Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCNC2)C1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCN(C[C@@H](O)COc3cccc4ncccc34)C2)C1
Temperature: 25 °C
Yield: 67 %

Procedure:
1-(Piperidine-3-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (79) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (230 mg) as a white solid. ESMS:MH+ 691.6
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]2)=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(N)ccc1O
Reactant: C=C(CC(=O)O)C(=O)O
Product: Cc1cc(N2CC(C(=O)O)CC2=O)ccc1O

Procedure:
In an analogous manner to that described in Example 2a), 4-amino-o-cresol is reacted with itaconic acid at 140° C. during 10 min to yield the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid as a light brown solid; MS: m/e=234 (M−H)+ which directly used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[CH:25]=1)[C:9](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH:34]O.O.[OH-].[Li+]>O>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[CH:25]=1)[C:9]([OH:10])=[O:34])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1C
Temperature: -10 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of [(R)-2-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-1-(4-methoxy-3-methyl-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (6.05 g, 13.3 mmol) in 4:1 tetrahdydrofuran/water (200 mL) at −10° C. was added sequentially 30% aqueous hydrogen peroxide (15 mL, 133 mmol) and a solution of lithium hydroxide monohydrate (1.63 g, 40 mmol) in water (20 mL). The reaction mixture was stirred at −10° C., and the progress of the reaction was monitored by thin layer chromatography. After 4 hours, thin layer chromatography indicated almost complete consumption of starting material. Saturated aqueous sodium sulfite solution (100 mL) was added. The mixture was concentrated to half of its original volume under reduced pressure to remove tetrahydrofuran, then extracted with dichloromethane (2×100 mL). The aqueous layer was separated and acidified to pH=4 with aqueous citric acid solution, extracted with ethyl acetate (2×250 mL). The organic layers were separated, combined, dried over sodium sulfate, concentrated under reduced pressure and dried in vacuo to give (R)-tert-butoxycarbonylamino-(4-methoxy-3-methyl-phenyl)-acetic acid as a white foam (2.2 g, 58%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[NH3:29]>>[NH2:29][C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1)=[O:3]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: N
Product: CC(Cc1ccc(OCC(N)=O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared analogously to Example 14 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with concentrated ammonia followed by purification of the base on a silica gel column using methylene chloride/methanol =9:1 as eluant.
Reaction SMILES: [CH2:1]([C:6]1([CH3:17])[O:11][C:10](=[O:12])[CH:9]([CH2:13][C:14]([OH:16])=[O:15])[S:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[N+](=[CH2:20])=[N-]>C(OCC)C>[CH3:20][O:15][C:14](=[O:16])[CH2:13][CH:9]1[S:8][CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([CH3:17])[O:11][C:10]1=[O:12]
Reactant: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC1(C)CSC(CC(=O)OC)C(=O)O1

Procedure:
To 4.7 g of 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid, dissolved in 50 ml of diethyl ether, there is added dropwise, with stirring and ice cooling, ethereal diazomethane solution, until a pale yellow color just remained. After the usual working up, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid methyl ester is obtained:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>O1CCCC1>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]([CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([CH2:25][CH2:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]1)[C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=C(N(C[C@H]1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-((S)-pyrrolidin-3-ylmethyl)acetamide (140 mg, 0.448 mmol) in tetrahydrofuran (3 mL) were added tert-butyl acrylate (0.085 mL, 0.583 mmol) and triethylamine (0.094 mL, 0.672 mmol), and the mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 110 mg of product as pale yellow oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](OCC)(=[O:9])[C:6]([CH3:8])=[O:7]>>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:9])[C:6](=[O:7])[CH3:8]
Reactant: NCCO
Reactant: CCOC(=O)C(C)=O
Product: CC(=O)C(=O)NCCO
Temperature: 120 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
Ethanolamine (16 g, 66 mmol) was added dropwise to stirred ethyl pyruvate (8 g, 69 mmol) at temperature between 22 and 48° C. Then the mixture was heated to 120° C. and stirred at this temperature for 3 hours. During the reaction, the formed ethanol and water were removed by distillation. The reaction mixture was cooled to room temperature and poured into 40 ml of water. The mixture was acidified to pH<1 and stirred for 30 minutes at room temperature. The solution was saturated with sodium chloride and extracted with ethyl acetate a few times. The ethyl acetate layer was evaporated to dryness. The remaining residual oil was purified by silica gel column chromatography using heptane/ethyl acetate to yield colorless oil (1 g, 9% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:18]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([F:38])[CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:36]=[CH:37][C:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:4]4[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])(=[O:12])=[O:11])[C:18]=3[CH:19]=2)=[O:24])=[CH:28][C:29]=1[F:38])[CH3:35]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCO3)cc1F

