Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][O:51][CH3:52].F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([N:48]([CH2:49][CH2:50][O:51][CH3:52])[CH2:47][CH2:46][O:45][CH3:44])=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: COCCNCCOC
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(CCOC)C(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.7 %

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and 2-methoxy-N-(2-methoxyethyl)ethanamine (376 mg) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (10 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:31](OCC)(=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC.O.C(O)(=O)C.C(O)C>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][C:15]([CH:31]([OH:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: -95 °C
Yield: 78.3 %

Procedure:
Benzyl 2-(2-benzyloxyethyl)-4-bromophenyl ether (24.0 g) was dissolved in 200 ml of tetrahydrofuran, 47.0 ml of 1.57 M n-butyl lithium in hexane was added to the solution with stirring at -95° C., and the mixture was subjected to 15 minutes of reaction. The reaction solution was added to a solution of 10.8 g of diethyl oxalate in 300 ml of tetrahydrofuran with stirring at -95° C., and the resulting solution was subjected to 1 hour of reaction. Then, 200 ml of ethanol and 755 mg of sodium borohydride were added in that order. The reaction solution was stirred at -35° C. for 45 minutes, 4.70 ml of acetic acid was added, and the mixture was stirred for 15 minutes. Then, a solution of 6.9 g of sodium bicarbonate in 300 ml of water was added and then the mixture was concentrated under reduced pressure. The resulting concentrate was extracted with ethyl acetate, and the extract was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=3/1) to give 19.9 g of ethyl 2-[4-benzyloxy-3-(2benzyloxyethyl)phenyl]-2-hydroxyacetate in an oily form.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33](C)(C)[O:34][SiH2]C(C)(C)C)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O>CCO.Cl>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1 h
Yield: 98.5 %

Procedure:
The product from step 4 (367 mg, 0.65 mmol) was dissolved in 4 mL of 1:1 EtOH:THF and 0.5 mL of water was added followed by the addition of 1 drop of concentrated aqueous HCl. The mixture was stirred for 1 hour (ppt formed) and the solid was collected by filtration, washed with THF and air dried overnight to give 286 mg (98%) of the title compound as a white solid. 1H-NMR (DMSO-d6) 9.00 (bs, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 8.02, (s, 1H) 7.96-7.86 (m, 2H) 7.80 (s, 1H), 7.49 (t, 1H), 7.46-7.30 (m, 6H), 7.28 (d, 1H), 7.26 (bs, 1H), 5.72 (s, 2H), 4.60 (s, 2H); LC-MS [M+H]+=447.3, RT=2.72 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([I:13])=[CH:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6]([I:13])=[CH:5]2
Reactant: Clc1nc2ccc(Br)cc2cc1I
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Temperature: 130 °C

Procedure:
6-Bromo-2-chloro-3-iodoquinoline (1.0 g, 2.7 mmol) and neat 4-methoxybenzylamine (3.6 mL, 27.1 mmol) was combined in a microwave vial and heated in a microwave at 130° C. for 15 min. The reaction mixture was purified by silica flash chromatography (0-30% EtOAc/Hex) to give 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CO[C:21](C)(C)[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:16][CH:17]=[CH:21][CH3:22]
Reactant: COC(C)(C)C
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 14.8 g of ethyltriphenylphosphonium bromide in 150 ml of t-butyl methyl ether was treated with 4.54 g of solid potassium t-butylate at -10° C. within 5 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The suspension was stirred at room temperature for 1 hour, then treated dropwise at 0° C. within 5 minutes with a solution of 6.4 g of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde in 40 ml of t-butyl methyl ether and stirred at room temperature for a further 15 hours. The mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and concentrated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and concentrated. Chromatographic separation of the resulting, yellowish oil (8.55 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 5.93 g (89%) of p-[trans-4-(3-pentenyl)cyclohexyl]benzonitrile as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:24]([C:25]([O:27][CH3:28])=[O:26])[CH3:29])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)OC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.7 g of methyl α-bromopropionate were dissolved in 30 ml of acetone. Then, to the obtained solution was added 1.4 g of anhydrous potassium carbonate and stirred at room temperature for 30 minutes. Then, the reaction mixture was heated under reflux for 30 minutes. After completion of the reaction, the formed solid substance was filtered off and the acetone was distilled off under reduced pressure to obtain 4 g of 1-methoxycarbonylethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N+:12]([O-])[CH:11]=[C:10]([O:24][CH3:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:32][C:11]1[N:12]=[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]2[CH2:15][CH2:16][N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[C:8](=[O:26])[C:9]=2[C:10]=1[O:24][CH3:25])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c[n+]([O-])c(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Product: COc1c(OC(C)=O)nc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
A solution of N-[6-(4-fluorobenzyl)-4-methoxy-2-oxido-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide (0.36 g, 0.889 mmol) in acetic anhydride (10 mL) was heated to 110° C. for 3 hours, then evaporated to dryness to give the intermediate 6-(4-fluorobenzyl)-4-methoxy-1-[methyl(methylsulfonyl)amino]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acetate (ES MS (M+1)=452). The crude material was dissolved in methanol (6 mL) and treated with sodium methoxide (30% by weight in methanol, 0.5 mL, 2.6 mmol). After 1 hour, the product mixture was neutralized with 6 N HCl, then concentrated. The residue was partitioned between CHCl3 and 10% KHSO4. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:8]1([C:6]2[N:5]=[C:4]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CNc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Sc1ccccc1
Product: CCOC(=O)CNc1cc(Sc2ccccc2)nc(-c2ccccc2)n1

