwise 113 g of acetyl chloride with stirring at a temperature not higher than 0° C., and was then added dropwise a solution of 100 g of 4-bromo-2-fluoro-biphenyl in 400 ml of methylene chloride. The mixture was reacted with stirring for 7 hours while gradually bringing it back to room temperature. The reaction liquid was poured into ice and diluted hydrochloric acid. The methylene chloride layer was washed successively with water, an aqueous solution of sodium hydrogen carbonate and water, and then dried over Glauber's salt. The solvent was then distilled off and the residue was recrystallized from acetone to give 96 g (82.2%) of 4-acetyl-2'-fluoro-4'-bromobiphenyl.
Reaction SMILES: [CH2:1]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+].Cl[CH2:39][CH:40]([OH:43])[CH2:41][OH:42]>O.CCOCC>[CH2:1]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:39][CH:40]([OH:43])[CH2:41][OH:42])=[O:21])=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCC=CCCCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCC=CCCCc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.35 g. of 4-(4-pentadecenyl)benzoic acid in 50 ml. of hexamethylphosphoramide is treated with 4.80 g. of 25% aqueous sodium hydroxide followed by 11.0 g. of 3-chloro-1,2-propanediol and then is heated at 140° C. for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile and then from carbon tetrachloride affords the product as a white solid.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].BrCCBr.[CH2:10]=[C:11]([CH2:14][CH2:15][CH3:16])[CH:12]=[O:13].[Cl-].[NH4+]>CCOCC>[OH:13][CH:12]([C:11](=[CH2:10])[CH2:14][CH2:15][CH3:16])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: C=C(C=O)CCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Product: C#CCC(O)C(=C)CCC
Temperature: 0 °C

Procedure:
To a stirred mixture of 12.16 g. of magnesium in 120 ml. of ether containing 200 mg. of mercuric chloride is added 2 ml. of propargyl bromide and 0.5 ml. of 1,2-dibromoethane. This mixture is stirred under argon until the reaction begins. To this is added with stirring a solution of 41.57 g. of 2-methylene valeraldehyde and 64.95 g. of propargyl bromide in 90 ml. of ether, dropwise, at a rate to maintain reflux. After addition is complete the mixture is refluxed 15 minutes, stirred at room temperature one hour, cooled to 0° C. and saturated ammonium chloride solution is added dropwise until reflux stops. The mixture is filtered through Celite, dried over magnesium sulfate and the ether is removed giving the product as a light orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:22][CH:23]([NH2:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:22][CH:23]([NH:33][C:12](=[O:14])[CH:11]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(=CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCC(C)N
Agent: CCOC(=O)Cl
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc([N+](=O)[O-])c1
Yield: 72 %

Procedure:
The 3-(3-nitrophenyl)-2-butenoic acid from Preparation 12 having a melting point of 147°-149° C. was reacted with ethyl chloroformate, followed by 1-methyldecylamine, according to the procedure of Preparation 22. This afforded a 72% yield of the title product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[CH2:26]([O:33][C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)C.[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(#N)C>[CH2:26]([O:33][C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]4[CH3:25])[C:5]4[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=4[N:7]=3)=[CH:43][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CC1(C)OB(c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C(=O)OC(C)(C)C)C2
Yield: 87.6 %

Procedure:
To a mixture of (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (by) (54 mg, 0.15 mmol), 6-(benzyloxy)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2-amine (ow) (prepared in Example 289, 61 mg, 0.15 mmol), Tetrakis(triphenylphosphine)palladium(0) (11.7 mg, 0.0101 mmol), Potassium carbonate (26.8 mg, 0.194 mmol) and Potassium acetate (19.9 mg, 0.203 mmol) was added Acetonitrile (0.56 mL) and Water (0.23 mL) under N2. The reaction was microwaved at 120° C. for 20 minutes. After evaporation of solvents, the residue was purified on a silica gel column to give the desired product (80 mg, 90% yield) as slightly brown powder. The 1H-NMR, TLC and LC-MS were identical to the one in Example 299.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:11]1([C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:17][C:18]([F:19])([F:20])[F:21])[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nn1CC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2)nn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360 mg, 1.21 mmol) and 1N aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH˜2 with 1N aqueous hydrochloric acid and concentrated to give 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C12H9F3N2O2 (m/e) 270, obsd 271 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)(=[O:10])[CH3:9].C(OC(C)C)(C)C>C(O)=O>[CH3:16][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[C:19]([CH2:1][N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:18]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CN1CCNCC1
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CC(=O)Nc1ccc(C)cc1CN1CCNCC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of formic acid (3.77 mL) at −10° C. was treated with 1-methylpiperazine (11.10 mL) dropwise whilst maintaining the temperature at −10° C. The reaction mixture was then allowed to warm to room temperature and treated with 4-acetamidobenzaldehyde (4.08 g). After stirring at 130° C. for 15 minutes the temperature was increased to 155° C. and stirring continued for 2.5 hours. The reaction mixture was allowed to cool to room temperature and treated with diisopropyl ether (50 mL). The insoluble material was washed with diethyl ether to give the title compound (3.98 g) as buff crystalline solid, m.p. 106–108° C. MS: 248 [MH]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](OC)=[O:22])[NH:12][C:11]=3[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][OH:27].[OH-].[K+]>C1COCC1>[OH:27][NH:26][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[NH:12][C:11]2[CH:25]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[CH:9][C:10]=2[N:14]=1
Reactant: COC(=O)CCCCCCc1nc2ccc(-c3ccccc3)cc2[nH]1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCc1nc2ccc(-c3ccccc3)cc2[nH]1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of methyl 7-(6-phenyl-1H-benzo[d]imidazol-2-yl)heptanoate (50 mg, 0.15 mmol) in THF at 0° C. was added 50% hydroxylamine solution (0.10 mL, 1.5 mmol). To this was added KOH (0.45 mL, 1M in MeOH, 0.45 mmol) dropwise. The reaction was stirred at 0° C. for 2 hr, briefly concentrated and neutralized by adding 1 N HCl solution until pH was 7. The white precipitate was collected by filtration and purified by biotage column chromatography to give N-hydroxy-7-(6-phenyl-1H-benzo[d]imidazol-2-yl)heptanamide 18 (27 mg). MS (M+1=338)
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@@H:5]([CH2:7][C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:18])[O:3]1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][C:5]1([CH2:7][C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:18])[O:3][C:2]([CH3:19])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O[Si](C)(C)C(C)(C)C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Reaction time: 0.08 h

