Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.BrC1C=CC2N(CC3N=CNC=3)CC[N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=O)CC=2C=1.ClC1C([N+:39]([O-:41])=[O:40])=CC=C(C)N=1.[C:43]1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[C:25]1([C:24]2[CH:23]=[CH:22][C:21]([N+:39]([O-:41])=[O:40])=[C:19]([CH3:43])[N:9]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A mixture of Compound B and 2-chloro-3-nitro-6-methylpyridine (0.42 g, 2.40 mmol) in THF (10 mL) was degassed with nitrogen. Tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol) was added and the mixture was stirred 30 minutes. 25 Phenylboronic acid (0.44 g, 3.6 mmol) and 2M Na2CO3 (1.8 mL) were added and the mixture was heated at 75° C. for 17 hours and stirred at room temperature for 48 hours. Methylene chloride was added and the mixture was filtered through celite and partitioned. The mixture was washed with saturated aqueous NaHCO3, dried (magnesium sulfate), filtered and evaporated to afford 0.77 g of brown solid. Flash chromatography (silica, 10% ethyl acetate/hexanes) afforded 0.37 g of Compound C (72%) as an off white solid and 0.05 g of 2-phenyl-3-nitro-6-methylpyridine (10%) as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>O(C1C=CC=CC=1)C1C=CC=CC=1.[Cu-]=O>[CH:18]1[C:19]2[N:20]([C:2]3[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=3)[C:21]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Nc1ccc(I)cc1
Agent: O=[Cu-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 190 °C

Procedure:
4-(9H-carbazol-9-yl)benzenamine (A) was prepared through the Ullmann Reaction following the procedures reported in the literature (Macromolecules 2004, 37, 5531-5537). A mixture of 4-iodobenzenamine (2.19 g, 10 mmol), copper (I) oxide (2.18 g, 20 mmol) and carbazole (3.35 g, 20 mmol) in 40 ml 1-phenoxybenzene was heated to 190° C. in an oil bath for 24 h under N2 atmosphere. The reaction mixture was cooled to room temperature and then filtered by fast silica gel column to remove excess copper complex and 1-phenoxybenzene. The filtrate was evaporated to dryness and passed through a silica gel column using hexane and ethyl acetate mixture (6:1) as eluent to give product, yielding 2.37 g (92%). 1H NMR (400 MHz, CDCl3): δ(ppm) 8.164-8.144 (d, J=8.0 Hz, 2H), 7.432-7.395 (t, J=8.0 Hz, 2H), 7.353-7.277 (m, 6H), 6.912-6.891 (d, J=7.6 Hz, 2H), 4.019 (w, 2H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH2:42][CH3:43])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (510 mg, 1.082 mmol) was dissolved in DMF (2163 μl). Then potassium carbonate (149 mg, 1.082 mmol) was added followed by iodoethane (96 μl, 1.190 mmol). After stirring at rt for 1 d, water was added. A gummy solid was collected with an aid of water, and dried. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 6-(benzylthio)-1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)quinolin-2(1 H)-one (534 mg, 99% yield) as white solid. Ink (ESI) [M+H]+=500.0. NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=6.94 Hz, 3 H) 4.01-4.13 (m, 2 H) 4.24 (s, 2 H) 6.60 (d, J=8.80 Hz, 1 H) 6.70 (d, J=9.59 Hz, 1 H) 7.18-7.35 (m, 6 H) 7.38-7.48 (m, 3 H) 7.49-7.63 (m, 3 H) 7.79 (d, J=2.15 Hz, 1 H) 7.96 (d, J=9.59 Hz, 1 H).
Reaction SMILES: CN[C:3]1([CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[CH:7][CH2:6]1)[CH:4]=[O:5].[S:13]([CH2:23][N+:24]#[C-:25])([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[C-:26]#N.[Na+]>>[CH3:26][N:11]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([C@H:4]2[O:5][CH:25]=[N:24][C@@H:23]2[S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: [C-]#N
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CNC1=CCC(C=O)(NC)C=C1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(N(C)C)cc2)cc1