Procedure:
The title compound, MS (ISP)=501.1 (M+H)+, was produced as described in example 1, steps 1-6. Step 3 was performed using 2-methoxy-5-methylbenzenesulfonyl chloride, furnishing 4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-amino-2-fluorobenzoate in step 5 and yielded 2-fluoro-4-{[4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[O:18][CH3:19].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([N:5]([CH2:4][C:3]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[C:10]([O:18][CH3:19])[CH:11]=1)(=[O:43])=[O:42]
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCO)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-difluorobenzyl)-N-heptyl-2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]acetamide (A)(132 mg, 0.294 mmol) was dissolved in DCM (10 ml). It was cooled in an ice-bath. Triethylamine (0.05 ml, 0.352 mmol) was added and then methanesulfonyl chloride (37 mg, 0.323 mmol) was dropped in. The cooling-bath was removed after 30 minutes. The mixture was stirred at room temperature overnight. LS-MS showed that ca 50% of A was not reacted. The mixture was cooled in an ice-bath and 0.05 ml of triethylamine was added, followed by 0.025 ml of methanesulfonyl chloride. After addition, the cooling-bath was removed and the mixture was stirred for 5 hours more. It was then washed with water (×2) and brine, dried (magnesium sulphate) and evaporated. Oil product 138 mg was left and used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=1)=[O:6]
Reactant: N=C(N)COCCc1cccc(Cl)c1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1cccc(Cl)c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=388.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[C:25]1([CH:35]=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: O=Cc1cccc2ccccc12
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc2ccccc12

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester was prepared from (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (2.5 g, 6.07 mmol) and 1-naphthaldehyde (2.0 g, 13.3 mmol) according to Procedure G, except for the following: after completion of the reaction, 100 mL of DCM was added and the organic washed with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]#[C:27][NH2:28].Cl>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1)[C:27]([NH2:28])=[NH:26]
Reactant: N#CN
Reactant: Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
2.0 g (6.1 mmol) of (Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and 1.0 g (23.7 mmol) of cyanamide are dissolved in 100 ml of ethanol and 10 ml of ethereal hydrochloric acid and heated for 24 hours in a glass bomb at 80° C. The solvent is distilled off. Chromatography of the residue on silica gel (ethyl acetate/methanol/glacial acetic acid/water=17:3:5:5) yields the product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([CH3:11])[CH3:10]>>[CH:9]1([O:12][C:13]2[CH:14]=[C:15]([C:2]3[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1
Product: Nc1ccc(-c2cccc(OC3CC3)c2)cc1
Yield: 7.5 %

