Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1cccc(Nc2nccc(NCCCN3CCOCC3)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine, 3, (0.2 g, 0.84 mmol) in THF (4 mL) is added diisopropylethylamine (0.29 mL, 1.67 mmol) followed by 3-morpholino-propylamine (0.245 mL, 1.67 mmol). The resulting mixture was heated to reflux for 6 hours. Another 2 equivalents of 3-morpholinopropylamine (0.245 mL, 1.67 mmol) is added and the reaction heated to reflux and stirred for 18 hours. The resulting mixture is heated to reflux for 18 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is diluted with 5 mL water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is diluted with 5 mL water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. This residue is purified over silica (6% MeOH in CH2Cl2 with 0.7% Et3N) to afford 0.120 g (41% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 1.68-1.75 (m, 2H), 2.34-2.40 (m, 6H), 3.30-3.35 (m, 2H), 3.55-3.58 (m, 4H), 5.97 (d, J=5.7 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 7.19-7.28 (m, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.80 (br s, 1H), 8.13 (br s, 1H), 9.19 (br s, 1H). MS (ESI, pos. ion) m/z: 348 (M+1).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH2:14]([N:21]([CH3:43])[C:22]([C:24]1[CH:37]=[N:36][C:35]2[C:26](=[CH:27][C:28]([F:42])=[C:29]3[C:34]=2[N:33]=[CH:32][C:31]([C:38](=O)[NH2:39])=[C:30]3Cl)[CH:25]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[CH2:14]([N:21]([CH3:43])[C:22]([C:24]1[CH:37]=[N:36][C:35]2[C:26](=[CH:27][C:28]([F:42])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]([C:38]#[N:39])[C:30]3=[O:4])[CH:25]=1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(Cc1ccccc1)C(=O)c1cnc2c(c1)cc(F)c1c(Cl)c(C(N)=O)cnc12
Agent: Cl
Solvent: c1ccncc1
Product: CN(Cc1ccccc1)C(=O)c1cnc2c3c(c(F)cc2c1)C(=O)C(C#N)C=N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Trifluoroacetic anhydride (0.5 ml) was added dropwise to a stirred, ice-cooled mixture of 8-(N-benzyl-N-methylcarbamoyl)-3-carbamoyl-4-chloro-5-fluoro-1,10-phenanthroline (0.3 g) in pyridine (3 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was acidified with 3M hydrochloric acid and stirred at ambient temperature for 18 hours. The mixture was filtered and the solid so obtained recrystallised from a mixture of methanol and ethyl acetate to give 8-(N-benzyl-N-methylcarbamoyl)-3-cyano-5-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline in 24% yield, mp 267-269° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[C:22](=O)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36].B.C1COCC1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CCN1CCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCC1=O
Agent: B
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1CCCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-(1-ethyl-2-oxoazepan-5-yl)-3,4-dihydro-2(1H)-quinazolinone (EXAMPLE 78) (9.7 mg, 0.018 mmol) in THF (0.2 mL) under N2 atmosphere was added BH3.THF (88 μL, 1.0M solution in THF). The reaction was stirred at RT overnight. The solvent was removed in vacuo, and the residue was dissolved in CH2Cl2. The resulting solution was washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the residue was re-dissolved in CH2Cl2 (0.5 mL) then cooled down to 0° C. To this was added Et3SiH (3 μL, 0.036 mmol) followed by BF3.Et2O (2.5 μL, 0.04 mmol), and the mixture was slowly warmed to RT over 2 hours. It was quenched with saturated solution of NaHCO3, then extracted with CH2Cl2 three times. The combined extracts were washed with brine and dried over Na2SO4. The crude residue was purified by preparative TLC eluting with 5% 2M NH3 in MeOH(CH2Cl2 to obtain 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-ethylazepan-5-yl)-3,4-dihydro-2(1H)-quinazolinone. 1H NMR (CDCl3, 500 MHz): selected data δ 1.03 (t, J=7.1 Hz, 3H), 1.6-1.87 (m, 6H), 2.52 (q, J=7.1 Hz, 2H), 2.56-2.73 (m, 5H). MS(ES) 530 (M+H); LC 1: 2.36 min.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]([C:15]2O[C:17]([NH:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[N:18][N:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>ClCCl>[N:26]1([C:17]2[N:20]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:15]([C:13]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:14])=[N:19][N:18]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCN1
