Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:34])[C:29]([O:31]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:35].[C-]#N.[Na+]>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:34])[C:29]([NH2:35])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)C(N)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 48 h
Yield: 78 %

Procedure:
A solution of (S)-ethyl 2-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-oxoacetate (245 mg, 0.525 mmol) in a 7 N ammonia solution in MeOH (10 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 48 h. The reaction mixture was then evaporated, washed with water and air dried to afford a residue then purified by silica gel flash chromatography with 50% then 75% EtOAc/hexanes as eluant to afford the title compound as colorless foam (180 mg, 78%). LC/MS (Method B) 3.31 min, [M+1]+ 438.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:7][NH:8][C:21](=[O:22])[CH2:20][Cl:19])=[O:6]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a mixture of 3,5-dichlorobenzohydrazide 5 (0.5 g, 2.4 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 92%) which was used for the next step without further purification. A mixture of 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 7 (0.52 g). Yield: 88%.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[C:31]([O:32]C)=[CH:30][C:29]3[C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][C:25]([CH3:37])([CH3:36])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].ClCCl.B(Cl)(Cl)Cl>C1COCC1>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[C:31]([OH:32])=[CH:30][C:29]3[C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][C:25]([CH3:37])([CH3:36])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: COc1cc2c(cc1C(=O)COc1ccc(C(=O)OCc3ccccc3)c(O)c1)C(C)(C)CCC2(C)C
Agent: ClB(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)OCc4ccccc4)c(O)c3)c(O)cc21
Temperature: 0 °C
Yield: 79.3 %

Procedure:
4 g (8 mmol) of benzyl 2-hydroxy-4-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate and 20 ml of dichloromethane are introduced into a flask. 24 ml (24 mmol) of a solution of boron trichloride in THF (1M) are added dropwise at -78° C. and under a stream of nitrogen and the temperature is allowed to rise to -20° C., then the reaction mixture is poured into ice-water. The mixture is extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained in purified by chromatography on a silica column, eluted with a dichloromethane/hexane mixture (50:50). 3.1 g (80%) of the expected ester of melting point 127°-128° C. are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:11]1([C:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCCC2)CC1

Procedure:
N-Acetyl-4-piperidinone (1.3 g, 9.2 mmol) was dissolved in toluene (10 ml), and pyrrolidine (0.72 g, 10.13 mmol) and p-toluenesulfonic acid hydrate (catalytic) were added. The reaction mixture was refluxed under an inert gas for 2 hours using a water separator, cooled slowly under an inert gas and concentrated in vacuo and the residue was dried. The crude product was employed immediately without purification. The yield was 1.87 g (>99%).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH2:20]([NH:22][C:23](=S)[NH:24][NH2:25])[CH3:21]>>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:23]([NH:22][CH2:20][CH3:21])=[N:24][N:25]=3)[N:14]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCNC(=S)NN
Product: CCNc1nnc2ccc(-c3cccc(N(C)C(=O)CC)c3)nn12
Yield: 20.4 %

