Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26](=O)[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[C:16]([O:15][C:13]([NH:12][CH2:11][C:7]1[CH:6]=[C:5]([CH:4]([OH:20])[C:3]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:2]=2[NH:1][CH2:26][CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:10]=[CH:9][CH:8]=1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: O=CC=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCC=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) produced in Example (1) and cinnamaldehyde.(0.5 g). To the solution was added acetic acid (0.11 g). To the mixture was added, while stirring at room temperature, cyano sodium borohydride (0.12 g). The reaction mixture was stirred for 40 minutes at 60° C., which was concentrated. The concentrate was subjected to extraction by the addition of water (30 ml) and ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give a-(3-tert-butoxycarbonylaminomethylphenyl)-5-chloro-2-[(3-phenyl)-2-propenyl]amino-benzyl alcohol (0.8 g) as a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(=O)CO[C:25]1[CH:30]=CC=C(O)[C:26]=1C(=O)C)C>>[CH2:30]([O:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:25]=[CH2:26]
Reactant: CCOC(=O)/C=C/c1oc2cccc(O)c2c1C
Reactant: CCOC(=O)COc1cccc(O)c1C(C)=O
Product: C=CCOc1cccc2oc(/C=C/C(=O)OCC)c(C)c12

Procedure:
Following the procedure of Example 116 but substituting an equivalent amount of ethyl E-3-(4-hydroxy-3-methylbenzofuran-2-yl)propenoate for the compound of Example 1, there was obtained the title compound, m.p. 79°-80° C.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:16][CH2:17][C:18]4([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]4)[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:27])[CH3:26]>O1CCCC1>[CH2:25]([NH:27][CH2:20][C:18]([CH2:17][NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][N:7]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:19])[C:21]([F:24])([F:23])[F:22])[CH3:26]
Reactant: CCN
Reactant: FC(F)(F)C1(CNc2cccc3c2cnn3-c2ccccc2)CO1
Solvent: C1CCOC1
Product: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.235 g, 3.7 mmol) in anhydrous tetrahydrofuran (5 ml) was added ethylamine (2M in tetrahydrofuran) (10 ml, 20 mmol). The reaction was stirred at room temperature for approximately 72 hours and then evaporated in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=O)[N:9]3CC[C@H:10]3[C:11]3[N:12](C=NC=3/C=C\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH2:33]>CN(C)C=O>[N:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]2[C:6]=1[C:5](=[O:33])[CH:4]=[CH:3][CH:2]=2
Reactant: O=C1c2c(Cl)cccc2-n2cnc(/C=C\Cl)c2[C@@H]2CCN12
Reactant: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1cccc2cnccnc1-2

Procedure:
2.21 g (6.9 mmol) of (S)-8-chloro-1-[(Z)-2-chlorovinyl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was heated to boiling under reflux for 4 hours together with 1.23 ml (8.3 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 300 ml of water and extracted five times with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there was obtained (S)-8-chloro-1-ethynyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4benzodiazepin-9-one of melting point 249°-250°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18](C)[C:19](=O)C(F)(F)F)[C@H:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)C(F)(F)F)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a mixed solution of the compound (0.66 g) obtained in step 4 in methanol (6.5 mL) and water (1.3 mL) was added potassium carbonate (0.35 g) at room temperature, and the mixture was stirred at 50° C. for 24 hr. Furthermore, potassium carbonate (1.70 g) was added, and the mixture was stirred at 50° C. for 6 days. The organic solvent was evaporated under reduced pressure, and the residue was poured into saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 0→9% methanol/ethyl acetate) to give the title compound (0.30 g, 58%) as a white amorphous solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](O)=[O:35].[I-].ClC1C=CC=C[N+]=1C.C(NCCCC)CCC>O1CCCC1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:34]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[N:8]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(N)N=C2c1ccccc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCNCCCC
Product: CCc1cc2c(s1)-n1c(C)nnc1C(NC(=O)c1cc3ccccc3[nH]1)N=C2c1ccccc1Cl
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To 120 ml of tetrahydrofuran were added 5.0 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 2.7 g of indole-2-carboxylic acid, 4.3 g of 2-chloro-N-methyl pyridinium iodide and 6.2 g of dibutyl amine, and the mixture was heated under reflux while stirring for 90 minutes. After the solvent was distilled off under reduced pressure, the residue was washed with diisopropyl ether. Ethanol was added to separate crystals, which were collected by filtration. The thus-obtained crystals were recrystallized from chloroform-ethanol to give 4.9 g of 4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, m.p. 284°-286° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C.C(=O)(O)[O-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Yield: 51.7 %