Reactant: CC(C)=CCNc1nnc(C(=O)NCc2cccc3ccccc23)o1
Solvent: ClCCl
Product: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCNCC1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.10 g 5-(3-methyl-but-2-en-1-ylamino)-[1,3,4]oxadiazole-2-carboxylic acid-(naphth-1-ylmethyl)-amide and 1.28 g piperazine is stirred for 15 min at 200° C. in a microwave. After cooling to ambient temperature dichloromethane is added, the organic phase is washed with water, dried over sodium sulphate and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→7:3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[CH3:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([CH3:34])[CH:33]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:30]2[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=2)=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2ccc(C(=O)NCCCCCC(=O)Nc3ccccc3N)cc2C)c1
Yield: 77 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 3,5-dimethyl phenyl boronic acid instead of phenyl boronic acid to obtain the title compound (35 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH:19]=2)[N:10]=[N:9]1>Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[N:10]=[N:9]1
Reactant: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1Cl
Agent: Cl
Product: Cc1c(C2=CCNCC2)nnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-Butyl 4-[1-(2-chlorophenyl)-5-methyl-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (40 mg) prepared in Example 10 was dissolved in 10% methanolic hydrochloric acid and stirred at room temperature for 3.5 hours and the solvent was evaporated in vacuo to give the title compound as a mixture.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>ClCCl>[CH3:35][O:34][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[C:31]=1[O:32][CH3:33])[C:26]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)=[O:27]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCOC(=O)C1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
To a mixture of ethyl piperazine-2-carboxylate dihydrochloride (2.0 g), triethylamine (1.2 ml) and dichloromethane (40 ml) is added dropwise, under ice-cooling while stirring, a solution of 3,4,5-trimethoxybenzoyl chloride (1.85 g) in dichloromethane (25 ml). The mixture is stirred for one hour, then the reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (eluent : ethyl acetate-acetone-hexane=2:1:2) to afford ethyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (2.5 g). This product is recrystallized from ethyl acetatehexane to give colorless crystals, m.p. 114-115° C.
Reaction SMILES: ClC(OCC)=O.[CH:7]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.Cl.Cl.[NH2:24][C:25]1[CH:57]=[CH:56][C:28]([O:29][C:30]2[CH:31]=[CH:32][C:33]3[N:37]=[C:36]([CH2:38][O:39][C:40]4[CH:53]=[CH:52][C:43]([CH2:44][CH:45]5[S:49][C:48](=[O:50])[NH:47][C:46]5=[O:51])=[CH:42][CH:41]=4)[N:35]([CH3:54])[C:34]=3[CH:55]=2)=[CH:27][CH:26]=1>CN(C)C=O.O>[CH:7]1([C:12]([NH:24][C:25]2[CH:57]=[CH:56][C:28]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:37]=[C:36]([CH2:38][O:39][C:40]5[CH:53]=[CH:52][C:43]([CH2:44][CH:45]6[S:49][C:48](=[O:50])[NH:47][C:46]6=[O:51])=[CH:42][CH:41]=5)[N:35]([CH3:54])[C:34]=4[CH:55]=3)=[CH:27][CH:26]=2)=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(O)C1CCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCC4)cc3)cc21
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
Ethyl chloroformate (87 mg) was added dropwise to a solution of cyclopentanecarboxylic acid (90 mg) and triethylamine (232 mg) in anhydrous N,N-dimethylformamide (8 ml) at ambient temperature. The mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg) in small portions. The mixture was stirred at ambient temperature for 5 hours and allowed to stand at the same temperature overnight. After concentration of the mixture, water was added to the reaction mixture and the insoluble product was isolated by filtration and washed with water and ethyl acetate to give the title compound (236 mg).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)/[CH3:4].[I-].[K+].II.C([O-])(O)=O.[Na+]>O.O1CCCC1>[CH3:4][C:3]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:1][N:2]=1