Procedure:
A solution of 5.0 g N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 4.3 g 4-ethyl-3-thiosemicarbazide was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 1.2 g of yellow crystals, mp 198°-199° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)CO1
Yield: 58 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.1) with 3,5-dichlorophenylboronic acid yielded the title compound (58% yield) as a pale yellow solid. MS (ISP): m/z=399.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=4)=[CH:23][C:22]=3[CH3:38])[N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].CO.Cl>C1COCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:22]([CH3:38])=[CH:23][C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:36])=[O:35])=[CH:32][CH:33]=4)=[CH:25][C:26]=3[CH3:27])[N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2cc(C)c(Oc3nc(Nc4ccc(C#N)cc4)nc4c3ncn4C)c(C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of methyl 4′-(2-(4-cyanophenylamino)-9-methyl-9H-purin-6-yloxy)-3′,5′-dimethylbiphenyl-4-carboxylate (110 mg, 0.22 mmol) and lithium hydroxide (100 mg, 2.38 mmol) in) in a mixture of THF (3 mL), MeOH (1 mL), and H2O (1 mL) was stirred at rt for 3 h. The reaction mixture was diluted with H2O (5 mL) and acidified (1 N HCl). The resulting precipitate was collected by filtration to yield the desired compound (90 mg). MS (ESI): m/z 491 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@H:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26](O)=[O:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:58]([NH:65][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C@H:14]1[CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]indol-5-yl acetic acid (1 g, 2.76 mmol) in DMF (5 ml) was added TBTU (0.97 g 3.04 mmol), Et3N (0.42 ml 3.04 mmol) and benzylamine (0.33 ml 3.04 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum and the residue chromatographed on Silica 5% MeOH/94% CHCl3 /1% 880 NH3 to give a pale yellow oil. yield: 0.81 g (80%) MS 468 (M+1), 392, 333.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:36]1[N:41]=[C:40]([NH2:42])[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][CH:37]=1>C(#N)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:7]1[C:8]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:36]2[N:41]=[C:40]([NH2:42])[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][CH:37]=2)[CH:6]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1ccc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
The amine hydrochloride salt 10 (35 mg) in acetonitrile (2 ml) is treated with N,N-diisopropylethylamine (54 eq) and 6-chloro-3-nitro-2-pyridylamine 11 (1.2 eq) and stirred at 90° C. for 2 h. The mixture is concentrated under reduced pressure and dried under vacuum. The crude product is purified by chromatography starting with 3% MeOH in methylene chloride and finishing with, 5% MeOH in methylene chloride to provide 12 as yellow solid (50–70%). The material is acidified with 2 equivalents of HCl and lyophilized to a dry powder.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cccc(Cn3cc(N)cn3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.99 min; [M+H]+=388.43.
Reaction SMILES: N1CCCC1.N1(CC(=C)C(=[O:16])C)CCCCC1.[N:18]1([CH2:24][CH:25]([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26]([CH3:28])=[O:27])[CH2:23][CH2:22]C[CH2:20][CH2:19]1>>[CH2:19]([N:18]([CH2:24][CH:25]([CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([OH:16])[CH2:32][CH2:31]1)[C:26](=[O:27])[CH3:28])[CH2:23][CH3:22])[CH3:20]
Reactant: C=C(CN1CCCCC1)C(C)=O
Reactant: CC(=O)C(CN1CCCCC1)CN1CCCCC1
Solvent: C1CCNC1
Product: CCN(CC)CC(CN1CCC(O)CC1)C(C)=O

Procedure:
The intermediate olefinic ketone is prepared by the procedure of H. M. E. Carwell [J. Chem. Soc., 1058 (1950)]. The ketone obtained from A., 22.8 g., in 25 ml. of ethanol was added to a solution of 25 g. of anhydrous oxalic acid in 75 ml. of ethanol. The mixture was cooled to 0° C., filtered to remove diethylamine hydrogen oxalate and the mother liquor evaporated to dryness under reduced pressure. The residue was dissolved in a little water, treated with potassium carbonate and extracted with ether. The ether was dried over anhydrous sodium sulphate and the residue obtained by solvent removal was distilled. After re-distillation the product was obtained as an oil, b.p. 82° C./18 mm. Similarly, the other 1,1-bis-(disubstituted aminomethyl)acetones obtained as in A. can be converted to the corresponding 3-disubstituted aminomethylbut-3-en-2-ones. The disubstituted amino term as previously indicated also comprises pyrrolidine and piperidine alicyclic ring analogs. For example, 3-(piperidinomethyl)but-3-en-2-one boils at 135°-139° C./15 mm. and is synthesized following the same procedure from 1,1-bis(-piperidinomethyl)acetone.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:17]1[O:18][C:19]([C:22](=[O:24])[NH2:23])=[N:20][N:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][NH:7][C@@H:9]([C:17]1[O:18][C:19]([C:22]([NH2:23])=[O:24])=[N:20][N:21]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
((1R)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2-phenylethyl)methylcarbamic acid tert-butylester (350 mg, 1.01 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added dropwise. The solution was stirred for 30 min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (6 ml) and the solvent was removed in vacuo. The residue was again dissolved in dichloromethane (6 ml) and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (10 ml). This phase was washed with water. The aqueous phase was lyophilized to give 247 mg of crude 5-((1R)-1-methylamino-2-phenylethyl)-[1,3,4]oxadiazole-2-carboxylic acid amide, which was used for the further synthesis.
Reaction SMILES: OC1C=C(C=CC=1[C:13](=[O:24])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1)C=CC(O)=O.[OH:25]C1C=CC(C=CC(O)=O)=CC=1C(=O)C=CC1C=CC(O)=C(O)C=1>>[C:13]([OH:24])(=[O:25])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1
Reactant: O=C(O)C=Cc1ccc(C(=O)C=Cc2ccc(O)c(O)c2)c(O)c1
Reactant: O=C(O)C=Cc1ccc(O)c(C(=O)C=Cc2ccc(O)c(O)c2)c1
Product: O=C(O)/C=C/c1ccc(O)c(O)c1

