Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCC[CH2:2]1.[F:23][C:24]([F:46])([F:45])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][C:34]([C:37]3[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=3)=[N:33]2)=[CH:28][CH:27]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:23][C:24]([F:46])([F:45])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][C:34]([C:37]3[CH:44]=[CH:43][C:40]([CH:41]=[CH2:2])=[CH:39][CH:38]=3)=[N:33]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Methyltriphenylphosphonium bromide (32.2 g, 90.0 mmol) and 1,8-diazabicycloundec-7-ene (14.9 mL, 99.0 mmol) were dissolved in tetrahydrofuran (260 mL) and refluxed for 30 minutes. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (15.0 g, 45.0 mmol) was added, and the reaction was heated at 65° C. for 5 hours. The solution was cooled and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with hexanes. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound was purified by flash column chromatography using 0-70% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (10.4 g, 67%): 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.58-7.47 (m, 2H), 7.39 (d, J=9.1 Hz, 2H), 6.77 (dd, J=17.6, 10.9 Hz, 1H), 5.84 (dd, J=17.6, 0.8 Hz, 1H), 5.32 (dd, J=10.9, 0.8 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 332 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][N:3]=1.Cl[CH:28]([C:31]1([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][CH:38]=[CH:37]3)[CH2:33][CH2:32]1)[CH:29]=O>C(O)(C)C.CO>[N:40]1[C:41]2[C:36](=[CH:35][C:34]([C:31]3([C:28]4[N:7]5[CH:6]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([N:14]7[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]7)=[N:12][CH:13]=6)[CH:4]=[N:3][C:2]5=[N:1][CH:29]=4)[CH2:33][CH2:32]3)=[CH:43][CH:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N)nc3)cn2)CC1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
A mixture of tert-butyl 4-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]piperazine-1-carboxylate (0.120 g, 0.337 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.0827 g, 0.337 mmol) in isopropyl alcohol (2.0 mL) was heated at 100° C. overnight. The mixture was diluted with methanol and purified by RP-HPLC (pH 10.0) to give the desired product (80 mg, 43.4%). LCMS: (M+H)=548.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:25]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:15]=[CH:16][C:17]=2[CH2:23]1)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2ccncc2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a mixture of N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (94.8 mg, 0.30 mmol) and isonicotinoyl chloride hydrochloride (56.1 mg, 0.32 mmol) in THF (2.0 mL) at room temperature was added N,N-diisopropylethylamine (0.157 mL, 0.90 mmol). After stirring for 3 hours at room temperature, an additional 21 mg of isonicotinoyl chloride hydrochloride was added and the reaction continued for 17 hours. The reaction was quenched with H2O, then treated with an EtOAc/saturated NaHCO3(aq) solution work-up to give an off-white solid. The solid was recrystallized from EtOAc/hexane to afford a white solid (115 mg, 91%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[CH:32]=[CH:31][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:19]=2)=[O:16])=[CH:13][N:12]=1>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:31]=[CH:32][C:11]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)=[N:12][CH:13]=2)=[CH:19][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)n1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
21 mg of sodium hydride was added to a solution of 84 mg of 3,5-dimethylpyrazole in 2 mL of DMF. The reaction mixture was stirred for 10 min, and then added 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide. The reaction was heated to 140° C. for 16 h. The mixture was quenched with MeOH and evaporated. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinamide. MS (Q1) 404.3 (M)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([NH:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20])[CH3:17]
Reactant: NCc1ncccn1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1ncccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
49.5 g (0.49 mol) of triethylamine are added to 49.5 g (0.45 mol) of 2-aminomethyl-pyrimidine in 450 ml of toluene and then 52 g (0.48 mol) of ethyl chlorocarbonic acid are added dropwise under cooling with ice. The mixture is subsequently stirred at room temperature for 2 hours. Triethylamine hydrochloride is filtered off with suction, the filtrate is washed with brine, dried with MgSO4, concentrated, and distilled.
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[NH:9][CH:8]=[CH:7][N:6]=[C:5]1[C:10]([O:12][CH3:13])=[O:11].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ncc[nH]c1=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1nccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
LiH (7.8 mg, 0.980 mmol) was added to the solution of methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (100 mg, 0.65 mmol) in DMF (3 mL) at 0° C. After 30 minutes stirring, (chloromethyl)benzene (0.15 mL, 1.30 mmol) was added to the reaction mixture at 0° C., and then the reaction was warmed to room temperature. After stirring for 4 hours, the reaction mixture was quenched with ice water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to give the crude material that was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 0.102 g (64%) of the desired product.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)#[N:3].ClC1C=C(N2[C:24]([C:25]3[CH:30]=[C:29](F)[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:23][C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=N2)C=CC=1F>>[Cl:32][C:27]1[CH:26]=[C:25]([C:24]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=3)[N:11]=[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: N#Cc1cccc(NN)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 3A and 3-cyanophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 540 mg of the title compound with 69% purity (25% of theory) are obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]2[CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]2)[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2.[C:41]([BH3-])#N.[Na+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]2[CH2:37][N:36]([CH3:41])[C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]2)[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: [BH3-]C#N
Reactant: O=C(O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
To a slurry of (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid trifluoroacetic acid salt (0.048 g, 0.084 mmol) formaldehyde (0.050 mL, 0.67 mmol) acetic acid (0.048 mL, 0.84 mmol) in 2 mL ACN was added sodium cyanoborohydride (0.011 g, 0.17 mmol). After 1 h, the reaction mixture was concentrated, dissolved in DMSO/TFA, and purified by RPHPLC, gradient of ACN/TFA in H2O/TFA to give (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1-methylpyrrolidine-2-carboxylic acid trifluoroacetic acid salt as a solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(F)ccc1F)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)ccc1F)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(2,5-difluoro-phenyl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI−): m/z=428.0 ([M−H]−, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:25])[CH3:24])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate phase was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 341.3 mg.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]([OH:25])=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([C:23]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:25])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Product: CC(C)N1CCC(Oc2ccc(C3(C(=O)N4CCN(C)CC4)CCOCC3)cc2)CC1
Yield: 48 %