Procedure:
A mixture of the above prepared N-(6-chloro-2-phenyl-4-pyrimidinyl)-glycine, ethyl ester is reacted with thiophenol, as in Example X, to afford N-(2-phenyl-6-phenylthio-4-pyrimidinyl)-glycine, ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([N:30](C)[C:31](=O)OC(C)(C)C)[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([NH:30][CH3:31])[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: COc1ccccc1NC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
For Example 10: To a solution of tert-butyl (S)-(2S)-1-((2S)-1-(2-(2-methoxyphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (40 mg, 72.2 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (1 mL, 13.0 mmol, Eq: 180) and the resulting solution was stirred at rt. After 2 h, the reaction mixture was concentrated in vacuo, the residue was treated with saturated aqueous NaHCO3 (5 mL) and the resulting mixture was extracted with DCM (2×5 mL). The combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-methoxyphenyl)-amide (22 mg), m/z=454 (M+H).
Reaction SMILES: C([O:3][P:4]([CH2:13][C@@H:14]([OH:25])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])C>Cl>[ClH:24].[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][CH2:15][C@H:14]([OH:25])[CH2:13][P:4]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:3])[OH:5])=[CH:23][CH:22]=1
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CNCc1ccc(Cl)cc1
Agent: Cl
Product: O=P(O)(Cc1ccccc1)C[C@@H](O)CNCc1ccc(Cl)cc1

Procedure:
A solution of 1.80 g of (2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester in 30 ml of semi-concentrated hydrochloric acid is heated under reflux, a whitish suspension forming after 30 minutes. The mixture is heated under reflux for a further 20 hours and cooled to 0°, and the solid portion is filtered off, washed with water and dried under reduced pressure at 60°. Recrystallisation from aqueous methanol and drying yield 3-(p-chlorobenzylamino)-2-(2S)-hydroxypropyl(benzyl)phosphinic acid hydrochloride having a melting point of 211.5°-212°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:18]([CH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][C:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:5]3)[CH2:13][CH2:14]1)=[O:19]
Reactant: O=C(O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1
Reactant: CN
Product: CNC(=O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
4-(5-Chloro-2-phenyl-1H-indol-7-yl)amino-cyclohexane-1-carboxylic acid prepared in Example 102 and methylamine (HCl salt) were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH:45]3[CH2:47][CH2:46]3)=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH:45]3[CH2:46][CH2:47]3)=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C4CC4)cc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K33) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (345 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].C[N+:13](C)(C)[CH2:14][C:15]1C=CC=C[CH:16]=1.C(#N)C=C.C(O)(=O)C>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][CH2:15][C:14]#[N:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: C=CC#N
Product: Cc1ccc2c(ccn2CCC#N)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
13 g (0.1 mol) of 5-methylindole are added to 4 ml of trimethylbenzylammonium hydroxide and 10 ml of acrylonitrile in 100 ml of dioxane while stirring. The mixture is then heated at 80° C. for 2 h and subsequently left to stand at room temperature for 3 days. Very dilute acetic acid is then added in order to neutralize the base. Extraction with EA (3×30 ml) is then carried out. The combined organic phases are dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 with DIP as eluent. Rf [DIP]=0.3.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[S:8][C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2cnc(-c3ccccc3)s2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2cnc(-c3ccccc3)s2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of 40e (0.357 g, 1 mmol.) in 40 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.848 g, 2 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1e (80.1%). 1H NMR (CDCl3) δ 8.33 (s, 1H), 8.04 (m, 2H), 7.51 (m, 3H), 7.18 (s, 2H), 3.96 (s, 3H), 3.93 (s, 6H); MS (ESI) m/z 378.1 (M+H)+.
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[N:12]=1.C1COCC1.[Li][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1.O>CCOCC>[CH3:36][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[N:12]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1cc(C)c(N=Cc2cccc(-c3c(CNc4ccccc4C)ccc4ccccc34)n2)c(C)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(NC(c2ccccc2)c2cccc(-c3c(CNc4ccccc4C)ccc4ccccc34)n2)c(C)c1
Temperature: -78 °C

