Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O>>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1O
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(OC)c(O)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-hydroxy-4-methoxybenzaldehyde gave the title compound as a yellow solid m.p.: 140-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cccc(Cl)n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1cccc(-c2cc(OC)c(OC)c(OC)c2)n1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (837 mg) and ethyl 6-chloropicolinate (733 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][O:10][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: CC(CO)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
To a solution of 73B (2.34 g, 10.9 mmol) in 30 mL DMF, was added imidazole (1.11 g, 16.3 mmol) and tert-butyldimethylsilyl chloride (1.97 g, 13.1 mmol). The mixture was stirred at rt for 3 h, then was diluted with hexanes. The organic phase washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 2.00 g of 73C as a colorless oil. MS (ESI) m/z 197.1 (M-OTBS)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH3:11])=[CH:4][CH:3]=1.CC1C=CC=C(C)[C:23]=1[NH2:24].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]([CH3:11])[N:12]([C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[C:23]2=[NH:24])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cccc(C)c1NC(C)CNc1ccc(Cl)cc1
Agent: Cl
Product: Cc1cccc(C)c1N1C(=N)N(c2ccc(Cl)cc2)CC1C

Procedure:
1-(4'-Chlorophenyl-amino)-2-(2',6'-dimethylphenylamino)-propane, applied as starting substance, is obtained with a yield of 50.9% by reacting N-(β-chlorophenyl)-4-chloro-aniline, a compound prepared as described in Example 27, point (b), with 2,6-dimethylaniline according to the method given in Example 25, point (a). The hydrochloride of the product melts at 170°-178° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[N+:14]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Product: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-phenyl-2-(1-H)-pyrazinone (5 g) was added in portions during 30 minutes to a stirred mixture of fuming nitric acid (30 ml) and sulphuric acid (5 ml) at -5° C. The mixture was stirred in the cold for 30 minutes, and the temperature of the mixture was then allowed to rise to 10° C. The mixture was then poured into ice-water (250 ml) to give 5-(4-nitrophenyl)-2-(1H)-pyrazinone recrystallised from dimethylformamide, m.p. 336°-338° C., δ (DMSO-d6) 8.15 and 8.30 (2d, 3-and 6- protons of pyrazinone ring), 8.18 (m, phenyl); ν max (Nujol mull) 3200-2500 (NH), 1690, 1675, 1545, 1510, 1349, 860 and 750 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[CH:8][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].CO>C1(C)C=CC=CC=1>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:15]
Reactant: c1csc(-c2ccno2)c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C)C=C(C#N)C(=O)c1cccs1
Yield: 87.3 %

Procedure:
A mixture of 5-(2-thienyl)isoxazole (4.3 kg) and dimethylformamide dimethylacetal (6.1 kg; Lancaster) in toluene (12 L; Barton) is heated at reflux. As methanol forms it is removed by distillation. Solid forms from the reaction mixture. The reaction mixture is cooled and diluted with methyl-t-butyl ether (8 L; Van Waters). The precipitate is collected by filtration and washed with methyl-t-butyl ether (4 L). The solid is slurried with acetone (10 L; Batron) and hexanes (10 L; Mallinckrodt), then filtered and washed with hexanes (4 L). After drying in vacuo there is obtained 5.124 kg of α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropane-nitrile (87% yield).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Br:28][CH2:29][C:30](Cl)=[O:31].C1(SC2CN[C@H](C(O)=O)C2)C=CC=CC=1>C(Cl)Cl>[Br:28][CH2:29][C:30]([N:11]1[CH2:12][C@@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:10]1[C:13]([OH:15])=[O:14])=[O:31]
Reactant: O=C(Cl)CBr
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C(O)[C@@H]1CC(Sc2ccccc2)CN1
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (4S)-4-(phenylthio)-L-proline (2.2 g., 10 mmole) in methylene chloride (50 ml., freshly distilled) is added bis(trimethylsilyl)acetamide (7.35 ml., 30 mmole). The reaction mixture is stirred at room temperature for 2 hours until it becomes almost clear. The reaction mixture is then cooled to -5° and bromoacetyl chloride (1.9 g., 1.0 ml., 12 mmole) is added dropwise keeping the temperature at -5°. After stirring overnight (-5° to room temperature), the reaction mixture is concentrated to about 50% of its volume, partitioned between saturated sodium bicarbonate/ethyl acetate and the layers are separated. The organic layer is extracted once more with saturated sodium bicarbonate. The combined aqueous layers are acidified to pH 2.0 with 10% potassium bisulfate and extracted with ethyl acetate (3×). The ethyl acetate fractions are combined, dried (Na2SO4) and concentrated to give 3.5 g. of (4S)-1-bromoacetyl)-4-(phenylthio)-L-proline as a viscous oil.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: C#CC(C)(C)O
Reactant: COc1ccc(C=O)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(C)(C)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a −78° C. stirred solution of 2-methylbut-3-yn-2-ol (0.89 g, 10.710 mmol) in dry THF (50 mL), n-BuLi (16.0 mL, 27.001 mmol, 1.6 M in hexane) was added dropwise over 5 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 3-chloro-4-methoxybenzaldehyde (1.8 g, 10.710 mmol) in dry THF (10 mL) was added and stirring was continued for an additional 3 h at RT. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4% EtOAc in hexanes to afford 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 26%) as a yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.Cl.ClC1C=CN=CC=1.O1CCOCC1>C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)nc1-n1cccc1

