Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH:8]=[N:9]O)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[NH2:9][CH2:8][C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]=1[OH:14]
Reactant: CC(C)(C)c1cccc(C=NO)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cccc(CN)c1O
Yield: 23.7 %

Procedure:
3-tert-butyl-2-hydroxybenzaldehyde oxime (550 mg, 2.9 mmol) in EtOAc (10 mL) and MeOH (10 mL) was hydrogenated at balloon pressure in the presence of 10% Pd on carbon (100 mg) for 15 h. The reaction mixture was filtered over celite and concentrated. The residue was dissolved in EtOAc and 0.5 N HCl (10 mL). The layers were separated and the aqueous layer was treated with 1N NaOH solution until pH=9. The resulting aqueous layer was extracted with CHCl3 (3×10 mL). The combined CHCl3 was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide to desired product (123 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:7]1([C:13]2[S:14][C:15]3[C:21](=[O:22])[CH:20]=[C:19](NCCN(C)C)[C:18](=[O:29])[C:16]=3[N:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([C:13]2[S:14][C:15]3[C:21](=[O:22])[C:20]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:19][C:18](=[O:29])[C:16]=3[N:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)CCNC1=CC(=O)c2sc(C3CCCCC3)nc2C1=O
Reactant: CN(C)CCN
Product: CN(C)CCNC1=CC(=O)c2nc(C3CCCCC3)sc2C1=O

Procedure:
The experimental protocol used is identical to that described for Stage 15.4 of Example 15, intermediate 101.4 replacing intermediate 15.3 and N,N-dimethylethylene diamine replacing aniline. A mixture of 80% and 9% of 2-cyclohexyl-5-{[2-(dimethylamino)ethyl]amino}-1,3-benzothiazole-4,7-dione and of 2-cyclohexyl-6-{[2-(dimethylamino)ethyl]amino}-1,3-benzothiazole-4,7-dione is obtained.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][C@H:7]2[O:13][CH:11]([OH:12])[C@H:10]([OH:14])[C@@H:9]([OH:15])[C@H:8]2[OH:16])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[C:11]([O:12][CH:11]1[O:13][C@H:7]([CH2:6][N:5]2[C:4](=[O:17])[C:3]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]3[C:1]2=[O:22])[C@H:8]([O:16][C:27](=[O:29])[CH3:28])[C@H:9]([O:15][C:9](=[O:15])[CH3:8])[C@H:10]1[O:14][C:7](=[O:13])[CH3:6])(=[O:12])[CH3:10]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1O[C@H](CN2C(=O)c3ccccc3C2=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 96 %

Procedure:
6-Deoxy-6-phthalimido-D-galactopyranose (2.9 g.) is acetylated with acetic anhydride (12 ml.) in pyridine (20 ml.) in the normal manner to give 1,2,3,4-tetra-O-acetyl-6-deoxy-6-phthalimido-D-galactopyranose (4.30 g., 96%) as a mixture of α- and β-anomers in the ratio of 1:1.6, [α]D27 +52.5° C. (C 1.0, chloroform); n.m.r. (chloroform-d): ∂ 5.70 (d, J1,2 8.0 Hz, H-1β), 6.33 (b, H-1α).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH2:21])[CH3:2].N1C=CC=CC=1.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Reactant: O=C(O)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
2-Amino-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (compound A) (2.5 g) produced by the above process was dissolved in anhydrous methylene chloride (40 ml). Pyridine (1.4 ml) and 3-(chloromethyl)-benzoyl chloride (compound B) (1.3 ml) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3-chloromethylbenzoylamino)-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (2.3 g, yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7](=[N:14]O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+]>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=NO)c2ccccc2)cc1
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Product: COc1ccc(C(N)c2ccccc2)cc1
Yield: 76.9 %

