Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CCN(S(F)(F)[F:25])CC>C(Cl)Cl>[F:25][CH:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC1F
Temperature: -20 °C
Yield: 66.7 %

Procedure:
To a solution of benzyl (3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-carboxylate (0.818 g, 3.26 mmol) in 20 mL CH2Cl2 at −20° C. was added DAST (0.946 mL, 7.16 mmol). The reaction mixture was stirred at −20 ° C. and then room temperature overnight. The reaction mixture was quenched with 30 mL half saturated NaHCO3, stirred at room temperature for 15 min and extracted with EtOAc (2×30 mL). The organic layer was dried and concentrated. The residue was purified by flash column chromatography (25% EtOAc in Hexane) to give pale yellow solid (0.551 g, 67%). 1H NMR (CDCl3) δ 7.36-7.29 (5H, m), 5.13 (2H, s), 5.09, 4.92 (1H, m), 3.95-3.91 (1H, m), 3.74-3.35 (4H, m), 3.37 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33]C)=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:14][C:13]1[S:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([OH:33])=[O:32])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole (2.13 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (1.65 g) and N,N-dimethylformamide (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.19 g, 44%) of 2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]3[CH2:17][NH:18][CH2:19][CH:13]3[C:12]2=[O:20])=[CH:7][CH:6]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.C(Cl)Cl>C(Cl)Cl.CO>[C:23]1([CH2:29][C:30]([CH:17]2[CH:14]3[CH:13]([C:12](=[O:20])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:21])[F:22])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)[CH2:19][NH:18]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1C2CNCC2CCN1c1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)C1NCC2C(=O)N(c3ccc(OC(F)(F)F)cc3)CCC21
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
5-(4-Trifluoromethoxy-phenyl)-octahydro-pyrrolo[3,4-c]pyridin-4-one, hydrochloride (80 mg, 0.24 mmol), 2-phenylacetyl chloride (74 mg, 0.48 mmol) and Et3N (0.12 g, 1.2 mmol) were added to DCM (10 mL), and the mixture was stirred for 12 h at ambient temperature. The product (45 mg, 46%) was obtained by prep-TLC (eluting with DCM/MeOH=25/1). 1H NMR (300 MHz, CDCl3): δ 7.34-7.23 (m, 9H), 3.90-3.54 (m, 7H), 3.23-3.20 (m, 2H), 2.78-2.75 (m, 1H), 2.07-2.02 (m, 1H), 1.83 (bs, 1H); LC-MS: [M+1]+ 418.7.
Reaction SMILES: [CH2:1](S([O-])(=O)=O)[CH2:2][CH3:3].[NH2:8][C:9]1[S:10][C:11]2[CH2:17][CH:16]([NH2:18])[CH2:15][CH2:14][C:12]=2[N:13]=1>>[NH2:8][C:9]1[S:10][C:11]2[CH2:17][CH:16]([NH:18][CH2:1][CH2:2][CH3:3])[CH2:15][CH2:14][C:12]=2[N:13]=1
Reactant: CCCS(=O)(=O)[O-]
Reactant: Nc1nc2c(s1)CC(N)CC2
Product: CCCNC1CCc2nc(N)sc2C1

Procedure:
In some embodiments, step one of the process may include the additional steps of heating a diamine to form a solution or melt in a heating step and adding the n-propyl halide or n-propyl sulfonate slowly over a period of time from, for example, about 0.5 hours to about 5 hours, in an additional step. In other embodiments, after the n-propyl halide or n-propyl sulfonate has been completely added to the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, the reaction may continue under heating for an additional period of time ranging from, for example, about 1 hour to about 12 hours, in a reaction step. In certain embodiments, the reaction mixture may be mixed by, for example, stirring for one or more of the steps above or the reaction mixture may be continually stirred from the heating step to the reaction step. Following the reaction step, the reaction mixture may be cooled and the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be isolated and purified.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH:9]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O1CCCC1>[CH:9]1([NH:15][C:16]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N-hydroxysuccinimide (11.5 g, 0.1 mol) was dissolved in 200 g of sufficiently dried tetrahydrofuran. To the solution was added dropwise 12.5 g (0.1 mol) of cyclohexyl isocyanate, and then a catalytic amount of triethylamine was added. After stirring at room temperature overnight, the reaction solution was decolored with active carbon and concentrated. The deposited crystal was filtered and washed with a small amount of ether to obtain 18.0 g of N-(cyclohexylcarbamoyloxy)succinimide represented by the following formula. Yield: 81.5%.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[O:22])[C:20]#[N:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:29])[C:26](Cl)=[O:27].C(N(C(C)C)C(C)C)C>C(O)(=O)C.[Pd].ClCCl>[CH3:23][O:24][C:25](=[O:29])[C:26]([NH:21][CH2:20][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:22])=[O:27]
Reactant: COc1cccc2c(C(=O)C#N)cn(CC3CCCCC3)c12
Reactant: COC(=O)C(=O)Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(=O)NCC(=O)c1cn(CC2CCCCC2)c2c(OC)cccc12
Reaction time: 14 h
Yield: 45 %

