Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:3]1[N:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nn1cccc1C(=O)c1ccccc1F
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccccc1F
Yield: 91.9 %

Procedure:
1-Amino-2-(2-fluorobenzoyl)pyrrole (41 g, 0.20 mol) and sodium bicarbonate (39 g, 0.46 mol) were combined in 400 ml of dichloromethane. To this stirred slurry was added ethyl chloroformate (24 g, 0.22 mol) over 3 minutes and the reaction mixture was refluxed for 5 hours, whereupon it was quenched with 200 ml of H2O and the organic layer separated. The organic extract was washed with H2O and brine, dried (MgSO4), filtered, and evaporated to an oil which crystallized upon trituration with hexane. Filtration yielded 50.8 g (92%) of crystals, m.p. 78°-80°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([Cu])#[N:22]>CC(N(C)C)=O.CCOC(C)=O>[N+:18]([C:3]1[CH:4]=[C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[C:21]#[N:22])([O-:20])=[O:19]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)ccc1Br
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (0.55 mmol) in DMA (4 mL) add CuCN (0.60 mmol). Stir the mixture 4 hours at 110° C. Cool to room temperature, dilute with 20 ml of EtOAc, and filter through celite pad. Wash the filtrated with brine, dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to give 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
7.8 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin--10-yl)-piperazine are treated, together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 100 ml of toluene, with 8.22 g of N-(β-chloroethyl)--oxazolidinone and the mixture is heated under reflux for 22 hours. Then the mixture poured on to water and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained crude liquid 3-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone. The maleate is prepared by treatment with maleic acid in ethanol/ether; melting point 173°-175° C.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([F:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([F:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(F)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(F)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-2-methylpropionitrile (90 mg, described in Example 46) and 4-trifluoromethylthiobenzoyl chloride (0.06 mL), the title compound was isolated as a white solid (95 mg, 62%). Rf=0.55 (1:1 EA/heptane). MS (ES): M/Z [M+H]=492. NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.60 (d, J=13.3 Hz, 1H), 7.58-8.22 (m, 5H) and 8.94 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −127.6 (d, J=5.3 Hz, 1F) and −42.0 (s, 3F).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](=[O:48])[C:32]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:40][CH:39]=3)([CH3:37])[CH2:33][O:34]2)=[CH:29][CH:28]=1>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:31]1([OH:48])[C:30]2[C:35](=[CH:36][C:27]([O:26][CH2:25][O:24][CH3:23])=[CH:28][CH:29]=2)[O:34][CH2:33][C:32]1([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:42][CH:43]=1)[CH3:37])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1.33 h
Yield: 98.5 %

Procedure:
9-(t-Butyl dimethylsilyloxy)-1-nonyne (7.1 g, 27.9 mmol) was dissolved in dry tetrahydrofuran (70 mL) under argon atmosphere, which was then cooled down to −78° C. n-Butyllithium (15.1 ml, 25.1 mmol, 1.66 mol/l solution in tetrahydrofuran) was slowly added dropwise thereto, and the mixture was stirred at −20° C. for 80 minutes. To this mixture was added dropwise 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-one (2.0 g, 5.58 mmol) dissolved in dry tetrahydrofuran (15 mL) at −20° C., and the resulting reaction mixture was stirred at the same temperature for 3 hours, and then stirred at −10° C. overnight. The reaction was quenched with water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (3.37 g, yield 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1Cl
Temperature: 135 °C

Procedure:
A solution was prepared from 100 g of the commercially available hemihydrate of 3-chloro-4-hydroxybenzoic acid in 300 mL of acetic anhydride. After adding 7 drops of concentrated sulfuric acid, the mixture was refluxed at 135° C. for 2 hrs. The product crystallized out on cooling. About 500 mL of cold water was added with stirring, which continued while cooling in an ice/water bath for 1 hr. After filtration and drying, the product was recrystallized from 350 mL of ethyl alcohol to yield 40 g of 3-chloro-4-acetoxybenzoic acid melting at 152-159° C.
Reaction SMILES: [C:1]([C:3]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:8][CH2:7][C:6]([C:9]([O:11]C)=[O:10])=[CH:5][CH2:4]1)#[N:2].O1CCCC1.[OH-].[K+]>CO.O>[C:1]([C:3]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:8][CH2:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CC=C(C(=O)O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate (0.07 g, 0.18 mmol) in methanol (0.5 mL, containing just enough tetrahydrofuran to solubilize the ester) under an argon atmosphere was added a solution of potassium hydroxide (0.03 g, 0.55 mmol) in water (0.4 mL). The resulting mixture was stirred at room temperature for 4 h, then poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 3N hydrochloric acid and extracted twice with ethyl acetate. The organic phase from the acid extraction was dried (sodium sulfate) and concentrated under reduced pressure to provide a viscous oil, which solidified upon standing. The solid was recrystallized from hexanes/methylene chloride (0.05 g, 82%): m.p. 161°-163° C.
Reaction SMILES: CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=[O:8].[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@H:32]3[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:30]([CH2:31]3)[NH:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1>>[CH2:16]1[O:17][C:18]2=[CH:19][C:20]3[CH2:21][CH2:22][N:23]4[C@H:32]([C:33]=3[CH:34]=[C:35]2[O:8]1)[CH2:31][C@H:30]1[C@H:25]([CH2:26][CH2:27][CH2:28][NH:29]1)[C:24]4=[O:36]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN[C@H]3C[C@@H]21
Product: O=C1[C@H]2CCCN[C@H]2C[C@H]2c3cc4c(cc3CCN12)OCO4

