Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[C:12](=O)[N:11]3[C@H:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:17][CH2:18][C@H:10]3[CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30].B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[C@H:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:17][CH2:18][C@@H:10]3[CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2C[C@@H]3CC[C@@H](c4ccc(OC)c(OC)c4)N3C(=O)C2=O)ccc1Cl
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCN3[C@H](CC[C@H]3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 0 °C
Yield: 30.9 %

Procedure:
(±)-cis-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine-3,4-dione (49.7 mg, 0.115 mmol) was dissolved in dry THF (10 mL) and BH3.THF (1 mL, 1 mmol) was added dropwise to the mixture, which was then heated at reflux overnight. The solution was cooled to 0° C. and MeOH (2 mL) was added dropwise. The solvent was removed by evaporation and the crude product was dissolved in MeOH (10 mL) and 12N HCl (2 mL). The solution was refluxed for 4 hours. The reaction mixture was concentrated (˜2 mL) followed by basification with 1N NaOH. The aqueous solution was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude products were purified by preparatory TLC eluting with CH2Cl2/MeOH (97:3) to yield the (±)-cis-(20.3 mg, 43.8%) and (±)-trans-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine (14.3 mg, 30.9%) with (±)-cis-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine eluting further up the plate. (±)-trans-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine 1H NMR (CDCl3) δ 7.20 (d, J=8.7 Hz, 1H, ArH), 6.89–6.83 (m, 3H, ArH), 6.47–6.40 (m, 2H, ArH), 4.16 (m, 1H), 3.95–3.84 (m, 1H), 3.90 (s, 3H, OCH3), 3.88 (s, 6H, OCH3), 3.58–3.46 (m, 1H), 3.41–3.36 (m, 1H), 3.26–3.22 (m, 1H), 2.99–2.71 (m, 3H), 2.34–2.20 (m, 2H), 1.95–1.83 (m, 1H), 1.64–1.54 (m, 1H). LCMS m/z 403 (M++1, 100, 1.90 min).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-fluoro-p-toluenesulfonanilide (486.6 g (1.80 mol) in acetic acid (955 ml), 97% fuming nitric acid (128.6 g (1.98 mol) was added dropwise, keeping the inner temperature at 45° C., over a period of 40 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 2 hours and left to cool to room temperature. Water (2000 ml) was then added and the mixture was stirred for 30 minutes. The crystals separated were filtered and washed with water to give 543.5 g (97%) of 4′-fluoro-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32](=[O:41])[CH2:33][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH3:30][O:31][C:32](=[O:41])[CH2:33][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6](=[O:7])[CH2:5][N:4]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N(CC(=O)O)c1ccccc1
Reactant: COC(=O)CNc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CN(C(=O)CN(C(C)=O)c1ccccc1)c1ccccc1

Procedure:
To 20 parts by volume of chloroform was added 0.96 part by weight of N-acetylphenylglycine. With ice cooling, 1.03 parts by weight of dicyclohexylcarbodiimide was added, and the mixture was stirred. Furthermore, 0.83 part by weight of phenylglycine methyl ester was added, and about 3 hours later, the temperature was returned to room temperature. The mixture was then stirred overnight. After the reaction, the precipitate was collected by filtration, and washed with chloroform. The filtrate was concentrated to dryness. The resulting solid was washed with ethyl acetate, and extracted with a mixture of chloroform and petroleum ether to give 1.2 parts by weight of the captioned compound having a melting point of 198° to 200°C.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][CH3:12])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=O)=[CH:17][CH:16]=1>>[I:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][CH3:12])[N:5]2[CH2:7][CH2:8][NH:9][CH:23]([CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:13])([F:25])[F:26])=[CH:16][CH:17]=3)[C:6]=12
Reactant: CCCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Product: CCCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(4-iodo-2-propyl-imidazol-1-yl)-ethylamine (9.260 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (2.730 g; 13.503 mmol) afforded 1-iodo-3-propyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.80 min.; [M+H]+=463.88 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29]1>>[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:11]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[O:12])[CH2:33][CH2:32]2)[CH2:30][CH2:29]1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2ccccc21

