Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH:17]([C:16]1[CH:19]=[CH:20][C:13]([CH2:12][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])=[CH:14][CH:15]=1)=[CH2:18]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Cn2c(C)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
This Example illustrates the synthesis of polymeric blocked developer PBD1. First, 1-(4-vinylbenzyl)-2-methylbenzimidazole was prepared. A suspension of 2-methylbenzimidazole (25.0 g, 0.19 mol), 4-chloromethylstyrene (31.8 g, 0.21 mol), powdered potassium hydroxide (10.6 g, 0.19 mol), and potassium carbonate (13.1 g, 0.1 mol) in 200 mL of dry tetrahydrofuran was stirred at 25° C. for 5 d. The reaction mixture was filtered, and the solid residue extracted with additional tetrahydrofuran. The combined liquids were concentrated at reduced pressure, and the resulting brown oil was triturated with ligroin and held at −15° C. for a few hours to induce crystallization. The ligroin was decanted from the product, which was then purified by recrystallization from 70% methanol/30% water. A cream colored solid product (43.2 g, 92%) was obtained after drying. 1H NMR (CDCl3) δ 2.61 (s, 3H), 5.28 (d, J=11.0, 1H), 5.33 (s, 2H), 5.75 (d, J=17.6, 1H), 6.7 (m, 1H), 7.05 (d, J=8.1, 2H), 7.25 (m, 2H), 7.37 (d, J=8.2, 2H), 7.78 (d, J=7.3, 1H). Electrospray mass spectrometry (ES-MS) m/e 249+ (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][C:7]=1[O:8]C.CC(O)=O>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)cc1F
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc(O)c(F)c2)oc2ccccc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a solution of 2′-hydroxyacetophenone (1.36 g, 10 mmol) in 20 mL anhydrous pyridine was added 3-fluoro-4-methoxybenzoyl chloride (1.89 g, 10 mmol) and the reaction mixture was stirred at rt for 15 h under a nitrogen atmosphere. The reaction mixture was poured into 200 mL of 2 N HCl. The formed solid was isolated by filtration, washed with water and dried under vacuum to give a white solid (2.76 g, 95.7%). The compound (2.68 g, 9.3 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered potassium hydroxide (1.57 g, 27.9 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (100 mL) was added, the solid was isolated by filtration and washed with water to give a yellow solid (1.83 g, 68%). The compound (1.78 g, 6.17 mmol) was suspended in 15 mL glacial AcOH. Five drops of conc. HCl was added and the reaction mixture was stirred at 110° C. for 2 h, then cooled to rt. Water (100 mL) was added. The formed solid was separated by filtration, washed with water and dried under vacuum to give 2-(3-fluoro-4-methoxyphenyl)chromen-4-one as a white solid (1.62 g, 97%). 2-(3-Fluoro-4-methoxyphenyl)chromen-4-one (1.6 g, 5.92 mmol) was suspended in 40 mL of Hi. Glacial AcOH (15 mL) was added and the reaction mixture was stirred at 110° C. for 4 h, then cooled to rt. Water (200 mL) was added, and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and methanol (15 mL) to give 1.1 g of 2-(3-fluoro-4-hydroxyphenyl)chromen-4-one (72%) as a pale yellow solid. MS (ES) m/z: 257.91 (M+1), 256.88 (M); Mp. 275-276° C.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:10]1[C:11](=[O:16])[CH2:12][CH:13]([NH:26][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Reactant: CCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCNC1CC(=O)N(CCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, nonylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10](O)[CH3:11])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:52]=[N+:53]=[N-:54])(C2C=CC=CC=2)=O)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:52]([C@H:10]([C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH3:11])=[N+:53]=[N-:54]
Reactant: C[C@@H](O)[C@@H](Cc1ccc(Cl)cn1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])[C@@H](Cc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24 g, 0.92 mmol), triphenylphosphine (1.5 g, 1.4 mmol) and diphenylphosphoryl azide (0.30 mL, 1.4 mmol) in 5 mL anhydrous THF was added diethylazodicarboxylate (0.24 mL, 1.4 mmol). After stirring at room temperature overnight, the resulting mixture was concentrated with silica gel (10 g) and the residue was loaded onto a silica gel column. Elution with 5 to 15% EtOAc in hexane afforded the title compound. 1H NMR (500 MHz, CD3OD): δ 8.35 (d, 1H), 7.52 (dd, 1H), 7.25-7.05 (m, 5H), 6.95 (d, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.15-3.05 (m, 2H), 1.14 (d, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>>[S:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:11][CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: C1CSCCN1
Product: N#Cc1ccccc1N1CCSCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and thiomorpholine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])=[CH:4][CH:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:11][C:10]=2[F:18])=[CH:4][CH:3]=1
Reactant: OCc1cc(F)c(Oc2ccc(Cl)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4ccc(Cl)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((6-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12