Procedure:
A solution of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine (150 mg, 0.506 mmol) and methyl 3-bromopropanoate (0.22 mL, 2.0 mmol) in THF (6 mL) was treated with triethylamine (0.28 mL, 2 mmol) and the reaction was heated at reflux for 4 hours. The reaction was allowed to cool and treated with an aqueous bicarbonate solution. The combined ethyl acetate extracts were washed with water, dried and concentrated to give 0.1 g of methyl hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-propanoate; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, 2H), 7.39 (dd, 2H), 7.32 (dd, 1H), 7.24 (d, 2H), 6.93 (d, 2H), 5.05 (s, 2H), 3.67 (s, 3H), 3.56 (s, 2H), 2.85 (t, 2H), 2.48 (t, 2H), 2.77-2.58 (m, 8H), 1.77 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:21][C:22]1[C:23]([F:29])=[N:24][CH:25]=[C:26]([OH:28])[CH:27]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([O:28][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:25]=[N:24][C:23]=1[F:29]
Reactant: Oc1cnc(F)c(Cl)c1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cnc(F)c(Cl)c1

Procedure:
The title compound was prepared according to the method described for Method Variation 1 using 3-cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 2) and 3-chloro-2-fluoro-5-hydroxypyridine and then purified using silica gel column chromatography eluting with 30-35% EtOAc in heptanes.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(OCC)(=O)C>C1CCCCC1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Yield: 43.7 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 1.15 g (3.50 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate, obtained in step 10.1., 1.99 g (10.49 mmol) of 3-(trifluoromethyl)phenyl-boronic acid, 2.97 g (13.99 mmol) of hydrated potassium phosphate and 0.40 g (0.35 mmol) of tetrakis(triphenyl-phosphine)palladium, and after chromatography on silica gel, eluting with a 35/65 and then 45/55 mixture of ethyl acetate and cyclohexane, 0.67 g of pure product is obtained in the form of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[N:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl>CN1CCCC1=O.CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[N:26]4[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Clc1ccc(Sc2ccc([C@@H]3CC[C@@H]4CCCCN43)cc2)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
A solution of 4.1 g (0.028 mole) of 4-chlorothiophenol in 40 mL of dry N-methylpyrrolidinone was added to 0.028 mole of sodium hydride (from 1.36 g of 50% sodium hydride washed free of oil with hexane) under an atmosphere of nitrogen. Then a solution of 5.3 (0.019 mole) of trans-3-(4-bromophenyl)octahydroindolizine in 50 mL of dry N-methylpyrrolidinone and 1.35 g of cuprous oxide was added to the mixture and the reaction mixture was refluxed overnight. Then the reaction was cooled to room temperature, MeOH was added, and the mixture was filtered. The solvent was evaporated in vacuo to a brown oil. The oil was flash chromatographed in SiO2 using 98% hexane, 2% acetone as the eluant. The product was collected in fractions 6 and 7, and evaporation of the solvent in vacuo gave an oil. The oil was treated with ethereal HCl to give a solid salt. The solid was recrystallized from acetonitrile to give 77 g (10% yield) of the title compound as a white solid, mp=198°-201° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([O:17][Si](C(C)(C)C)(C)C)[CH2:15][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([OH:17])[CH2:15][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.3 %

Procedure:
t-Butyl (3R,4S)-3-benzyloxycarbonylamino-4-(t-butyldimethylsilanoxy)pyrrolidine-1-carboxylate (54 g) was dissolved in THF (400 mL), followed by addition of a solution (167 mL) of 1 M tetrabutyl ammonium fluoride in THF with ice cooling, and the mixture was stirred at room temperature for 3.5 h. Water was added, then the mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=1:1-1:2) to obtain t-butyl (3R,4S)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (38 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[CH:3]=[N:4]2)[N:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cnn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-pyrazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.11) (0.44 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.027 g, 6%). MS (ISP) 451.1 [(M+H)+]; mp 206° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:16]1([C@H:26]([N:28]([CH2:36][C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][NH:39][CH2:38]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CS(C)=O>C(OCC)(=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:39]2[CH2:40][C@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:37]([CH2:36][N:28]([C@@H:26]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[CH3:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:38]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(c2ccc(C#N)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A 650 mg portion of potassium carbonate and 339 mg of 4-fluorobenzonitrile were added to a mixture of 1.0 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 10 ml of DMSO and stirred overnight at 110° C. After cooling down to room temperature, the reaction solution was mixed with ethyl acetate, washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 723 mg of tert-butyl {[(3R,4S)-1-(4-cyanophenyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless amorphous substance. EP: 532.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(Br)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(Br)c1)Oc1ccccc1