Procedure:
The title compound (60 mg, 48%) was prepared from 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid and N-methyl piperazine similarly to the procedure used for example 150. 1H NMR (400 MHz, CDCl3) δ 1.05 (d, 6H), 1.79-1.81 (m, 2H), 2.00-2.03 (m, 7H), 2.15 (s, 3H), 2.18-2.22 (m, 2H), 2.37-2.42 (m, 2H), 2.77-2.79 (m, 3H), 2.99 (m, 1H), 3.27-3.56 (m, 4H), 3.78 (t, 2H), 3.87-3.89 (m, 2H), 4.28 (m, 1H), 6.88 (d, 2H), 7.14 (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[N:13]=[CH:12][N:11]=[C:10]3O)[CH:2]=1.O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:10]1[C:9]2=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:15][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: Oc1ncnn2cc(-c3cccnc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnn2cc(-c3cccnc3)cc12
Temperature: 100 °C
Yield: 33.2 %

Procedure:
To a suspension of 6-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.30 mmol) in 10 mL of toluene were added POCl3 (0.18 mL, 1.88 mmol) and DIEA (0.09 mL, 0.5 mmol). The suspension was heated at 100° C. for 7 h. After cooling down, the excess POCl3 was removed under reduced pressure. The residue was suspended in EtOAc, and then neutralized with sat. NaHCO3. The organic layer was then washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by flash column chromatography to afford the title compound (23 mg, 33%). MS(ESI+) m/z 231.2/233.2 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[I:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Ic1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 54 %

Procedure:
20.3 g (0.12 mol) of diphenylamine, 60.9 g (0.15 mol) of 4,4'-diiodobiphenyl, 19.3 g (0.14 mol) of anhydrous potassium carbonate, 1.52 g (0.024 mol) of copper powder, and 20 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 21 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 1/3 mixture of toluene and n-hexane) to obtain 29.0 g (yield: 54.1%) of N-(4'-iodo-4-biphenylyl)-N,N-diphenylamine. The melting point of the product was from 139.5° C. to 140.5° C.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].Br[CH2:52][CH:53]([OH:56])[CH2:54][OH:55]>O.[OH-].[Na+]>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:52][CH:53]([OH:56])[CH2:54][OH:55])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: OCC(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CC(O)CO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 160 h