Procedure:
In a manner analogous to Preparation 1,4-dimethylaminobenzaldehyde (0.19 g, 1.26 mmol), tosylmethylisocyanide(0.23 g,1.20 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 345.5 (M+H+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:20]=1[C:21]([OH:23])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1>CO.O.[Pd]>[CH3:28][C:24]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH2:11])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
1.21 g of 2-[(N-benzyloxycarbonyl-L-valyl)amino]-6-methylbenzoic acid was dissolved in a mixture of 99 ml of methanol and 1 ml of water, followed by adding 200 mg of 10% Pd-C. The mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. Pd-C was filtered off and the filtrate was concentrated to give 830 mg of 6-methyl-2-(L-valylamino)benzoic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[CH3:11]OC(OC)N(C)C.Cl.[NH2:20][C:21]([NH2:23])=[NH:22].C(=O)([O-])[O-].[K+].[K+].C(OCCO)C>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[CH:11][N:20]=[C:21]([NH2:23])[N:22]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Product: Nc1nccc(-c2ccc(Br)cc2)n1

Procedure:
4-(4-Bromophenyl)pyrimidin-2-amine was prepared by the reaction of 4-bromoacetophenone with N,N-dimethylformamide dimethyl acetal followed by cyclisation with guanidine hydrochloride in presence of suitable base such as potassium carbonate in refluxing dimethylene glycol monoethyl ether. 1H NMR (300 MHz, DMSO-d6) 6 6.69 (br s, 2H), 7.11 (d, J =5.1 Hz, 1H), 7.67 (d, J =8.4 Hz, 2H), 7.99 (d, J =8.1 Hz, 2H), 8.29 (d, J =4.8, 1H.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:6][CH2:7][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]5[NH:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:3][CH2:4]2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To the solution (3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (99 mg, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and stirred at room temperature for 1 h. The solvent was removed in vacuo, dichloromethane added (15 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to yield the title compound (59 mg, 61%) as white powder. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.71-0.89 (m, 4H), 1.00 (s, 3H), 1.28-1.46 (m, 5H), 1.50-1.68 (m, 2H), 1.68-1.89 (m, 8H), 1.89-2.00 (m, 2H), 2.11-2.31 (m, 2H), 2.86-3.02 (m, 2H), 3.02-3.14 (m, 2H), 3.47-3.70 (m, 4H), 3.75-3.91 (m, 1H). MS (M+1): 389.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22](O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C:16]([NH2:15])=[N:17][CH:18]=[CH:19]3)[CH2:9]1
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Product: Nc1nccc2cc(OC3CCCNC3)ccc12
Yield: 12.1 %

Procedure:
This compound was prepared from racemic 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (207 mg, 1.02 mmol) and 1-amino-6-hydroxyisoquinoline (198 mg, 1.23 mmol) by the Mitsunobu procedure described in 3C, subsequent Boc deprotection according to procedure described in 3D gave racemic 6-(piperidin-3-yloxy)-isoquinolin-1-ylamine (30 mg), El-MS: m/z=244.4 [M+H]+.
Reaction SMILES: CSC(=S)N.[Na].[C:7]([O:10][CH2:11][C@H:12]1[N:15]([S:16]([O-:19])(=[O:18])=[O:17])[C:14](=[O:20])[C@H:13]1[NH:21][C:22](=[O:37])[C:23]([C:27]1[N:28]=[C:29]([NH:32]C(=O)CCl)[S:30][CH:31]=1)=[N:24][O:25][CH3:26])(=[O:9])[CH3:8].[Na+:38]>>[C:7]([O:10][CH2:11][C@H:12]1[N:15]([S:16]([O-:19])(=[O:18])=[O:17])[C:14](=[O:20])[C@H:13]1[NH:21][C:22](=[O:37])[C:23]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)=[N:24][O:25][CH3:26])(=[O:9])[CH3:8].[Na+:38]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1COC(C)=O)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1COC(C)=O)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
Under ice-cooling and stirring, 41 mg of sodium monomethyldithiocarbamate is added to 4 ml of an aqueous solution containing 150 mg of sodium cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (syn-isomer). The mixture is stirred at room temperature for 30 minutes, and another 10 mg of sodium monomethyldithiocarbamate is added. The stirring is continued for an additional 30 minutes, and the reaction mixture is filtered. The filtrate is then washed with ether, and the aqueous layer is purified by column chromatography on Amberlite XAD-II and then lyophilized to give sodium cis-4-acetoxymethyl-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:20][CH2:21][C:22](O)=[O:23])[C:9]2=[S:25])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30]O[CH2:28][CH2:27]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:20][CH2:21][C:22]([N:26]3[CH2:31][CH2:30][CH2:28][CH2:27]3)=[O:23])[C:9]2=[S:25])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Solvent: C1CCOC1
Product: O=C(CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S)N1CCCC1