Reactant: CC(/C=C/c1ccc([N+](=O)[O-])cc1)=N/O
Agent: II
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc([N+](=O)[O-])cc2)on1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of tetrahydrofuran and water (10 mL). To the stirred solvent were added (2Z,3E)-N-hydroxy-4-(4-nitrophenyl)but-3-en-2-imine (0.5 g, 2.42 mmol), potassium iodide (0.81 g, 4.85 mmol), iodine (1.23 g, 4.49 mmol) and NaHCO3 (0.81 g, 9.7 mmol). The mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water (25 mL), sodium thiosulphate solution (30 mL) and saturated brine solution (30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents. The product was obtained as yellow solid (0.31 g, yield: 62.6%). MS (ESI, 120 eV): m/z=205.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 8.24-8.27 (t, 2H), 7.85-7.87 (t, 2H), 6.49 (s, 1H), 2.33 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[CH3:13][C:14]1([CH2:18][OH:19])[CH2:17][O:16][CH2:15]1>>[CH:8]1([C:7]2[C:2]([O:19][CH2:18][C:14]3([CH3:13])[CH2:17][O:16][CH2:15]3)=[CH:3][C:4]([C:11]#[N:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: CC1(CO)COC1
Reactant: N#Cc1cc(Cl)c(C2CC2)cn1
Product: CC1(COc2cc(C#N)ncc2C2CC2)COC1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-cyclopropyl-pyridine-2-carbonitrile (example 215b), (3-methyloxetan-3-yl)methanol (CAN 3143-02-0) as starting materials and isolated (1.73 g, 83%); MS (ESI, m/z): 245.5 (M+H+).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH2:18])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH:18][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NC1CCCC1
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Cyclopentanone (0.12 mL, 1.38 mmol) was added to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 230 mg, 1.26 mmol) in anhydrous methanol (10 mL) at 25° C. under a nitrogen atmosphere. After stirring for 10 min, glacial acetic acid (0.5 mL) and sodium cyanoborohydride (260 mg, 3.15 mmol) were added sequentially, and the resulting mixture was stirred at 50° C. for 30 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-cyclopentylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (237 mg, 0.94 mmol, 75%), as a yellow oil. LC-MS (ESI) calcd for C15H25NO2 251.19, found 252.0 [M+H+].
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[C:24]#[CH:25]>CN(C)C=O.[Cu]=O>[O:14]([C:10]1[N:9]=[C:8]([CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:2]([CH:25]=[CH:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Reactant: C#CC(=O)OCC
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of 2-((4-iodophenoxy)methyl)-6-phenoxypyridine (160 mg) in dimethylformamide (2 ml), 0.116 ml of ethyl propiolate and 69 mg of copper (II) oxide were added, and the reaction solution was stirred at 110° C. for 15 hours. The reaction solution was cooled and then Celite-filtered, and the filtrate was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (0:100-20:80-33/67)) to afford the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:3]1.[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20]>CCOCC>[CH3:18][Si:19]([CH2:22][C:11]1([OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:3][C:2]1=[O:1])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C1CCCCCCC(=O)C(=O)N1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: CCOCC
Product: CCOC(=O)C1CCCCCCC(O)(C[Si](C)(C)C)C(=O)N1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Ethyl 2,3-di-oxo-1-azacyclodecane-10-carboxylate (5.02 g, 20.81 mmol) is dissolved in ether (50 mL), and cooled to 0° C. Trimethylsilylmethylmagnesium chloride (42.0 mL of a 1.0M solution in ether, 42.0 mmol) is added dropwise, the reaction is stirred at 0° C. for 20 minutes, and then heated to reflux overnight. The reaction is quenched with saturated ammonium chloride, and extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give separately the two diastereomers of ethyl 3-(trimethylsilylmethyl)-3-hydroxy-2-oxo-1-azacyclodecane-10-carboxylate; major isomer, m.p. 129°-130° C.; minor isomer, m.p. 175°-177° C.