Procedure:
Following a procedure similar to that described in Preparation 12, but using 9.4 g of 4-methoxybenzophenone oxime, 33.9 g of ammonium acetate, 7.46 g of sodium cyanoborohydride, and 79 ml of a 17-19% by volume aqueous solution of titanium trichloride, 6.78 g of the title compound were obtained as an oily substance.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([S:23]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(c1ccccn1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.3 g (11.8 mmol) of N-methylpyridin-2-amine in 25 mL of DCM are added, at 0° C., 3.3 mL (23.6 mmol) of triethylamine and then, portionwise, 2.5 g (11.8 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to document WO 98/40332). After stirring for 12 hours at room temperature, the reaction medium is taken up in 100 mL of DCM, washed successively with 100 mL of water and 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 4/1 cyclohexane/EtOAc mixture. After concentrating under reduced pressure, 2.8 g of 6-chloro-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide are obtained in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14]C)[CH:8]=2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc2cc(O)ccc2nc1Cl
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.01 g, 4.54 mmol) in dry CH2Cl2 (36 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer at 0° C. under N2 was added dropwise BBr3 (1.0 N solution in CH2Cl2, 13.60 mL, 13.60 mmol). After complete addition, the bath was removed and stirring was continued overnight at RT. The reaction mixture was then added dropwise to a mixture of water and ice (50 mL) under stirring. After complete addition, the mixture was stirred for 30 min at RT and then filtered to give, after drying, 2-chloro-6-hydroxyquinoline-3-carbaldehyde as a yellow solid (0.77 g, 82% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7]C2)[O:4][CH2:3][CH2:2]1.O=C1CCC(C(OCC)=O)C1.O=C1CCC(C(OCC)=O)CC1>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CCOC(=O)C1CCC(=O)C1
Agent: CCOC(=O)C1CCC(=O)CC1
Product: CCOC(=O)C1CCC2(C1)OCCO2