Procedure:
Add 570 ml of phosphorus oxychloride to 57 g (200 mmol) of 5,6-diphenylfuro[2,3-d]pyrimidin-4(3H)-one. Stir the mixture under reflux for 3 h, then cool it and concentrate it under reduced pressure. Stir the residue with ice-water for 30 min and then admix it with dichloromethane. Wash the resulting organic phase three times with water, dry it over sodium sulphate and concentrate it under reduced pressure. 58 g (93.2% of theory) of the target product are obtained.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[N:52]1([CH2:58][CH2:59][OH:60])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([N:55]5[CH2:56][CH2:57][N:52]([CH2:58][CH2:59][OH:60])[CH2:53][CH2:54]5)=[O:39])=[CH:32][CH:31]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)O)cc3)cn2)cc1
Reactant: OCCN1CCNCC1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(CCC(=O)N3CCN(CCO)CC3)cc2)cn1
Yield: 24.6 %

Procedure:
Using 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionic acid (100 mg) obtained in Step A in Example 1-D-168 and 2-piperazin-1-yl-ethanol (23 mg) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propan-1-one was obtained, and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-170) as a pale yellow powder (20 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]=[CH:5][CH2:6][C@@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:36])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH2:26][CH3:27])[C:18]([O:28]CC2C=CC=CC=2)=[CH:17][C:16]=1[CH2:15][CH2:14]3>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][C@@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:36])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH2:26][CH3:27])[C:18]([OH:28])=[CH:17][C:16]=1[CH2:15][CH2:14]3
Reactant: CCOc1cc2c(cc1OCc1ccccc1)CC[C@H]1[C@@H]3[C@@H](CC=CC(=O)OC)CC(=O)[C@@]3(C)CC[C@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc2c(cc1O)CC[C@H]1[C@@H]3[C@@H](CCCC(=O)OC)CC(=O)[C@@]3(C)CC[C@H]21
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.7 %

Procedure:
4-(3-Benzyloxy-2-ethoxy-17-oxo-estra-1,3,5(10)-trien-15α-yl)but-2-enoic acid methyl ester (3.17 g, 6.30 mmol) was dissolved in THF (80 ml) and MeOH (80 ml). Pd/C 10% (50% in water, 0.3 g) was added. The mixture was stirred at 1 atm H2 (balloon) at RT for 48 h. The mixture was filtered over Celite. The filter cake was rinsed with MeOH (200 ml) and the filtrate was concentrated in vacuo to provide 2.8 g (6.72 mmol, >100%) of a greenish solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:20])([F:21])[F:19])=[O:41])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
0.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.1g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: C(OC([NH:8][C:9](=[N:64]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:63]=[CH:62][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:54]([O:56]C(C)(C)C)=[O:55])[CH2:29][C:30]3[N:34]=[CH:33][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[O:26])=[C:20]([Cl:61])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:10]([C:11]1[CH:63]=[CH:62][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:54]([OH:56])=[O:55])[CH2:29][C:30]3[N:34]=[CH:33][NH:32][CH:31]=3)=[O:26])=[C:20]([Cl:61])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)[C:9]([NH2:64])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(=O)OC(C)(C)C)c(Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3c[nH]cn3)C(=O)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of tert-butyl N-{[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]acetyl}-1-trityl-L-histidinate (265 mg) in dichloromethane (2.70 mL) was added trifluoroacetic acid (0.619 mL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and washed with water, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS silica gel column chromatography (0.01 M hydrochloric acid-acetonitrile), and the purified product was dried under reduced pressure to obtain N-({4-[(4-carbamimidamidobenzoyl)oxy]-2-chlorophenyl}acetyl)-L-histidine 2 hydrochloride (54.1 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]([OH:14])=O)([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([NH2:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:28]([NH:36][C:12](=[O:14])[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Reactant: CCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9.7 g. of 3-(2-nitrophenyl)propenoic acid, 5.6 g. of triethylamine and 240 ml. of dichloromethane was stirred at room temperature for 20 minutes, and then it was cooled in an ice-bath. To the mixture was then added, dropwise, during 15 minutes, a solution of 6.0 g. of ethyl chloroformate in 20 ml. of dichloromethane. After 15 minutes of stirring, a solution of 7.1 g. of octylamine in 20 ml. of dichloromethane was added dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium carbonate, 1 N hydrochloric acid, water and saturated sodium chloride. The resulting solution was dried and evaporated in vacuo, leaving 14.5 g. (95%) yield of the title compound as a tan solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][C@H:9]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])=[O:30])[C@H:10]([O:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH2:11]2.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39]>CO>[CH3:39][C:38]([NH:42][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]([O:27][CH2:28][C:29]([N:31]([CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH3:37])=[O:30])[CH:10]([O:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH2:11]2)([CH3:41])[CH3:40]
Reactant: CCCN(CCC)C(=O)CO[C@H]1Cc2c(cccc2OCC2CO2)C[C@H]1OCC(=O)N(CCC)CCC
Reactant: CC(C)(C)N
Solvent: CO
Product: CCCN(CCC)C(=O)COC1Cc2cccc(OCC(O)CNC(C)(C)C)c2CC1OCC(=O)N(CCC)CCC