Procedure:
To a solution of (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxoacetonitrile (975 mg, 3.29 mmol) in acetic acid (40 ml) under nitrogen was added 10% palladium on charcoal (90 mg). The reaction was placed under a hydrogen atmosphere and stirred for 14 h. The reaction mixture was then filtered through a pad of dicalite. The dicalite was washed with acetic acid and the combined filtrate evaporated to leave a red oil. The red oil was taken up in dichloromethane (50 ml) and to this was added methylchlorooxoacetate (0.393 ml, 4.28 mmol) followed by N-ethyldiisopropylamine (1.7 ml, 9.87 mmol) dropwise. The reaction was stirred for 1 h and poured into a separating funnel. The organics were washed sequentially with 2M aqueous hydrochloric acid (50 ml), 5% aqueous sodium carbonate (50 ml) and brine (50 ml). The organics were dried over sodium sulfate, filtered and the solvent removed in vacuo to leave a brown oil. The oil was purified by flash chromatography using dichloromethane followed by 66% (v/v) diethyl ether in heptane to afford N-[(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxo-ethyl]oxalamic acid methyl ester (573 mg, 1.48 mmol) as a yellow/brown solid.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3[F:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=5[F:18])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cccc(-c2cccn3nc(Cl)nc23)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1F

Procedure:
4-{4-[8-(2-Fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.248 g, 0.893 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.296 g, 1.07 mmol) in a manner analogous to Example 311a and 311b to give product (0.312 g, 67%). MP=98-102° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.63 (s, 1H), 8.83 (d, 1H), 7.60 (m, 3H), 7.25 (m, 3H), 7.10 (m, 3H), 4.05 (m, 2H), 3.90 (s, 3H), 2.80 (br m, 2H), 2.60 (m, 1H), 1.45 (m, 2H), 1.75 (m, 2H), 1.41 (s, 9H). MS=518 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(OCC)(=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][CH2:10][C:11]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]([NH:1][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Br)ccc1NCC1(O)CCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1cc(Br)ccc1NCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of 1-([(2-amino-4-bromophenyl)amino]methyl)cyclopentanol (Step B, 1.3 g, 4.15 mmol) in ethyl acetate (100 mL) was added pivaloyl chloride (511 mg, 4.15 mmol) at room temperature. After stirring for 2 h at room temperature, the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 as eluent) to afford the title compound (1.3 g, 75%) as a beige amorphous.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH:2][CH3:1])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)ccc1CCBr
Solvent: C1CCOC1
Product: CNCCc1ccc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methylamine in THF (2 M, 200 mL) was added 1-(2-bromo-ethyl)-4-fluoro-2-nitro-benzene (13.2 g, 0.053 mole) in a pressure bottle, the reaction mixture was stirred at 60° C. overnight and the solvent was removed. The solid residue was treated with sodium hydroxide (1 N, 100 mL) and the aqueous extracted with methylene chloride (2×100 mL). The combined organic layers were washed with water (100 mL), saturated sodium chloride (100 mL), dried (sodium sulfate) and concentrated to provide 10.4 g of the title compound as a dark brown oil. 1H NMR (DMSO-d6): 7.60 δ (dd, 1H); 7.35 δ (dd, 1H); 7.20 δ (d of t, 1H); 3.05 δ (t, 2H); 2.85 δ (t, 2H); 2.40 δ (s, 3H); 1.60 δ (broad, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]1([C@@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:29][C@H:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: C[C@H](N)c1ccccc1