Procedure:
The title compound (98 mg) was prepared from 4-bromoaniline (1 g, 5.81 mmol) and 3-isopropoxyphenylboronic acid (1.96 g, 7.55 mmol) as a yellow liquid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH:34]=O)=[CH:4]1)[CH3:2].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH2:34][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (10 g, 21.12 mmol) in Dichloromethane (DCM) (150 mL) was added pyrrolidine (2.61 mL, 31.7 mmol), sodium triacetoxyborohydride (8.95 g, 42.2 mmol) and AcOH (0.060 mL, 1.056 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS showed completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF), using a 120 g column and eluting with MeOH/DCM (0-20%). The product was further purified with reverse phase automatic silica column chromatography (Combiflash RF), using a 150 g golden column and eluting with acetonitrile/water (0-60%) to afford 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (4.6 g, 8.70 mmol, 41.2% yield) as a pale yellow solid. LCMS: (M+H)+: 529.4.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22](O)=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>C1(C)C=CC=CC=1.CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC#N
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1OC1CCCC1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a magnetically-stirred suspension of 2-[4-(3-cyclopentyloxy-4-methoxyphenyl) piperidin-1-yl]-2-oxo-acetic acid (2.5 mmol, 0.868 g) in dry toluene (25 mL) at room temperature was added oxalyl chloride (2.0M solution in CH2Cl2 ; 2.75 mmol, 1.38 mL) dropwise over 10 minutes, followed by DMF (4 drops). The resulting homogenous solution was stirred at room temperature for 30 minutes, after which time saturated NH3 /CH3CN (25 mL) was added dropwise over 30 minutes. A white solid precipitated out of solution, and the heterogeneous mixture was stirred for 1 hour at room temperature. The solution was diluted with H2O to dissolve the white precipitate and the volatiles were removed in vacuo. The solid was partitioned between saturated NaHCO3 (150 mL) and EtOAc (150 mL) and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with H2O (300 mL), dried (Na2SO4) and concentrated in vacuo to yield the title compound as a white foam, mp=66°-66.5° C. (1.8 mmol, 0.640 g, 74% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15](C)([C:19](O)=O)[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)(C(=O)O)C(=O)O)cc2s1
Solvent: O
Product: CCOC(=O)c1cc2ccc(C(C)C(=O)O)cc2s1
Temperature: 210 °C
Yield: 91.3 %

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl](methyl)malonic acid (0.19 g, 0.590 mmol) was suspended in H2O (5 mL) before heating at 210° C. in a microwave reactor for 40 seconds. The suspension was diluted with H2O (50 mL) and the products extracted into EtOAc (2×75 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 0.15 g of product (white solid, 91%). 1H NMR (DMSO-d6) δ 12.41 (br s, 1H), 8.14 (s, 1H), 7.95 (br s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.37 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.81 (q, J=7.2 Hz, 1H), 1.40 (d, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1

Procedure:
A solution of 3.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 1.9 g of potassium carbonate in 100 ml of acetone was refluxed for 30 hours under an inert atmosphere with 11 ml of epichlorohydrin and the insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was purified by chromatography over silica (eluent:chloroform/acetone/TEA 6:3:1). Fractions having a Rf=0.45 were evaporated to dryness and the residue was empasted with ether, filtered and dried under reduced pressure at 60° C. to obtain 3.65 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide melting at 171° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13]([NH:25][CH:26]([CH3:28])[CH3:27])[C:14]3[N:15]([C:17](=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl>O1CCOCC1.O>[C:20]([N:18]1[C:17](=[O:24])[N:15]2[CH:16]=[C:11]([C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9][CH2:10]3)[N:12]=[C:13]([NH:25][CH:26]([CH3:28])[CH3:27])[C:14]2=[N:19]1)([CH3:22])([CH3:23])[CH3:21]
Reactant: CCOC(=O)C1(c2cn3c(=O)n(C(C)(C)C)nc3c(NC(C)C)n2)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1nc(C2(C(=O)O)CCCC2)cn2c(=O)n(C(C)(C)C)nc12
Temperature: 60 °C

Procedure:
A solution of 400 mg of the product of Step A in 1,4-dioxane (10 mL) was treated with 6N KOH (2.0 mL) and the mixture was heated at 60° C. for three h. The reaction was cooled to ambient temperature, diluted with water, and the pH adjusted to 2 with 2N HCl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4, filtered, and concentrated to afford 1-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid as a white solid. MS (M+H+)=360.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([NH2:27])([C:25]#[N:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])(O)=O.[Na+]>CCO>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([C:25]#[N:26])([NH:27][C:6]([C:5]2[CH:9]=[CH:10][N:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:8])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: COc1cc(C(=O)O)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)ccn1
Reaction time: 46.5 h

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 2,7-hydrate (1.06 g, 3.26 mmol) was added to a solution of 2-methoxy-isonicotinic acid (500 mg, 3.26 mmol) and 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (669 mg, 2.97 mmol) in EtOH (8.0 ml) at room temperature, and the mixture was stirred for 46.5 hours. An aqueous NaHCO3 solution was added to the reaction mixture, followed by extraction with AcOEt three times. The organic layers were washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH2Cl2/MeOH=99:1 to 95:5) to give 4-cyano-4-[(2-methoxy-pyridine-4-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless form (901 mg, 84%).