Procedure:
A solution of 1.5 g (0.0029 M) of cis-2,2'-[[1,2,3,4-tetrahydro-5-(oxiranyl-methoxy)-2,3-naphthalenediyl]bis(oxy)]bis-[N,N-dipropylacetamide] in 5 ml of methanol and 20 ml of t-butylamine is stirred at room temperature overnight. The solution is evaporated in vacuo to give 1.7 g of oil. This material is dissolved in ether and extracted with 5% aqueous HCl. The aqueous layer is basified with aqueous NaOH and extracted with ether. The ether is washed (saturated NaCl solution), dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a dense oil, 1.52 g.
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:19](OC)(OC)OC.S(Cl)(Cl)=O>CO>[O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:19])=[O:6]
Reactant: O=C(O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: COC(OC)OC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoic acid (Example 11, A19, 50 mg, 0.19 mmol) and trimethyl orthoformate (60.7 mg, 3 eq.) were dissolved in methanol (4 mL), and thionyl chloride (68.1 mg, 3 eq.) was added dropwise. The reaction was stirred at room temperature for 3 h. The solvent were evaporated and the crude was treated with Dowex 1×8 OH to give the methyl 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoate A20 (36 mg, 69%). 1H NMR (400 MHz, CDCl3): 2.77 (s, 4H), 3.73 (s, 3H), 7.91 (dd, 1H), 8.33 (d, 1H), 8.54 (s, 1H), 8.59 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 81 %

Procedure:
To a 50 mL flask was added 5 (220 mg, 1 mmol) and 5 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 192 g (81%) of 6 as a yellow solid: 1H NMR (DMSO-d6) δ 1.82 (m, 4H), 2.63 (s, 3H), 2.84 (m, 2H), 2.96 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH2:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)[OH:13]>>[C:7]([NH:11][CH2:10][CH2:9][O:13][C:12]1[CH:19]=[CH:18][C:16]([O:17][CH2:9][CH2:10][NH:11][C:7](=[O:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=1)(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(O)cc1
Reactant: c1ccc(C2=NCCO2)cc1
Product: O=C(NCCOc1ccc(OCCNC(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
In German Pat. No. 1,062,253, A. Jager describes the preparation of various ether and carboxamide compounds by treating certain substituted oxazolines with certain phenols, with the exclusion of water. A mixture of phenol and 2-phenyloxazoline refluxed for 7 hours yielded PhCONHCH2CH2OPh as a product. Similarly, p-bis(oxazolinyl)benzene and phenol gave N,N'-bis(β-phenoxyethyl)terephthalamide. Finally, Jager found that a mixture of 2-phenyl-2-oxazoline and hydroquinone produced 1,4-bis(β-benzamidoethoxy)benzene.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1>O.CN(C)C=O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH2:1])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCOc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(CN)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 103.9 %

Procedure:
A solution of 1.25 g of sodium azide in 2.5 ml of water was added to a solution of 900 mg of p-chloromethyl(heptyloxy)benzene in 25 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 6 hours. After cooling, the reaction mixture was diluted with water, and the product was extracted with ether. The ether layer was washed in sequence with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A solution of the thus-obtained residual oil in 10 ml of tetrahydrofuran was added dropwise at 0° C. over 5 minutes to a suspension of 200 mg of lithium aluminum hydride in 15 ml of tetrahydrofuran. The resultant mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. Then, sodium sulfate decahydrate added to decompose the excess lithium aluminum hydride. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give 860 mg of p-heptyloxybenzylamine.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20](I)[CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([CH3:24])[C:21]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1c(C)cc(F)cc1I
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)cc(C)c2OC)c(N)n1

Procedure:
The same procedure as described in Example 376 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 1-fluoro-3-iodo-4-methoxy-5-methyl-benzene (Example 382) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-3-methyl-phenyl)-methanone. MS (M+H)+, 322.
Reaction SMILES: [NH2:1][NH2:2].N.[Cl:4][C:5]1[N:6]=[N:7][C:8](Cl)=[CH:9][CH:10]=1>O>[Cl:4][C:5]1[N:6]=[N:7][C:8]([NH:1][NH2:2])=[CH:9][CH:10]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NN
Agent: N
Solvent: O
Product: NNc1ccc(Cl)nn1
Yield: 85.9 %

Procedure:
To a solution of 25% aqueous hydrazine (4.25 1) and 32% ammonia (7.5 1) in water (23.7 1) 3.6-dichloropyridazine (3 kg) was added, while maintaining a gentle stream of nitrogen. The mixture was headed at reflux for 2 hours and, after cooling, the precipitate was collected, washed with water and dried to afford 2.5 kg (85.9%) of 3-chloro-6-hydrazinopyridazine, m.p. 140°-141° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:25]([OH:24])[CH:26]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: OB(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cc(O)cc(C(F)(F)F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-hydroxy-5-(trifluoromethyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 27 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 2.83 min (Method A); M+H=454 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 10.38 (s, br, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 8.12-8.07 (m, 1H), 7.93-7.87 (m, 1H), 7.58-7.53 (m, 1H), 7.21-7.16 (m, 1H), 7.13-7.09 (m, 1H), 7.07-7.03 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 1.93 (s, 3H))