Product: CCCN(CC(=O)N[C@@H](C)c1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and (1S)-1-phenylethanamine: MS (APCI) m/z 390 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11]Cl)[CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H](CCl)COc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-3-{[(2R)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]([CH:12]1[CH2:14][CH:13]1[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]#[N:27])=[O:16])=[O:11])[CH3:8]>O1CCCC1>[CH2:7]([O:9][C:10]([CH:12]1[CH2:14][CH:13]1[CH:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]#[N:27])[OH:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CC1C(=O)c1ccc2[nH]cc(C#N)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1C(O)c1ccc2[nH]cc(C#N)c2c1
Temperature: -45 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A suspension of lithium aluminum hydride (0.3 g, 7.94 mmol) in anhydrous tetrahydrofuran (50 ml) was cooled to −45° C. and treated with a solution of the 2-(3-Cyano-1H-indole-5-carbonyl)-cyclopropanecarboxylic acid ethyl ester (1.12 g dissolved in 10 ml THF). The mixture was stirred for 1 h and quenched with water followed by sodium hydroxide solution. The aluminum salts were removed by filtration. The filtrate was concentrated in vacuo to afford 2-[(3-cyano-1H-indol-5-yl)-hydroxy-methyl]-cyclopropanecarboxlic acid ethyl ester (1.0 g) as an amber oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([I:28])=[C:6]([C:18]([I:27])=[C:19]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[C:20]=1[I:21])[NH:7][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])([OH:3])=[O:2].[OH-].[Na+].Cl>O>[C:1]([C:4]1[C:5]([I:28])=[C:6]([C:18]([I:27])=[C:19]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[C:20]=1[I:21])[NH:7][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])([OH:3])=[O:2]
Reactant: COC(=O)CCCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(N(C)C(C)=O)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(C)c1c(I)c(NC(=O)CCCCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
To a mixture of 143.8 g. of methyl 3'-carboxy-2',4',6'-triiodo-5'-(N-methylacetamido)adipanilate (Example 33) and 150 ml. of water was added dropwise 145 ml. of 10% sodium hydroxide solution. The reaction mixture was heated on a steam bath for two hours and then cooled and acidified with 3N hydrochloric acid solution. The solid product was collected and recrystallized from acetic acid to give 3'-carboxy-2',4',6'-triiodo-5'-(N-methylacetamido)adipanilic acid in the form of a colorless solid, m.p. 267°-271° C. (dec.).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].C(O)=O>CCO.O>[NH2:20][C:19]1[C:14]2[N:15]([C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)=[N:12][C:13]=2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CCO
Product: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of trans-4-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester (150.00 mg, 0.33 mmol) in EtOH (3.00 mL) was added solution of sodium hydroxide (67.8 mg, 1.69 mmol) in H2O (0.500 mL) at 0° C. Then the mixture was stirred at rt. overnight. The solvent was then removed under reduced pressure to give a residue which was dissolved in H2O (3 ml). The solution was acidified to pH 1 by formic acid. The product precipitated out and was collected by filtration and dried on high vacuum pump. 1H NMR (400 MHz, MeOD) δ 1.59-1.88 (m, 4H), 2.03-2.21 (m, 4H), 2.35-2.46 (m, 1H), 3.09-3.20 (m, 1H), 6.99 (d, J=5.1 Hz, 1H), 7.04-7.20 (m, 5H), 7.35-7.45 (m, 2H), 7.53-7.63 (m, 3H). MS (ES+): m/z 428.97 (MH+). HPLC: tR=2.25 min (OpenLynx, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=O)[S:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].C(Br)C=C>CC(C)=O>[CH3:8][O:9][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:6]=1[S:7][CH3:12]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: COc1ccc(O)cc1SC
Reaction time: 24 h
Yield: 93.8 %