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, t-butyldimethylsilyl ester (20.9 g, 72.4 mmol) in carbon tetrachloride (200 ml) was treated with N-bromosuccinimide (14.18 g, 79.6 mmol) and 2,2′-azobisisobutyronitrile (0.30 g) and the resulting mixture was heated under reflux while irradiating with a 500 W lamp. After approximately 5 minutes, a mild exothermic reaction was observed and the mixture was heated for an additional 5 minutes. The reaction mixture was then cooled in an ice bath and the floating succinimide was filtered and washed with a small amount of carbon tetrachloride. The filtrate was used immediately as such for the next step. 1H NMR (400 MHz, CDCl3) δ: 0.27 (s, 3), 0.28 (s, 3), 0.94 (s, 9), 1.66 (s, 3), 1.84 (s, 3), 3.62 (m, 2).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (610 mg) in N,N-dimethylformamide (20 mL) is added successively 2-dimethylaminoethyl chloride hydrochloride (1.08 g) and potassium carbonate (2.0 g), and the mixture is stirred at room temperature for 18 hours. To the reaction mixture is added ethyl acetate, and the mixture is washed with water and saturated brine and dried over anhydrous sodium sulfate. The resultant crude product is purified by column chromatography in silica gel (Solvent; chloroform:methanol=20:1→10:1) to give 4-[2-(dimethylamino)-ethoxy]benzaldehyde (640 mg, yield; 66%) as a pale yellow oil. MS (APCI) m/z: 194 [M+H]+
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:16][CH2:15][N:14]([C:12]([NH:11][CH:2]3[CH:3]4[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][CH:1]3[CH2:8]5)[CH2:4]4)=[O:13])[CH2:19][CH2:18]2)[CH2:20]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a solution N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (50 mg, 0.108 mmol) and DIEA (27.86 g, 0.22 mmol) in dry CH2Cl2 (2-mL) at 0° C. under nitrogen was added dropwise a solution of acetyl chloride (9.28 mg, 0.12 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred overnight at rt and evaporated to give a residue, which was purified by preparative HPLC to provide a white solid 1-acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (5.2 mg, 12%). 1H NMR (400 MHz, CD3OD): δ=1.61 (s, 1H), 1.653 (d, 2H), 1.72 (s, 1H), 1.88 (m, 10H), 2.015 (d, 5H), 2.286 (s, 3H), 3.027 (t, 2H), 3.867 (s, 1H), 4.088 (d, 4H), 7.044 (t, 1H), 7.191 (t, 2H), 8.082 (d, 1H); LC-MS (4 min) tR=1.59 min, m/z=408(M++1).
Reaction SMILES: CC1C=CC(C(O)=O)=CC=1[CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:18]=1.N1C=CC=CC=1.IC1C=C(C=CC=1C)C(O)=O.CCN(C(C)C)C(C)C>C(N(CC)CC)C.C(OCC)(=O)C.CN(C=O)C>[C:12]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:18]=1)#[CH:11]
Reactant: Cc1ccc(C(=O)O)cc1CCc1cncc(CN2CCCC2)c1
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cncc(CN2CCCC2)c1

Procedure:
4-methyl-3-{[5-(pyrrolidin-1-ylmethyl)pyridin-3-yl]ethyl}benzoic acid can be prepared in a manner similar to that described above for the Sonogashira reaction. 3-Ethynyl-5-<pyrrolidin-1-ylmethyl)pyridine and 3-iodo-4-methylbenzoic acid are used as coupling partners. Alternatively, the solvent (DMF) can be replaced by ethyl acetate and the base (Hunig base) can be replaced by triethylamine. The product can be isolated by filtration of the crude reaction mixture. The filter cake is washed sequentially with a solvent such as ethyl acetate and then water, then dried in a vacuum oven. Further purification can be achieved by slurrying the solids in water adjusted to pH 3 with the addition of concentrated HCl. After filtration and water wash, the product can be dried in a vacuum oven.
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH:20]1([CH2:23][S:24][CH:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1>COCCOC.C(OCC)(=O)C>[CH:20]1([CH2:23][S:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:17]#[N:18])[CH2:27][CH2:26]2)[CH2:22][CH2:21]1
Reactant: O=C1CCC(SCC2CC2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#CC1CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
Potassium-t-butoxide (16.10 g, 144 mmol) was added to a stirred, cooled (0° C.) mixture of TOSMIC (15.84 g, 81 mmol) and 4-[(cyclopropylmethyl)thio]cyclohexanone (11.5 g, 62.4 mmol) in DME (125 ml) and the mixture was stirred at room temperature for 3 h. The mixture was cooled, diluted with ethyl acetate, washed with brine, dried, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a Biotage 65i cartridge, eluting with EtOAc/isohexane to give two separated isomers. Combined yield of 4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (7.1 g, 36.3 mmol, 58.3% yield)