Procedure:
The reaction is carried out in the same way as in Stage B of Example 90 but starting from 15.40 g (0.0887 mol) of 6-chloro-3-nitro-2-aminopyridine and by using 12.9 g (0.0976 mol; 1.1 eq) of 2,5-dimethoxytetrahydrofuran, 14.64 g (0.0976 mol; 1.1 eq) of 4-chloropyridine hydrochloride and 300 cm3 of 1,4-dioxane. The solution is brought to reflux for 6 h. At the end of the reaction, the precipitate is taken up in ethyl ether.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]([C@H:8]3[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(F)c3)cc2)CC1
Temperature: 25 °C

Procedure:
Into a reaction vessel under an atmosphere of nitrogen, 1-iodo-4-(trans-4-pentylcyclohexyl)benzene (T26; 50.0 g), 3-fluorophenylboronic acid (T27; 21.5 g), potassium carbonate (58.0 g), Pd (Ph3P)2Cl2 (2.95 g), water (200 ml), toluene (200 ml), and Solmix A-11 (200 ml) were put and heated under reflux for 8 hours. After the reaction mixture had been cooled to 25° C., the solution was poured into water (1,000 ml) and toluene (500 ml) and mixed. The mixture was then allowed to stand to be separated into two layers of an organic layer and an aqueous layer. Extraction into an organic layer was carried out and the resulting organic layer was fractionated. The extracts were washed with water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by means of fraction-collecting column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The residue was further purified by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (volume ratio of ethyl acetate Solmix A-11=1:1) and then dried, whereby 37.3 g of 3-fluoro-4′-(trans-4-pentylcyclohexyl)biphenyl (T28) was obtained. The yield based on the compound (T26) was 82.0%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:10]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 111.3 %

Procedure:
A mixture of 4-fluorobenzaldehyde (0.242 g, 1.95 mmol), 1-isopropylpiperazine (0.335 mL, 2.34 mmol), and K2CO3 (0.323 g, 2.34 mmol) in DMF (2.44 mL) was heated at 120° C. overnight. The mixture was diluted with EtOAc (200 mL), washed with 10% aqueous LiCl (3×75 mL) and brine (75 mL), dried over Na2SO4, and filtered. The volatiles were removed under vacuum to yield 4-(4-Isopropylpiperazin-1-yl)benzaldehyde (0.504 g) as an orange solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[C:7]=3[C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:22]>>[Cl:22][C:8]1[C:7]2[C:13](=[O:20])[C:14]3[C:19]([C:6]=2[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: ClOCl
Reactant: Cc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccccc1-3
Product: Cc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccccc1-3
Yield: 73.4 %

Procedure:
A mixture of 3-methyl-5H-indeno[2,1-c]quinoline-6,7-dion obtained in reference example 5 (700 mg, 2.7 mmol) and phophorous oxychloride (10 ml, 107 mmol) was refluxed with heat for 1.5 hours. The reaction mixture was distilled to dryness. To the residue was added water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and dissolved in chloroform to filter off undissolved substances. Recrystallization from benzene to give 550 mg (yield 73.4%) of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH2:24]([O:20][C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
At 0° C., diethyl azodicarboxylate (3.4 mL) was added to a THF solution (13 mL) of 4-amino-3-nitrophenol (1.0 g), benzyl alcohol (1.0 g) and triphenyl phosphine (1.9 g), and stirred at room temperature for 5 hours. The reaction liquid was diluted with ethyl acetate, and the organic layer was washed with aqueous 1 N sodium hydroxide solution, aqueous saturated sodium hydrogencarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/8 to 3/7) to obtain 4-(benzyloxy)-2-nitroaniline (1.2 g) as a red solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:11](=[O:13])(=[O:12])[NH:14][CH2:15]1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccncc1S(N)(=O)=O
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)N1CNS(=O)(=O)c2cnccc21