Procedure:
5-Hydroxy-1,3-benzoxathiol-2-one (2g, 11.9 mmol) [prepared according to J. Org. Chem. 1990, 55, 2736] was dissolved in acetone (13 mL) and treated with potassium carbonate (3.29 g, 23.8 mmol) followed by allyl bromide (1.13 mL, 13.1 mmol). The mixture was then stirred under nitrogen atmosphere for 24 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water and diethyl ether (50 mL each). The organic fraction was separated and the aqueous layer re-extracted with diethyl ether (50 mL). The combined organic fractions were dried (MgSO4) and evaporated to a brown oil. Purification by flash chromatography [SiO2; pentane/ ethyl acetate (95:5→90:10)] afforded the desired compound as a colourless oil (1.9 g, 77%); δH(CDCI3, 400 MHz) 4.50 (2 H, d), 5.28 (1 H, d), 5.38 (1 H, d), 6.00 (1 H, ddt), 6.83 (1 H, dd), 6.91 (1 H. d), 7.15 (1 H, d)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:3][CH:2]=1.[NH2-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11])[CH3:25]
Reactant: CCI
Reactant: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccncc1)c1ccccc1C(=O)N1CCCCC1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 22.4 g of 1-[2-(4-pyridinylamino)benzoyl]piperidine (Example 1b) in 45 ml of dimethylformamide was added dropwise to a suspension of sodium amide (from 4.8 g of 50% oil suspension, washed free of oil) in 115 ml of dimethylformamide. The mixture was stirred for one hour, and then 6.5 g of ethyl iodide was added dropwise. The reaction mixture was stirred for two hours, then filtered and concentrated in vacuo. The residue was partitioned between water and ether and the ether-soluble material recovered (15.2 g). The latter was recrystallized from ethyl acetate--pentane to give 13 g of 1-{2-[ethyl-(4-pyridinyl)amino]benzoyl}piperidine, m.p. 123°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15](Cl)=[O:16])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])=[CH:22][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CCC(C)N(Cc1ccc(Cl)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=O)Nc1ccccc1
Yield: 83 %

Procedure:
19 g (0.2 mole) of aniline were dissolved in 300 ml of toluene. To the resulting solution, a solution of 26 g (0.1 mole) of N-[4-chlorobenzyl]-N-sec.-butyl-carbamoyl chloride in 70 ml of toluene was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and the the solution was stirred at a temperature of 70°-80° C for about 5 hours. The solution was cooled to precipitate aniline hydrochloride, which was then separated by filtration. The toluene layer was washed with 100 ml of water and dried with anhydrous sodium sulfate. Then, the toluene was distilled off. The residue was subjected to recrystallization from a mixture of hexane and ethyl alcohol, whereby 26.3 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylurea were obtained. Yield: 83%. Melting point: 80°-81.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:28]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of tert-butyl (R)-2-(4-aminophenyl)morpholine-4-carboxylate (3.2 g, CAS 1260220-42-5) in DMF (25 ml) was added NBS (2.05 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient: 0% to 70% EtOAc in heptanes) to give tert-butyl (R)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (3.71 g, 90%) as an off-white solid. MS (ISP): 359.1 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [CH:1](=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11].[OH-:13].[Na+]>O.[Ag-]=O>[C:1]([OH:13])(=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11]
Reactant: [OH-]
Reactant: CCC=CCCC=CC=CC=O
Agent: O=[Ag-]
Agent: [Na+]
Solvent: O
Product: CCC=CCCC=CC=CC(=O)O
Temperature: 20 °C

Procedure:
2,4,8-Undecatrienal is added to a suspension of silver (I) oxide (1.1 eq) in water. The mixture is stirred at 20° C. and concentrated sodium hydroxide solution (equal weight to the aldehyde), is added over 30 minutes allowing the batch to exotherm to 60° C. The solution is filtered through celite, and the aqueous filtrate acidified to pH 1 with hydrochloric acid solution, to give 2,4,8-undecatrienoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]([O:20]CC)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]([OH:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
Hydrolysis of ethyl 7-(p-chlorophenylsulfonamido)-3[3-(3-pyridyl)propyl]heptanoate in 3 mL methanol with 5.2 mL (5.2 mmol) of 1N sodium hydroxide according to procedure described in the previous examples yields 7-(p-chlorophenylsulfonamido)-3-[3-(3-pyridyl)propyl]heptanoic acid, m.p. 95-97°.