Procedure:
To a solution of 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid (1 eq), 1-3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 eq) and morpholine (1.7 eq) in THF is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The organics are dried and concentrated under vacuum. The residue is purified by chromatography on silica to give 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)-1-(pyrrolidin-1-yl)propan-1-one.
Reaction SMILES: [SH-:1].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4]>>[NH2:3][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[SH:1].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[SH:1])([O-:5])=[O:4]
Reactant: [SH-]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Product: Nc1ccc(S)c(N)c1
Product: O=[N+]([O-])c1ccc(S)c([N+](=O)[O-])c1

Procedure:
Employing standard chemical reactions, the 2,4-diaminothiophenol was prepared by first reacting sodium hydrosulfide with 2,4-dinitrochlorobenzene to produce 2,4-dinitrophenylmercaptan. The 2,4-dinitrophenylmercaptan was reduced with zinc and hydrochloric acid to produce 2,4-diamino-thiophenol.
Reaction SMILES: O=S(Cl)[Cl:3].[CH:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][C@H:13]([NH2:17])[C:14]([OH:16])=[O:15])[CH:6]=1.[CH3:18][CH2:19]O>>[NH2:17][CH:13]([CH2:12][C:7]1[CH:6]=[CH:5][CH:10]=[C:9]([OH:11])[CH:8]=1)[C:14]([O:16][CH2:18][CH3:19])=[O:15].[ClH:3]
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Reactant: CCO
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(N)Cc1cccc(O)c1
Product: Cl
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To 20 mL of EtOH at −5° C. was added, with stirring, 0.2 mL of SOCl2 slowly. The clear colorless solution was cooled to −5° C. and 510 mg of meta-Tyrosine was added. After 5 min, the resulting solution was refluxed overnight. The solution was concentrated to afford 157 as HCl salt (690 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:28][C:29]#[N:30])[CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg (0.26 mmol) of 5-chloro-N-[1,3-dioxo-2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-4-yl]-2-thiophenecarboxamide, 0.022 ml (0.31 mmol) of α-bromoacetonitrile and 0.072 ml (0.51 mmol) of triethylamine in 2.5 ml of DMF are stirred at room temperature overnight. The mixture is concentrated and the residue is taken up in dichloromethane, washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The product is crystallized with ether, filtered off with suction and dried under high vacuum. Alternatively, the product can be purified by chromatography on silica gel (dichloromethane/methanol mixtures).
Reaction SMILES: [C:1]([C:3]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:24]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:24])=[O:7]
Reactant: COc1ccc(CC(C#N)(CCC(=O)O)CCC(=O)O)cc1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(Cc2ccc(OC)cc2)CCC1=O
Yield: 95 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 53.94 gm. (0.169 mole) of the dimethyl ester of 4-cyano-4-(p-anisyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 1100 ml. of the tetrahydrofuran, 38.0 ml. (0.34 mole) of the potassium tert-butoxide, and 270 ml. of the 2.5 N hydrochloric acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 46.2 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(p-anisyl)cyclohexanone as a gum.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1[N:17]2[C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[CH2:20][CH2:21][C@@H:22]([NH2:23])[C:16]2=[N:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:45][C:46]1[CH:60]=[CH:59][C:49]([C:50]([NH:52][C:53]2([C:56](O)=[O:57])[CH2:55][CH2:54]2)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[Cl:45][C:46]1[CH:60]=[CH:59][C:49]([C:50]([NH:52][C:53]2([C:56](=[O:57])[NH:23][C@@H:22]3[CH2:21][CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[N:17]4[CH:13]=[CH:14][N:15]=[C:16]34)[CH2:54][CH2:55]2)=[O:51])=[CH:48][CH:47]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 g, 151 mmol) to a 10° C. slurry of (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (30 g, 151 mmol), 1-hydroxybenzotriazole (20 g, 151 mmol), triethylamine (41.97 mL, 301 mmol), and 1-[(4-chlorobenzoyl)amino]cyclopropanecarboxylic acid (40 g, 166 mmol) in THF (300 mL). Remove the ice bath, warm the mixture to ambient temperature, and stir it for 4 hours. Pour the mixture into water (1.0 L) and extract with ethyl acetate (1.0 L). Wash the organic phase with saturated sodium bicarbonate (500 mL), dry over magnesium sulfate, filter, and concentrate under reduced pressure. Slurry the residue in ethyl acetate (300 mL) and heat to 71° C. Cool to ambient temperature, filter the precipitate, and wash with ethyl acetate (100 mL) to give the title compound (38.8 g, 61%): MS (m/z): 421 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:15]O>Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cl
Product: COC(=O)CCCCCCCCCCBr
Reaction time: 72 h