Procedure:
Ethyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate was synthesized in a manner similar to the synthesis of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate, but with ethyl 3-oxocyclopentanecarboxylate substituted for ethyl 4-oxocyclohexanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[S:37])=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:30][CH:31]=4)=[S:37])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CC(C)c1ccc(N=C=S)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CC(C)c1ccc(NC(=S)Nc2cccc3cc4cccc5c4c(c23)C(=O)N(CCN(C)C)C5=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.90 mmole) were dissolved in 20 ml of acetonitrile. 309 μl (2 molar equivalents) of 4-isopropylphenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. Two more equivalents of 4-isopropylphenyl isothiocyanate was added and the reaction mixture was again stirred for 24 hours at room temperature. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 428 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=93%) which was characterized as follows:
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@:5]([CH3:45])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[C:21]([C:41]([F:44])([F:43])[F:42])[CH:20]=3)=[CH:17][N:18]=2)[CH2:4][O:3]1>C(#N)C.O>[NH2:6][C@@:5]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=3)=[C:21]([C:41]([F:44])([F:43])[F:42])[CH:20]=2)=[CH:17][N:18]=1)([CH3:45])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1ncc(-c2ccc(OCCCCCc3ccc(C(F)(F)F)cc3)c(C(F)(F)F)c2)s1
Solvent: O
Solvent: CC#N
Product: C[C@](N)(CO)c1ncc(-c2ccc(OCCCCCc3ccc(C(F)(F)F)cc3)c(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared from (R)-tert-butyl 2,2,4-trimethyl-4-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.50 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=533.4; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.66 (d, 1H, J=2.0 Hz), 7.56 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.52 (d, 2H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=8.8 Hz), 4.07-4.03 (m, 4H), 2.70 (t, 2H, J=7.8 Hz), 1.89-1.82 (m, 5H), 1.74-1.67 (m, 2H), 1.57-1.50 (m, 2H).
Reaction SMILES: C[O-].[Na+].CO.[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=1[C:14]([OH:16])=[O:15].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[O:30][CH:31]=1.[Cl-].[Na+]>CN1CCCC1=O>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:6][C:7]3[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=3)[O:10][CH2:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=3[C:14]([OH:16])=[O:15])[N:28]=2)=[CH:37][CH:36]=1
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Reactant: Cc1cccc(COc2cccc(O)c2)c1C(=O)O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cccc(COc2cccc(OCc3coc(-c4ccc(F)cc4)n3)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
18.6 g of 30% strength solution of sodium methoxide in methanol (104 mmol) are added to 15.9 g (51.6 mmol) of 2-(3-hydroxyphenoxymethyl)-6-methyl-benzoic acid (hemisolvate with N-methylpyrrolidone) in 70 ml of N-methylpyrrolidone while stirring at room temperature. After five minutes, 10.0 g (47.3 mmol) of 4-chloromethyl-2-(4-fluorophenyl)oxazole are added, and the mixture is stirred at room temperature for 23 h and finally heated at 50° C. for one hour. 500 ml of 19% strength sodium chloride solution are added to the reaction solution, and the resulting mixture is extracted twice with 225 ml of ethyl acetate. The combined ethyl acetate phases are extracted three times with 225 ml of water, and the combined aqueous phases are acidified to pH=3 with 2 M hydrochloric acid. The resulting crystals are filtered off with suction and washed with water. The product is purified further by crystallization from isopropanol. 2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]phenoxymethyl}-6-methylbenzoic acid is obtained as colorless crystals in a yield of 58.3%, melting point 168-173° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[OH:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>COCCOC.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:16]#[C:15][CH2:14][OH:13])=[CH:18][CH:19]=1
Reactant: OCC#Cc1ccc(B(O)O)cc1
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: OCC#Cc1ccc(-c2ncccn2)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A mixture of 2-bromopyrimidine (1.00 g, 6.29 mmol) and Pd(Ph3P)4 (220 mg, 0.19 mmol) in ethylene glycol dimethyl ether (25 mL) was stirred for 10 min, a slurry of sodium bicarbonate (1.58 g, 18.81 mmol) and [4-(3-hydroxy-1-propynyl)phenyl]boronic acid (1.32 g, 7.50 mmol, prepared as described in Reference Example 235) in water (25 mL) was added, and the mixture was heated to reflux for 4 h. The cooled reaction mixture was diluted with methylene chloride (100 mL) and washed with water (100 mL). The aqueous layer was extracted with dichloromethane (25 mL) and the combined organic layers were dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 3:2 hexane/ethyl acetate) provided 1.04 g (79%) of the title compound as a yellow solid. MS 211 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C@@H:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[ClH:28]>O1CCOCC1.CCO>[ClH:1].[ClH:28].[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[NH:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g) and 4N hydrogen chloride in dioxane solution (5 ml) in EtOH (10 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with hexane was collected by filtration to give ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (0.9 g).ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].Cl.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.74 g) was added to a solution of 8-bromooctanoyl chloride (3 g) in benzene (20 ml), and the mixture was stirred at room temperature for 1.5 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.36 g of 8-bromo-1-phenyl-1-octanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[AlH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:9][NH2:10])=[CH:4][CH:3]=1
Reactant: N#CC(c1ccc(Cl)cc1)N1CCCC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(c1ccc(Cl)cc1)N1CCCC1
Yield: 30 %