Procedure:
Fraction 2a was chromatographed on #3 Whatman paper, eluting with butanol-acetic acid-water (6:1:4) to separate any remaining caffeic acid. The eluate was concentrated and chromatographed on #3 Whatman paper. Elution with ethyl formate-acetic acid-toluene (4:1:5) produced the two isomers of the dimer in the following amounts: 73 mg. of 3-hydroxy-4-(3',4'-dihydroxycinnamoyl)-cinnamic acid, decomp. 135°-140° C. and 68 mg. of 4-hydroxy-3-(3',4'-dihydroxycinnamoyl)-cinnamic acid, decomp. 135°-140° C. The structural identity of the compounds was confirmed using ultraviolet scanning and nuclear magnetic resonance (NMR).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3]>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of 3-(aminosulfonyl)benzoic acid (Fluorochem) (150 mg, 0746 mmol) in THF (1 mL) was added dropwise at 0° C. Borane-THF complex (3.73 mL, 3.73 mmol). The resulting solution was stirred 10 min at 0° C., and then at room temperature overnight. The reaction mixture was carefully quenched with 10 mL of water at 0° C. The reaction mixture was diluted with 30 mL of EtOAc and 20 ml of water. The aqueous layer was further extracted with 30 mL of EtOAc. The combined organic solutions were washed with brine (30 mL), dried over an hydrophobic frit and concentrated under reduced pressure. The residue was loaded in dichloromethane to a silica cartridge (20 g), and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (86.4 mg, 62%) as a gum. LCMS (System A) RT=0.41 min, ES+ve m/z 188 (M+H)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:27][C@@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[C:11]([CH:26]=1)[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:13])#[N:6]>O.C(O)(=O)C>[C:2]([N:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:10]2[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:26][C:11]=2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[O:13])[CH2:29]1)(=[O:1])[NH2:3]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCNC2)cc1OC
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCN(C(N)=O)C2)cc1OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
A solution of potassium cyanate (53 mg) in water (1.5 mL) was added to a solution of (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (100 mg) in acetic acid (1.5 mL). The mixture was stirred for 3 hours at 60° C. and then for 2 hours at 90° C. The reaction mixture was concentrated in vacuo and the residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by thin layer chromatography developed with 5% methanol in chloroform. The obtained product was triturated with diethyl ether to give (R)-2-(1-carbamoylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (22 mg) as a powders.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][C:3]=1[OH:25].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[CH:4][C:3]=3[OH:25])=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)c(O)c2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)c(O)c2)C1
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a microwave vial were added 4-(4-bromo-3-hydroxyphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.172 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (0.26 mmol), Cs2CO3 (0.52 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.00735 mmol). The mixture was purged with nitrogen followed by the addition of 1,4-dioxane (1 mL) and water (0.5 mL). The suspension was heated for 16 h at 100° C., at which point LCMS analysis indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title product as a white solid (20 mg, 26%). MS(ES)+ m/e 445.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[OH-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10]#[N:11]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: BrCC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CC(CC1CCCCC1)c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 18.5 parts of 2,4-dichlorobenzeneacetonitrile and 180 parts of N,N-dimethylformamide is stirred and cooled in an ice-bath while nitrogen gas is introduced. 3.2 Parts of a sodium hydroxide solution 78% are added portionwise and the whole is stirred for one hour. Then there are added dropwise, during a one hour-period, 17.8 parts of (bromomethyl)cyclohexane while still cooling and while nitrogen gas is still introduced. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto water. The precipitated product is filtered off and triturated in a mixture of methanol and water. The product is filtered off and dried, yielding 25.5 parts of 2,4-dichloro-α-(cyclohexylmethyl)benzeneacetonitrile; mp. 58.8° C.
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:17][C:18]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:19]=1[CH:20]=O>CO.[OH-].[Na+]>[Br:26][C:23]1[CH:22]=[C:19]2[C:18](=[CH:25][CH:24]=1)[N:17]=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:20]2
Reactant: Nc1ccc(Br)cc1C=O
Reactant: O=C(O)CCCCCC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Temperature: 110 °C
Yield: 102.8 %

Procedure:
7-Oxo-7-phenylheptanoic acid (5.00 g, 22.7 mmol) and 2-amino-5-bromobenzaldehyde (5.45 g, 27.2 mmol) were dissolved in a solution of methanol (100 mL) and 2 M NaOH (30 mL). The reaction mixture was heated to 110° C. in an oil bath and refluxed overnight. The reaction was concentrated, acidified with 10% aq. HCl to pH 1 and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 8.97 g, LCMS (M+H)=384).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:29][C:30]([CH3:33])=[CH:31][N:32]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:28]4[C:27]([CH3:26])=[N:32][CH:31]=[C:30]([CH3:33])[N:29]=4)[CH2:35][CH2:36]3)=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3Cl)CC2)n1

Procedure:
In analogy to example 1,1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS [59215-42-8]) to give the title compound as a colorless solid. MS: 555.2 ([M+H]+)