Procedure:
A mixture of 13.25 g of 11-bromoundecanoic acid, 100 mL of methanol and 10 drops of hydrochloric acid was stirred for 3 days in a closed flask. The solvent was removed in vacuo and the residual oil was redissolved in ether (100 mL). This solution was subsequently washed twice with 25 mL of a saturated NaHCO3 solution, once with water (25 mL) and once with brine (25 mL). Drying over sodium sulfate and removal of the solvents in vacuo gave 13.32 g of the product as a yellowish oil, which was sufficiently pure to use in the next step. 1H NMR (200 MHz, CDCl3): δ 3.65 (s, 3H); 3.39 (t, 2H); 2.28 (t, 2H); 1.90-1.78 (m, 2H); 1.70-1.50 (m, 2H); 1.50-1.21 (m, 12H) ppm. IR (neat, cm−1): 2928 (m); 2855 (m); 1741 (s).
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][S:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)COc1ccc(Cl)cc1
Yield: 73 %

Procedure:
133.7 g (0.41 mol) of 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were heated to 100° C. with 64 g (0.5 mol) of 4-chlorophenol and 69 g (0.5 mol) of potassium carbonate in 500 ml of toluene for 5 hours. The mixture was then allowed to cool and was filtered. The filtrate was extracted by shaking with dilute sodium hydroxide solution, rinsed with water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 110.5 g (72% of theory) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a yellowish oil with a refractive index nD20 of 1.5932.
Reaction SMILES: FC1C(F)=CC=CC=1C1C=C[C:12]([O:15]CCCCCCOC(=O)C=C)=[CH:11][CH:10]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].BrCCCCCCO>>[C:12]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])(=[O:15])[CH:11]=[CH2:10]
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCCCBr
Agent: OCCCCCCBr
Product: C=CC(=O)OCCCCCCCCBr
Yield: 78 %

Procedure:
The same procedure as in the synthesis (a) of Example 2 was repeated except that 34.7 g of 8-bromo-1-octanol were used instead of 30 g of 6-bromo-1-hexanol to give 34.1 g (Y., 78%) of 8-acryloyloxy-1-bromooctane. GC; 97%
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9](Cl)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: C1CNCCN1
Reactant: Nc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: Nc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 8-amino-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 206°-208° C.) and piperazine.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20](O)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:25]1([C:20]([C:15]2[CH:16]=[N:17][N:18]([CH3:19])[C:14]=2[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[C:3]([N:2]([CH3:1])[CH3:24])[N:23]=[C:6]3[CH:7]=2)=[O:13])=[O:21])[CH2:28][CH2:27][CH2:26]1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), azetidine (123 l, 1.82 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (398 μl, 2.28 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at room temperature under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording 4-(azetidine-1-carbonyl)-N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (119 mg, 70.9%) as an off-white solid. Mp.: 240-1° C. MS: m/z=369.1 (M+H+).