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline. Light yellow foam (72%). MS (ESI): m/z=440.092 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.[N:27]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(OP(C#N)(=O)OCC)C.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:30]3[CH2:31][CH2:32][CH2:33][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:29]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)O)cc4)cnc3N)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoic acid (108 mg, 0.3127 mmol) in DMSO (1 mL) were added tert-butyl 1,4-diazepane-1-carboxylate (187.9 mg, 0.9381 mmol), diethylcyanophosphonate (124.7 mg, 114.3 μL, 0.6879 mmol) and DIPEA (121.2 mg, 163.3 μL, 0.9381 mmol). The reaction mixture was heated at 80° C. overnight, allowed to cool and filtered and the resultant taken on to the next step without further purification (122 mg, 75% Yield).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH2:22][C:23](Cl)=[N:24][OH:25])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28]>O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 94-1-3 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added tiethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (18.0 mg, 13.5%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][O:4]1)[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:10]([C:3]1([CH2:1][CH3:2])[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][O:4]1)[CH3:11]
Reactant: CCC1(CC)CC(O)CCO1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC1(CC)CC(=O)CCO1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of crude 2,2-diethyloxan-4-ol (500 mg, 3.2 mmol) in CH2Cl2 (10 ml) were added NMO (750 mg, 6.41 mmol) and 4 A molecular sieves (2 g). The solution was stirred for 30 mins and then TPAP (34 mg, 0.096 mmol) was added in one portion. The reaction was allowed to stir for 10 h. After checking the TLC, the alcohol was gone. It was filtered through a short pad of SiO2. The filtrate was concentrated and purified by normal phase SiO2 chromatography (0% to 50% EtOAc/hexanes) to give 2,2-diethyloxan-4-one (365 mg, 73%).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=[C:16](OC)[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[NH4+:39].[NH4+].C([O-])(=O)C.[NH4+]>C(O)C.C(OCC)(=O)C>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=[C:16]([NH2:39])[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(C)N1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N=C(N)N1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
111 mg (0.234 mmol) of 4-(3-chlorophenyl)-2-methoxyl-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide was dissolved in 5 ml of ethanol. 67.4 mg (0.702 mmol) of ammonium carbonate and 11.8 mg (0.187 mmol) of ammonium acetate were added to the obtained solution, and they were stirred at 80° C. for 2 days. The reaction mixture was diluted with ethyl acetate. An insoluble matter thus formed was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (100% dichloromethane) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=4[Cl:29])[C:22]([O:24]C)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O[Li].O.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=4[Cl:29])[C:22]([OH:24])=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a suspension of methyl 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (31 g, 61 mmol) in THF (200 mL) and H2O (100 mL) was added LiOH.H2O (6.42 g, 153 mmol). The reaction mixture was stirred at room temperature overnight. Then it was acidified with 2N HCl to pH 2-3, and concentrated to remove most of solvent. The resulting precipitate was washed by water, dried to give the carboxylic acid, 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (27.3 g, 91%). LC-MS: (ESI, m/z)=494 [M+1]+
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[S:40][C:36]=2[CH:35]=1>>[Cl:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([N:41]3[CH2:46][CH2:45][N:44]([C:9]([C:8]4[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=4[N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:11])[CH2:43][CH2:42]3)[S:40][C:36]=2[CH:35]=1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.25 mmol 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) in 0.7 ml dimethylformamide 0.26 mmol TBTU, 1.6 mmol N-ethyldiisopropylamine and 0.25 mmol 6-chloro-2-piperazin-1-yl-benzothiazole were successively added. The reaction was then stirred at RT for two hours, concentrated in vacuo and treated with 5 ml water. The solid is filtered off and recrystallized form methanol to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21](=[S:29])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:21](=[S:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:18][CH:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=1)[C:14]([F:15])([F:16])[F:17]
Reactant: Cc1nn(Cc2ccccc2)cc1C(O)C(F)(F)F
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(OC(=S)Oc1ccccc1)c1cnn(Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanol (compound 314.3, 1.15 g, 4.26 mmol) in toluene (15 mL) were added 4-dimethylaminopyridine (1.47 g, 12.0 mmol) and phenyl chloromethanethioate (1.04 g, 6.02 mmol). The reaction mixture was stirred for 1 h at 60° C. under nitrogen, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/15) as the eluent to yield 1.34 g (77%) of the title compound as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+].CCOC(C)=O>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-bromo-1-(2-naphthyl)ethanone in acetone was added NaN3 (1 eq.) and the mixture was stirred at RT for 24 h. EtOAc was added (10 vol.) and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 10% EtOAc/Petroleum ether to obtain the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.39 (1H, s), 8.02-7.82 (4H, m), 7.69-7.50 (2H, m), 4.68 (2H, s). MS (ES) C12H9N3O requires: 211, found: 212 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[O:21][N:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:6]([C:5]4[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=4)=[O:7])[CH2:25]3)[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C3CCCNC3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCC(c2nc(-c3ccc(F)cc3)no2)C1
Yield: 30 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 4-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (already prepared before in the Example 4 (B)). Yield: 30% (white powder); mp=82-83° C.; Rf=0.25 (DCM/MeOH:98/2);
Reaction SMILES: [NH2-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:10]#[N:11].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1>COCCOC.O>[C:10]([C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:25][CH2:26]1)#[N:11]
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: N#CC(c1ccccn1)c1ccccn1
Agent: [NH2-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1N1CCN(CCC(C#N)(c2ccccn2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 0.21 g of 95% sodium amide in 2 mL of 1,2-dimethoxyethane was added dropwise a solution of 0.78 g of 2,2-bis-(2-pyridyl)acetonitrile (prepared as described in Heterocycles 1995, 40, 757) in 8 mL of 1,2-dimethoxyethane, with stirring under a nitrogen atmosphere at room temperature. After 1 h, there were added dropwise, 1.02 g of 1-(2-chloroethyl)-4-(2-methoxy-phenyl)piperazine dissolved in 4 mL of 1,2-dimethoxyethane. The resultant reaction mixture was then refluxed for 20 h, followed by cooling to room temperature, and was then poured cautiously into 40 g of ice, diluted with water, and extracted with ethyl acetate. The combined organic phases were then washed with water, dried on sodium sulphate, and then evaporated thoroughly under vacuum. The obtained crude was then purified by flash chromatography (ethyl acetate-methanol gradient from 10:0 to 9:1). The recovered fractions were then evaporated to complete dryness, affording 1.13 g of the title product (68.4%).
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]([CH3:44])=[CH:42][CH:43]=2)[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]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
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(-c3ccc(C)nc3)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-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (301 mg, 72%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].Cl[C:14]([CH3:27])=[CH:15][C:16]1[S:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[N+:20]=1[CH2:21][CH3:22]>C(#N)C>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[CH2:1]([N+:3]1[C:6]2[C:19](=[CH:18][CH:26]=[CH:25][CH:7]=2)[CH:23]=[CH:5][C:4]=1[C:27]#[C:14][CH:15]=[C:16]1[N:20]([CH2:21][CH3:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17]1)[CH3:2]
Reactant: CC[n+]1c(C=C(C)Cl)sc2ccccc21
Reactant: CCN(CC)CC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCN1C(=CC#Cc2ccc3ccccc3[n+]2CC)Sc2ccccc21
Reaction time: 0.08 h