Procedure:
A mixture of 1 g of 4-isopropylaminopyridine-3- sulfonamide (Preparation 3) and 1 g of paraformaldehyde in 20 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 3 hours. After cooling, the crystalline precipitate is filtered and washed with isopropanol. The precipitate is dissolved in 150 cm3 of hot methanol. The possible insoluble material is filtered. The filtrate is concentrated to dryness and the residue is taken up in 30 cm3 of water. The aqueous suspension is adjusted to a pH of 7-7.5 (NaHCO3) and the precipitate corresponding to the title compound is filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O:49]=[C:50]1[N:54]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[C:53]2[CH:61]=[CH:62][CH:63]=[CH:64][C:52]=2[NH:51]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:58]3[CH2:57][CH2:56][CH:55]([N:54]4[C:53]5[CH:61]=[CH:62][CH:63]=[CH:64][C:52]=5[NH:51][C:50]4=[O:49])[CH2:60][CH2:59]3)=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (11-4) (1.78 g, 5.84 mmol), NBS (1.14 g, 6.42 mmol) and benzoylperoxide (0.28 g, 1.17 mmol) in chloroform (25 mL) was heated to reflux for 24 h. Concentrated in vacuo and the residue was dissolved in MeOH (15 mL) and THF (15 mL). To this solution was added 4-(2-keto-1-benzimidazolinyl)-piperidine (1.39 g, 6.42 mmol) and diisopropylethylamine (3.8 g, 29.2 mmol). The mixture was stirred overnight and concentrated. The residue was treated with Na2CO3 (20 mL, 2M) and extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated in vacuo. The solid was purified by silicon gel chromatography (2–4% MeOH in CH2Cl2) to give 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (11-5). 1H NMR (CDCl3) δ 8.70 (s, 1H), 7.98 (s, 1H), 7.37–7.25 (m, 7H), 7.17–7.19 (m, 2H), 7.03–7.09 (m, 4H), 4.31–4.37 (m, 1H), 3.54 (s, 2H), 2.98 (m, 2H), 2.41–2.46 (m, 2H), 2.13–2.18 (m, 2H), 1.78–1.80 (m, 2H). LRMS m/z (M+H) Calcd: 520.0, found: 520.2.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:20][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19])[CH:10]([CH3:15])[CH2:11][CH2:12][C:13]=3[C:2]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCCCC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 24.4 %

Procedure:
In a 200 ml autoclave were placed 4.6 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of piperidine and 50 ml of hexamethylphosphoric triamide and the mixture was reacted at 160° C. on an oil bath for 5 hours. After completion of reaction hexamethylphosphoric triamide and piperidine were distilled off under reduced pressure and to the residue was added ethyl acetate and crystallized. Recrystallization from dimethylformamide-water give 1.3 g of 9-chloro-8-(1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 246° to 248° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12]C)=O)=[O:7])(C)(C)C.Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CCCCCCC.CCOC(C)=O>[Si:27]([O:12][CH2:10][C@H:9]1[C@H:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:19][CH:20]=2)[O:7][C:6](=[O:5])[NH:8]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate 12 starting with (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate and (3-bromopropoxy)(tert-butyl)dimethylsilane. TLC (heptane/EtOAc 1:1) Rf=0.49; tR=1.832 min (UPLC 1); LC-MS: [M+H] 496; Rt 1.62 min (LC-MS method 1); 1H NMR (400 MHz, CDCl3): 7.30 (d, 2H), 6.95 (d, 2H), 5.27 (br s, 1H), 5.22 (d, 1H), 4.13 (dd, 2H), 4.00 (m, 2H), 3.80 (m, 3H), 3.74 (m, 2H), 2.01 (m, 2H), 0.93 (s, 9H), 0.91 (s, 9H), 0.10 (s, 6H), 0.06 (s, 6H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1>O>[N+:1]([C:7]1[CH:6]=[CH:5][C:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2ccccc2CC1
Solvent: O
Product: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: -35 °C

Procedure:
A flask containing 90% nitric acid was cooled to at −35° C. using an acetonitrile-dry ice bath. 5,6,8,9-Tetrahydro-benzocyclohepten-7-one (0.5 g, 0.003 mol) was added in portions over 30 minutes. The mixture was warmed slightly to at −20° C. for 1.5 h until all of the material was dissolved. The mixture was poured over ice and water and the resulting precipitate was collected by filtration and washed with water. The solid was dried at under vacuum overnight to give a tan solid (0.58, 78%), 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.40 (d, 1H, J=8.4 Hz), 3.03 (m, 4H), 2.65 (m, 4H),
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6][C:7]([F:25])([F:24])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1.[CH3:26]I.O>CN(C)C=O>[CH:3]1([S:6][C:7]([F:24])([F:25])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([O:15][CH3:26])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 60% sodium hydride (75 mg, 1.87 mmol) in N,N-dimethylformamide (50 ml), 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (0.50 g, 1.44 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (270 mg, 1.87 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.31 g, yield: 60%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]([N:9]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]>>[C:5]([N:9]1[C:13](=[O:14])[C:12]([NH:1][CH2:2][CH2:3][OH:4])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]
Reactant: NCCO
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Yield: 55 %

Procedure:
The title compound was prepared as described for Example 49 from 2-aminoethanol and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide. The residue was purified by silica gel column chromatography (Horizons Biotage) using DCM as eluent to give the title compound (1.788 g, 55%) as an oil. 1H NMR (500 MHz): δ 7.50-7.44 (m, 5H), 6.81 (t, 1H), 4.69 (t, 1H), 3.29-3.22 (m, 2H), 3.86-2.80 (m, 2H), 1.64 (s, 9H); 13C NMR (125 MHz DMSO-d6): 159.9, 136.1, 132.1, 130.0, 129.2, 125.9, 105.4, 61.2, 59.5, 46.6, 27.8; Mass Spectrum: M+H+ 325.