Procedure:
A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether and the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamate, m.p. 88°-90° C.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[CH3:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][NH:16][CH:15]=1)=[O:13].[CH:19]1([N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[CH2:22]C[CH2:20]1.IC1C=CC(OC2CCN(C(C)C)CC2)=CC=1>>[CH:19]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([N:16]3[CH:17]=[CH:18][C:14]([C:12]([NH:11][CH3:10])=[O:13])=[CH:15]3)=[CH:34][CH:35]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:20]
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CNC(=O)c1cc[nH]c1
Agent: CC(C)N1CCC(Oc2ccc(I)cc2)CC1
Agent: Cn1ccc(C(=O)O)c1
Product: CNC(=O)c1ccn(-c2ccc(OC3CCN(C(C)C)CC3)cc2)c1

Procedure:
The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by N-methyl-1H-pyrrole-3-carboxamide and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 4-(4-iodophenoxy)-1-isopropylpiperidine.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[O:15])=[CH:3][CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C=CC(=O)O)cc1
Yield: 37.4 %

Procedure:
In 200 ml of dichloromethane were dissolved 5.4 g of anisol and 4.98 g of maleic anhydride, and 9.95 g of anhydrous aluminum chloride was added gradually under ice-cooling with stirring. Then, the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced presource, and poured into a mixture of 10 ml of conc. hydrochloric acid and 150 g of ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The ethyl acetate was removed from the solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of hexane and diethyl ether to give 3.85 g of 3-(4-methoxybenzoyl)acrylic acid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OCCNCCO
Product: N#Cc1ccc(CN(CCO)CCO)cc1

Procedure:
4-{[Bis-(2-hydroxyethyl)-amino]-methyl}benzonitrile was prepared according to the general method as outlined in Example 1 (Step 4) starting from diethanolamine (10.2 g, 97 mmol) and α-bromo-p-tolunitrile (15.8 g, 81 mmol). Yield, (68%); white solid; mp 163° C. MS: 221.2 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]([CH2:14][OH:15])[OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)OCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.2 %

Procedure:
1-Octanoyl-rac-glycerol (10.00 g, 45.81 mmol) and DMAP were placed in a flame-dried round bottom flask, followed by triethylamine (13.0 ml, 93.27 mmol) and CH2Cl2 (200 ml). When the solid dissolved, trityl chloride (14.07 g, 50.47 mmol) was added and the mixture was stirred at room temperature for two days. The mixture was poured into ice water and the two phases were separated. The organic layer was washed three times with 1 N HCL and twice with water, dried over MgSO4, and evaporated. The product was purified by chromatography in two batches, (150 g silica gel each with hexanes:ethyl acetate (8:1) solvent) to yield compound 43, 1-octanoyl-3-O-trityl-rac-glycerol (9.96 g, 47% yield).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([OH:28])(=O)[CH2:25][CH3:26].[NH2:29][CH2:30][CH2:31][CH:32]1[C:44]2[C:43]3[NH:42][C:41](=[O:45])[CH2:40][O:39][C:38]=3[CH:37]=[CH:36][C:35]=2[CH2:34][CH2:33]1>CN(C)C=O.O>[O:45]=[C:41]1[CH2:40][O:39][C:38]2[CH:37]=[CH:36][C:35]3[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][NH:29][C:24](=[O:28])[CH2:25][CH3:26])[C:44]=3[C:43]=2[NH:42]1
Reactant: CCC(=O)O
Reactant: NCCC1CCc2ccc3c(c21)NC(=O)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)NCCC1CCc2ccc3c(c21)NC(=O)CO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (372.0 mg, 1.9 mmol.) and 1-hydroxybenzotriazole monohydrate (257 mg, 1.9 mmol.) were suspended in N,N-dimethylformamide (2.5 mL). To the suspension was added, under ice-cooling, propionic acid (0.11 mL, 1.4 mmol.). This reaction mixture was stirred for one hour at room temperature, and, then, cooled again with ice, to which was added dropwise a solution of 9-(2-aminoethyl)-1,7,8,9-tetrahydroindeno[5,4-b][1,4] oxazin-2(3H)-one (300 mg, 1.3 mmol.) in N,N-dimethylformamide (1.5 mL). The mixture was stirred for one hour under ice-cooling. The reaction mixture was poured into water, and the organic matter was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of silica gel column chromatography (chloroform:methanol=10:1) to afford the title compound (yield 253.0 mg, 88%).