Procedure:
Triethylamine (2.1 ml, 0.015 mol) is added to a stirred suspension of 2-(2-chloropropenyl)-3-ethylbenzothiazolium perchlorate and anhydro-1-ethyl-2-sulfoquinolinium hydroxide (1.19 g, 0.005 mol) in acetonitrile. The mixture is stirred for 5 minutes, filtered, and the filtrate is diluted to 200 ml. with ether. The ether is decanted and the residue treated with methanol (25 ml). After chilling, the solid is collected and recrystallized from methanol. The yield of purified dye is 0.32 g (14%) mp indistinct.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:20])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:12]2=[C:13]([N:24]3[CH2:27][CH2:26][CH2:25]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:20])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(Cl)c2CC1
Reactant: C1CNC1
Product: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(N3CCC3)c2CC1

Procedure:
The product was prepared using 10-chloro-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester and azetidine as the amine in route 1 (step e).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1
Reactant: CC(C)CC(O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(CC(C)C)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Methyl 4-hydroxybenzoate (609 mg, 4.00 mmol), 1-(4-bromophenyl)-3-methylbutan-1-ol (1.95 g, 8.00 mmol) and triphenylphosphine (2.10 g, 8.00 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.58 mL, 8.00 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with 0.1 M HCl (3×100 mL) and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave (+/−)-methyl 4-(1-(4-bromophenyl)-3-methylbutoxy)benzoate (1.4 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.89-7.83 (m, 2H), 7.46-7.40 (m, 2H), 7.21-7.16 (m, 2H), 6.83-6.78 (m, 2H), 5.16 (dd, J=9, 4.7 Hz, 1H), 3.83 (s, 3H), 1.99-1.91 (m, 1H), 1.88-1.75 (m, 1H), 1.58-1.51 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).