Procedure:
N,N'-Bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(2,3-dihydroxypropylaminocarbonyl)-phenyl]urea (0.353 g, 0.257 mmol) was dissolved in a mixture of water (8 ml) and 2M aqueous NaOH (0.9 ml) together with 1-bromo-2,3-dihydroxypropane (0.136 ml, 1.55 mmol). After stirring at room temperature for 160 h, the solution was neutralized using a strongly acidic cation exchange resin. After evaporation, the residue was purified using preparative HPLC. Yield: 100 mg (27%) of the product as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(O)CCCCl
Reactant: C1=COCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(CCCCl)OC1CCCCO1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-chloro-4-hydroxynonane (Example A, Step 2) (11.0 g., 0.062 mole) and dihydropyrane (5.2 g., 0.062 mole) cooled in an ice bath is added 5 drops of hydrochloric acid (conc.). A slight exothermic reaction is noted and when this is complete the reaction is allowed to come to room temperature, then stand for 2 hours. At the end of this period several pellets of sodium hydroxide are added and the reaction is distilled in vacuo. The yield of 1-chloro-4-(2-tetrahydropyranyloxy)nonane is 12.5 g. (77%), boiling 96°-102°/0.1 mm. Upon redistillation a boiling point of 90°-92°/0.1 mm. is obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Br[CH2:7][C:8]([NH:10][C:11]1[C:28]([OH:29])=[C:27]2[C:14]([CH2:15][CH:16]3[C:25]([C:26]2=[O:30])=[C:24]([OH:31])[C:23]2([OH:32])[CH:18]([CH:19]([N:38]([CH3:40])[CH3:39])[C:20]([OH:37])=[C:21]([C:34]([NH2:36])=[O:35])[C:22]2=[O:33])[CH2:17]3)=[C:13]([N:41]([CH3:43])[CH3:42])[CH:12]=1)=[O:9]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:40][N:38]([CH3:39])[C@H:19]1[C@H:18]2[C@:23]([OH:32])([C:24]([OH:31])=[C:25]3[C@H:16]([CH2:17]2)[CH2:15][C:14]2[C:27](=[C:28]([OH:29])[C:11]([NH:10][C:8](=[O:9])[CH2:7][N:3]([O:4][CH3:5])[CH3:2])=[CH:12][C:13]=2[N:41]([CH3:42])[CH3:43])[C:26]3=[O:30])[C:22](=[O:33])[C:21]([C:34]([NH2:36])=[O:35])=[C:20]1[OH:37]
Reactant: CNOC
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Product: CON(C)CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 51.2 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 10 g of N,O-dimethylhydroxylamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 1.0 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.495 g of the product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:22]=2)O1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:22]=1)[CH:11]=[CH:10]2
Reactant: COC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: COC(=O)C1CC=C(c2ccc3cc(O)ccc3n2)CC1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)(O)[C:27]#[CH:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:3]3[CH:28]=[CH:27][C:26]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)([C:23]4[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)[O:1][C:2]=32)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(O)c2cc(OC)ccc2c1
Reactant: C#CC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OC)cc2c2c1C=CC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2
Yield: 38.1 %

Procedure:
A solution of methyl 4-hydroxy-6-methoxy-2-naphthoate (1.0 g, 4.3 mmol) and 1,1-di(4-methoxyphenyl)prop-2-yn-1-ol (1.16 g, 4.3 mmol) in toluene (45 cm3) containing acidic alumina (Brockmann 1), (4.0 g) was refluxed for 45 minutes. The cooled solution was filtered and the alumina was washed well with EtOAc (200 cm3). The organic filtrate was washed with aqueous sodium hydroxide (2M, 2×50 cm3) and water (100 cm3). Removal of the dried (Na2SO4) EtOAc gave an oil which was flash chromatographed over silica using 25% EtOAc in hexane as the eluent to afford a pale yellow solid. Recrystallisation from EtOAc/hexane gave methyl 9-methoxy-2,2-bis(4-methoxyphenyl)-2H-naphtho[1,2-b]pyran-5-carboxylate (yield=0.79 g, theoretical yield=2.08 g 38%, m.p. 162.5-164.0° C. (uncorrected)).
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH:5]([OH:7])[CH3:6].[C:13]([Cu])#[N:14].CN(C=O)C.[C-]#N.[Na+]>O>[F:12][C:3]1[C:4]([CH:5]([OH:7])[CH3:6])=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[C:13]#[N:14]
Reactant: CC(O)c1cc(F)cc(Br)c1F
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)c1cc(F)cc(C#N)c1F
Yield: 95.4 %

Procedure:
A mixture of 9.39 g of 3-bromo-2,5-difluoro-α-methylbenzyl alcohol, 3.82 g of CuCN and 117 mL of DMF is stirred and heated at reflux for 7 hours under N2. When the mixture has cooled, 100 mL of 5% aqueous NaCN is added followed by 350 mL of H2O 30 minutes later. The black solution is extracted with 4×150 mL of CH2Cl2 and these combined extracts washed with H2O, saturated NaHCO3 and H2O (150 mL each) and stripped in vacuo to furnish 6.92 g (95% yield) of 2,5-difluoro-3-(1-hydroxyethyl)-benzonitrile as a brown oil. The product exhibits an M+1 ion at 184 in the mass spectrum and appropriate infrared and N.M.R. spectral data.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl:31][CH2:32]Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:32][Cl:31])=[O:24])=[CH:26][CH:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)O)cc1
Reactant: ClCCl
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)OCCl)cc1

Procedure:
4-(N-benzyloxycarbonyl-L-valyloxy)benzoic acid was esterified by the method described in Example A-I-1, step d. The title compound (0.95 g) was obtained after silica gel column chromatography (0, 1% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.80.