Procedure:
Similarly, replacing the d-10-camphorsulfonic acid salt of (8aS,12aS,13aS)-3-methoxy-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one with compounds of formula (IA), obtained, for example, as described in Example 4C, and following the procedures of Example 5A above, the corresponding compounds of formula (I) as a free base are made.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]1>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: O[C@@H]1CCNC[C@@H]1O
Product: Cc1c(-c2ccc(C(=O)N3CC[C@@H](O)[C@@H](O)C3)s2)noc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3S,4R)-3,4-Piperidinediol (CAS [868051-84-7]) in the same manner as the (3R,4S) isomer (Example 87) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.43 min, [M+1]+ 377.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])(=[O:7])[NH2:6]>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:12]([O:3][CH2:2][CH2:1][O:4][C:12](=[O:13])/[CH:11]=[CH:10]\[C:9](=[O:14])[NH:8][C:5](=[O:7])[NH2:6])(=[O:13])/[CH:11]=[CH:10]\[C:9](=[O:14])[NH:8][C:5](=[O:7])[NH2:6]
Reactant: OCCO
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)OCCOC(=O)/C=C\C(=O)NC(N)=O
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A mixture of 3 g of ethylene glycol (0.048 moles), 12 g of N-carbamylmaleimide (0.086 moles) and 0.3 g of zinc chloride (0.0022 moles) in 70 mL of acetonitrile was heated to reflux. After 3 hours, a lot of solid material had been produced from the mixture. The mixture was filtered and the solids washed with acetonitrile and dried to afford 11.7 g of ethylene glycol bismaleurate. M.P.: 158°-60° C.; 1H NMR (DMSO-d6): δ 10.5 (s, 2 H), 7.2-7.8 (m, 4 H), 6.2-6.4 (m,4H),4.3(s,4H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([OH:23])[CH3:22]>O1CCOCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:16])[O:23][CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: N#CCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)CCCOc1cccc(CN2CCCCC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
An ice-cold solution of 4-(3-piperidinomethylphenoxy)butyronitrile (0.9 g) prepared as described in Example 17 in a mixture of ethanol (5 ml) and dioxan (5 ml) was saturated with hydrogen chloride gas. The mixture was left for 16 hours during which time the temperature rose to ambient. The solvent was then removed by evaporation to yield a hydrochloride salt of ethyl 4-(3-piperidinomethylphenoxy)butyrimidate as a colourless oil. The imidate salt was mixed with 4-methylcarbamoylmethyl-o-phenylenediamine (0.6 g) prepared as described in Example 8 and ethanol (38 ml) and the mixture was heated under reflux for 41/2 hours. The solvent was removed by evaporation in vacuo and the residue dissolved in water. The aqueous solution was washed with ethyl acetate and then aqueous ammonia solution (S.G. 0.880) was added until the solution was alkaline. The solution was extracted with ethyl acetate and the extracts were washed and dried. Partial removal of the ethyl acetate caused crystallisation of 5-methylcarbamoylmethyl-2-[3-(3-piperidinomethylphenoxy)propyl]benzimidazole (m.p. 111°-115° C.) as colourless crystals. [Formula I E=--(CH2)3.O, J is hydrogen, R1 =methyl, R2 =H, NR3R4 =piperidino, m=1, and p=1].
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6](OCC)(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:17]1([CH:23]=[C:24]2[C:29](=[O:30])[C:28](=[CH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][S:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[O:13]=[C:6]1[O:30][C:29]2[C:28](=[CH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][S:26][CH2:25][C:24]=2[CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)OC2=C(CSCC2=Cc2ccccc2)C1c1ccccc1

Procedure:
To an ethanolic solution of sodium ethoxide [prepared from 555 mg (24 mg atom) of sodium in 50 ml of ethanol] is added diethyl malonate (3.52 g, 22 mmole) in 50 ml of absolute ethanol. After heating at reflux temperature for 2 hours, tetrahydro-3,5-bis(phenylmethylene)-4H-thiopyran-4-one (5.84 g, 20 mmole) is added. The resulting solution is then heated at reflux temperature for 2 hours.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Br[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2cc(C(F)(F)F)ccn2)c(-c2ccc(F)cc2)s1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-bromo-4-(trifluoromethyl)pyridine, Pd2dba3, BINAP, and NaOtBu in toluene was purged with argon, and then stirred at 70° C. for 12 h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 492.97 (M+H).
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:48][C:49]1[N:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:11]=[C:10]([C:21]([NH:56][CH2:55][C:52]2[CH:51]=[N:50][C:49]([CH3:48])=[N:54][CH:53]=2)=[O:22])[CH:9]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ncc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added (2-methylpyrimidin-5-yl)methanamine (8.5 mg, 0.069 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:4][CH2:3][CH2:2][CH2:1][NH2:5]
Reactant: c1ccncc1
Reactant: NCCCN
Product: NCCCNc1ccccn1
Yield: 76 %