Procedure:
To a solution of 1.05 g (2.23 mmol) of mesityl{[6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridin-2-yl]methylene}amine in 20 ml of THF 7.60 ml (5.60 mmol) of 0.74 M PhLi in ether was added by vigorous stirring at −78° C. The resulting mixture was heated to room temperature and then stirred for 10 min. Further on, 2 ml of water was added, and then the reaction mixture was poured into 50 ml of water. The crude product was extracted with 3×20 ml of ether. The organic extract was washed by 2×30 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 0.90 g (66%) of yellow oil. Anal. calc. for C39H37N3: C, 85.52; H, 6.81; N, 7.67. Found: C, 85.73; H, 6.98; N, 7.54. For 1H NMR (in CDCl3) see FIG. 2—Bottom spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:11][C:12](=[O:14])[CH:13]=1)=O.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)(=O)C>[CH:15]1([N:21]2[C:12](=[O:14])[CH:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]2=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=C1C=C(c2ccccc2Cl)C(=O)O1
Solvent: CC(=O)O
Product: O=C1C=C(c2ccccc2Cl)C(=O)N1C1CCCCC1
Yield: 52 %

Procedure:
To a solution of 2-(2-chlorophenyl)maleic anhydride (125.0 g) in acetic acid (1.2 1) is added cyclohexylamine (59.4 g) and the mixture is refluxed for 12 hours. The solvent is distilled off and the residue is dissolved in ethyl acetate (500 ml). This solution is successively washed with 5% hydrochloric acid (150 ml), sodium hydrogen carbonate solution (500 ml) and water (150 ml) and dried over magnesium sulfate. The solvent is distilled off and the residue is distilled off to give N-cyclohexyl-(2-chlorophenyl)maleimide (oil) (90.2 g), b.p. 171°-176° C./0.8 ton.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8](=[NH:12])OCC.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>O1CCCC1>[ClH:1].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8](=[NH:12])[CH2:7][C:3]1[S:2][CH:6]=[CH:5][CH:4]=1
Reactant: COC(CN)OC
Reactant: CCOC(=N)Cc1cccs1
Agent: Cl
Solvent: C1CCOC1
Product: COC(CNC(=N)Cc1cccs1)OC
Yield: 117.8 %

Procedure:
A mixture of ethyl 2-thiopheneethanimidate monohydrochloride (ester) (0.05 mol) in tetrahydrofuran (100 ml) was stirred under nitrogen. 2,2-dimethoxyethanamine (0.05 mol) was added portionwise upon cooling and the mixture was stirred overnight. The mixture was evaporated, yielding 15.6 g (100%) of N-(2,2-dimethoxyethyl)-2-thiopheneethanimidamide monohydrochloride (interm. 1).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])#[N:3]
Reactant: O=C(O)c1ccccc1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)c1ccccc1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with benzoic acid in analogy to experiment A1 to give (2S,4R)-1-benzoyl-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as an amorphous solid. MS: 432.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1>C(O)C.[Pd]>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CC(=O)CCC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)CC(=O)CCC2
Yield: 77.1 %

Procedure:
A solution of ethyl (E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)acrylate (400 mg) in ethanol (8 ml) was hydrogenated over 10% palladium on carbon (24 mg). After removing the catalyst, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1) as an eluent to give ethyl 3-(8-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)propionate (311 mg).