Reaction SMILES: [CH:1]1=[CH:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12]1.C(=O)(O)[O-:14].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]12[O:14][CH:12]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]2
Reactant: O=C([O-])O
Reactant: C1=CCCC=CCCCC=CC1
Agent: C1=C/CC/C=C/CCC/C=C/C/1
Agent: C1=C/CCC2OC2CC/C=C/CC/1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C1=CCCC2OC2CCC=CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of E,E,E-1,4,8-cyclododecatriene (22.5 g, 139 mmol, available commercially from Alfa Aesar) in methylene chloride (200 ml) was added sodium bicarbonate (12 g, 139 mmol). The mixture was cooled to 0° C. and m-chloroperbenzoic acid (24 g, 166 mmol) was added in small portions over 2 hours. The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to ambient temperature. Filtration, washing with sodium hydrogen sulphate (2 portions of 30 ml 10% aq. solution) and distillation of the methylene chloride solvent yielded the crude product. The crude product was dissolved in MTBE, washed with aqueous NaHCO3, water and brine. The solvent was evaporated and the product (31.3 g; 30% starting material, 63% monoepoxide; 7% diepoxide) purified by distillation. The pure monoepoxide crystallised spontaneously (yield=79% taking into account recovered substrate).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.[H-].[K+].Br[CH2:45][C:46]([OH:48])=[O:47].Cl>O1CCCC1.O.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][CH2:45][C:46]([OH:48])=[O:47])[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: O=C(O)CBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CCO)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(F)(F)F)N(CCOCC(=O)O)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-ethanol (0.17 mmol) in tetrahydrofuran (5 mL), add potassium hydride (0.67 mmol) at room temperature. After stirring for 30 minutes add bromoacetic acid (0.25 mmol) as a solution in tetrahydrofuran (1 mL). After stirring an additional 0.5 h, quench the reaction with wet tetrahydrofuran (2 mL), dilute with water (1 mL), and ethyl acetate (5 mL). Neutralize the reaction with 5M HCl, separate the organic phase, and wash the aqueous with ethyl acetate (2×5 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0.5-4%) to afford the title compound as a colorless foam. MS (ES+): 655 (M+H).
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:3]=[C:2]1[CH2:4][C:5](=[O:6])[N:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:1]1=[O:8]
Reactant: C=C1CC(=O)OC1=O
Reactant: CCCCCCCCN
Solvent: c1ccncc1
Product: C=C1CC(=O)N(CCCCCCCC)C1=O
Temperature: 90 °C

Procedure:
A solution of itaconic anhydride (0.1 M) in pyridine (20 ml)was treated with octylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1([C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3]>C(#N)C>[CH2:1]([O:4][C:5]([NH:7][C:8]1([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC1(c2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: CC#N
Product: C=CCOC(=O)NC1(c2ccc(C(=O)O)cc2)CC1
Reaction time: 4 h

Procedure:
A solution of 1.46 g of tert-butyl 4-(1-allyloxycarbonylaminocyclopropyl)benzoate in 10 mL of acetonitrile was combined with 1 g of montmorillonite and refluxed for 3 hours. Then more montmorillonite was added and the mixture was boiled for 4 hours. The suspension was filtered hot, the inorganic material was extracted 3× with hot acetonitrile and filtered off, and the acetonitrile solutions were combined and evaporated down. Residue: 0.8 g of crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:8]1[NH:12][N:11]=[N:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([N:10]1[N:11]=[N:12][C:8]([C:2]([CH3:1])([CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(C)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)c1nnn(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a stirred mixture of α,α-dimethyltetrazole-5-acetic acid, ethyl ester (J. Med. Chem. 1996, 39, 2354-2366.) (6.87 g, 37.3 mmol) and K2CO3 (12.3 g, 89.0 mmol) in acetone (200 mL) was added benzyl bromide (4.45 mL, 37.4 mmol) at ambient temperature. The resulting mixture was stirred at 50° C. for 18 h and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (10:1) to give 6.14 g (60%) of the title compound as a colorless oil.