Procedure:
To a solution of propane-1,3-diamine (310 ml, 3.63 mol) in dry pyridine (75 ml) kept under an atmosphere of nitrogen 2-bromopyridine (70 ml, 0.73 mol) was added. The reaction mixture was heated at reflux for 18 h, cooled and the volatiles evaporated in vacuo. To the residue was added tetrahydrofuran (1 l) and the precipitate was filtered off and washed with tetrahydrofuran (0.5 l). The solvent was evaporated in vacuo and the residue purified by distillation at 95-97° C. and 2×10-2 mbar affording 83.37 g (76%) of N-(pyridin-2-yl)propane-1,3-diamine.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:17]=[C:16]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C>[OH-].[Na+].C(O)C.O>[CH:20]1([C:18]([C:16]2[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=2)[C:4]([OH:23])=[O:3])=[O:19])[CH2:22][CH2:21]1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)C2CC2)c1

Procedure:
Stir the crude 5-cyclopropanecarbonyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.38 mmol) in 1 N NaOH (1 mL) and ethanol (1 mL) for 3 h at room temperature. Dilute the mixture with water (5 mL) and wash the aqueous solution with diethyl ether (2×3 mL). Acidify with 1 N HCl (1 mL) and extract with ethyl acetate (3×5 mL). Wash the combined organic layer with saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound as a crude residue which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[C:18]([N:25]1[CH2:30][C@@H:29]2[CH2:31][C@H:26]1[CH2:27][NH:28]2)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>ClCCl>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:28]3[CH2:27][C@@H:26]4[CH2:31][C@H:29]3[CH2:30][N:25]4[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:3][N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nnc(-c2ccccc2)c2ccccc12
Temperature: 90 °C

Procedure:
To a 20 mL reaction vial was added 1-chloro-4-phenylphthalazine BSL-1 (300 mg, 1.25 mmol) and (1S,4S)-2-boc-2,5-diazabicyclo[2.2.1]heptane (494 mg, 2.5 mmol, 2 eq). The mixture was heated under nitrogen at 90° C. for 1 h. The reaction was cooled to room temperature and the solid mass was dissolved in dichloromethane (50 mL) and washed once with 5 mL of sat. NaHCO3 and once with 50 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (70% ethyl acetate in hexanes) afforded (1S,4S)-tert-butyl 5-(4-phenylphthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (BSL-3). MS (M+H)+=403.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:10]([CH3:19])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:18][C:11]1([C:14]([F:17])([F:15])[F:16])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:19]
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CCC1(O)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCC1(O)C(F)(F)F

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-methyl-4-trifluoromethylpiperidine (5.1 g, 18.68 mmole) and 20% palladium hydroxide (1 g) in methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.) for 12 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-methyl-4-trifluoromethyl-piperidine as oil. Yield 3.4 g (99%), C7H12F3NO, m/z 184 (M+1)
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[CH2:29][N:28]([S:30]([O-:33])(=[O:32])=[O:31])[C:27]1=[O:34])=O)(C)(C)C>C(O)=O.C(Cl)Cl>[NH2:25][C@H:26]1[CH2:29][N:28]([S:30]([OH:33])(=[O:32])=[O:31])[C:27]1=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(S(=O)(=O)[O-])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=CO
Product: N[C@H]1CN(S(=O)(=O)O)C1=O
Reaction time: 4 h
Yield: 51.9 %

Procedure:
(S)-3-[(t-Butoxycarbonyl)amino]-2-oxo-1-azetidinesulfonic acid, tetra-n-butylammonium salt (3.06 g) is dissolved in 18 ml of 97% formic acid, stirred for 4 hours, diluted with methylene chloride, filtered, washed and dried to give 0.52 g of the title compound; melting point 208°-210° C., dec.; [α]D21 =-39.9[c=2, water].
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20].CC(C[AlH]CC(C)C)C.C1COCC1.CCCCCCC>C1COCC1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20]
Reactant: COC(=O)CCc1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCO)nc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 37-1 (0.45 g, 1.40 mmol) in THF (8 mL) chilled to −78° C. was added DIBAL 1.0M in THF heptane (4.22 mL, 4.22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 3 hr, then quench with slow addition of Rochelle's salt solution (3 mL). The resulting mixture was allowed to warm to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was concentrated and flash column separation using a 20-100% ethyl acetate/hexane gradient gave 37-2. (0.22 g, 55%). LRMS (ES) (M+H)+: observed=278.1, calculated=278.4.