Procedure:
To a solution of (4-Chloro-phenyl)-pyrrolidin-1-yl-acetonitrile (3.52 g, 15.2 mmol; in Tetrahydrofuran (96 mL) was added Lithium tetrahydroaluminate (1225 mg, 32.28 mmol) and the reaction was refluxed over night. The reaction was quenched with H2O (1.22 ml), 2M NaOH (aq) (1.22 ml) and H2O (2.44 ml). The solid was filtered off and the reaction was concentrated, to yield 2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethanamine (1.14 g, 30% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][O:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][O:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)CC1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid methyl-ester hydrochloride (6 mmol, 1.2 eq.) to obtain a residue. The residue was chromatographed on silica gel eluting sequentially with 1% methanol in dichloromethane and then 2% methanol in dichloromethane to give the title compound:
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12]C)[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].C(O)(=O)C.C>Br>[OH:12][C:6]1[CH:7]=[C:8]([CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:14])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution containing 8.0 kg of 5-nitrovanillin and 8.7 kg of acetic acid in 35 kg of conc. hydrobromic acid was refluxed for 20 h. 0.6 kg of charcoal was added and the mixture was filtered. 32 kg of water was added with stirring and the solution was cooled to -10° C. and stirring was continued for 2 h more. The crystalline product was filtered and washed with water. Yield 5.66 kg (80%), m.p. 135°-137° C.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=[CH:23]2)[C:17]=1[CH:26]([C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1)O.[OH-].[K+]>ClCCl>[CH3:33][C:31]1[N:32]=[C:28]([CH2:26][C:17]2[C:18]3[C:24]([CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:25][C:16]=2[CH3:15])[S:29][CH:30]=1
Reactant: Cc1csc(C(O)c2c(C)cc3cccccc2-3)n1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Cc2c(C)cc3cccccc2-3)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylsilane (178 μL, 1.11 mmol) was added slowly to 2 mL of trifluoroacetic acid (TFA) at room temperature. The mixture was cooled to 0° C. and mixed for 30 min. A fresh solution of (2-methylazulen-1-yl)(4-methylthiazol-2-yl)methanol 5 (100 mg, 0.371 mmol) in dichloromethane was then added slowly to the mixture being stirred at 0° C. The reaction was kept at 0° C. for 2 h and then warmed to room temperature. Afterward, the mixture was poured into cold 20% KOH to quench the reaction. The organic layer was extracted into diethyl ether and washed with water and brine, dried with MgSO4 and purified using flash chromatography (ethyl acetate and hexane). The purified material was dried down into a blue solid. Yield: 64.3 mg, 68%. 1H NMR (400 MHz, CDCl3) δ 8.19 (t, J=10.38 Hz, 2H), 7.49 (t, J=9.90 Hz, 1H), 7.21 (s, 1H), 7.17-7.10 (m, 2H), 6.60 (s, 1H), 4.68 (s, 2H), 2.60 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 152.1, 149.0, 140.1, 137.0, 135.8, 134.4, 131.5, 123.2, 122.7, 117.8, 113.1, 29.3, 17.0, 15.0. HRMS (ES) calcd. MH+ [C16H16NS]+ 254.0925. found 254.0990.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](O)(=O)[CH2:11][OH:12].[OH-].[Na+]>>[OH:9][C:3]1[C:2]2[NH:1][C:10]([CH2:11][OH:12])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CO
Reactant: Nc1cccc(O)c1N
Agent: [Na+]
Agent: [OH-]
Product: OCc1nc2cccc(O)c2[nH]1
Yield: 54.6 %

Procedure:
To a solution of 40 ml 4M CHl 1.1 g (0.0087 mol) of 2,3-diaminophenol and 2 g (0.026 mol) of glycolic acid were added and the solution was heated under reflux for 20 h. Upon cooling the reaction mixture was alkalized with 10M NaOH to pH 8.5. The volatiles were removed under reduced pressure and the residual oil was suspended in methanol. The suspension was filtered and evaporated to dryness in vacuo. Chromatography on silica gel and elution with methylene chloride:methanol (10:2) gave 0.78 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]([Cl:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[C:8]([Cl:14])=[N:9][C:10]([CH2:13][Br:22])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2ccccc2)c(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(CBr)ccc1-c1ccccc1

Procedure:
A solution of 3-Phenyl-2-chloro-6-methylpyridine (0.094 g, 0.462 mmol), NBS (0.086 g, 0.485 mmol) and AIBN (0.008 g, 0.046mmol) in CCl4 (3 mL) were heated at reflux for 2 hours. The solvent was evaporated and the residue chromatographed (Silica gel, 100% CH2Cl2 to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].[CH2:18](I)[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:18]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[N:14]([CH3:15])[CH:13]=[N:12][C:11]=2[C:2]1=[O:1])[CH2:19][CH2:20][CH3:21]
Reactant: Cn1cnc2c(O)nc3ccccc3c21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2ncn(C)c2c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
3.0 g (0.015 mole) of 4-hydroxy-1-methyl-1H-imidazo[4,5-c]quinoline was suspended in 50 ml of dimethylformamide, and 0.80 g (0.020 mole) of 60% sodium hydride was added with ice cooling, followed by stirring at 50° C. for 30 minutes. Then, the mixture was again ice-cooled and 2.6 ml (0.023 mole) of n-butyl iodide was added dropwise, followed by stirring at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residues, followed by extraction with chloroform. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: chloroform/methonal=17/1), followed by recrystallization from isopropanol-isopropyl ether, to afford 2.5 g of Compound 1.