Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([CH3:24])[CH:18]2[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>COCCOC>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][CH3:13])=[CH:23][CH:22]=3)[CH:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]2[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCOC(=O)CC1c2cc(OC)ccc2NC1C
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1c2cc(OC)ccc2N(c2nc(Cl)nc3ccccc23)C1C

Procedure:
A mixture of 2,4-dichloroquinazoline (3.2g.), ethyl 5-methoxy-2-methylindolin-3-ylacetate (4.0g.) and triethylamine (2.23ml; dried over potassium hydroxide pellets) in dry 1,2-dimethoxyethane (50ml.) was heated under reflux for 30 mins. The mixture was evaporated in vacuo, and to the residue was added water (100ml.) and ethyl acetate (50ml.). The aqueous layer was separated and extracted with ethyl acetate (2 × 30ml.), and the extracts were washed with water (30ml.), dried(MgSQ 4) and evaporated. The residual syrup slowly crystallised to give ethyl 1-(2-chloroquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate, m.p. 111°-112° C. This indoline ester (3.6g.) was added to a solution of sodium (0.5g.) in methanol (50ml.; dried over magnesium methoxide), and the resulting solution was heated under reflux for 18 hrs. After removal of methanol in vacuo, the mixture was added to water (50ml.) and acidified with acetic acid to give 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetic acid hemihydrate, m.p. 115°-120° C. This acid (3.0g.) was dissolved in dry methanol (40ml.) containing concentrated sulphuric acid (0.1ml.), and the mixture was heated under reflux for 5 hrs. Saturated sodium acetate solution (2ml.) was added, and the mixture was evaporated in vacuo. The residue was partitioned between water (50ml.) and ether (40ml.). After separation, the aqueous layer was extracted with ether (2 × 20ml.). The ether extracts were washed successively with saturated sodium hydrogen carbonate solution (20ml.) and water (20ml.), dried (Na2SO4), and evaporated to give methyl 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methhylindolin-3-ylacetate as a dark yellow syrup [pure by TLC (system A); NMR: 5--OCH3 at 6.3τ; 2-- OCH3 at 6.15τ ].
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH3:5].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)C=CC=CC=1>CN(C=O)C>[CH2:3]([O:6][C:7]1[N:8]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:35][CH:36]=2)[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH3:5]
Reactant: CCCOc1nc2ccccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to a stirred solution of 2-propoxybenzimidazole (0.71 g) in DMF (10 ml) under ice-cooling. The mixture was stirred for 20 minutes, to which was added N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl) tetrazole (2.3 g), followed by stirring at room temperature for 5 hours. To the reaction mixture was added ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was dissolved in methanol (50 ml), to which was added 1N-HCl (15 ml), followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated, to which were added water (15 ml) and ethyl acetate (15 ml). The mixture was made alkaline with 1N NaOH and shaken. The aqueous layer was adjusted to pH 3-4 with 1N-HCl and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to yield crystals. Recrystallization from ethyl acetate--methanol gave colorless crystals (0.58 g, 35%), m.p. 177-179° C. (decomp.).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([NH:16][C:17]2[CH:18]=[C:19]([C@@H:23]([OH:43])[CH2:24][NH:25][C:26]([CH3:42])([CH3:41])[CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50]Cl)([CH3:47])[CH3:46]>CN(C=O)C.C(OCC)(=O)C>[C:7]1([S:13]([NH:16][C:17]2[CH:18]=[C:19]([C@@H:23]([OH:43])[CH2:24][NH:25][C:26]([CH3:41])([CH3:42])[CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][C:34]([C:38]([O:40][CH2:50][CH2:49][N:48]([CH:52]([CH3:54])[CH3:53])[CH:45]([CH3:47])[CH3:46])=[O:39])=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(CCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert. butoxide (58 mg, 0.58 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid [free base (Zwitterion) of Example 6; 300 mg, 0.58 mmol] in 2 ml DMF. Then the reaction mixture is stirred for 10 minutes at RT and 2-diisopropylamino-ethyl chloride hydrochloride (115 mg, 0.58 mmol) is added. After 72 hours stirring at RT the reaction mixture is diluted with 30 ml of ethyl acetate and extracted four times with 15 ml ice water. The organic phase is dried on magnesium sulphate, acidified with about 0.5 ml TFA and the solvent is eliminated in vacuo. The crude product is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: COC1(c2ccc(F)c(Cl)c2)CCNC1
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Example 22. (+3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 83% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 4), 242 (34), 227 (20), 157 (32), 71 (bp).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1ccc(C)c(N=C=S)c1
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(C)ccc2C)C1=S
Yield: 42.7 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,5-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (10.6 g) as an off-white solid, m.p. 176°-178° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.70; H, 6.46; N, 11.27. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][NH:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:37]([O:44][C:45]([CH2:47][C:48](O)=[O:49])=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][N:11]([C:48](=[O:49])[CH2:47][C:45]([O:44][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:46])[CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CNC(C(=O)OC)C2
Reactant: O=C(O)CC(=O)OCc1ccccc1
Agent: Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CN(C(=O)CC(=O)OCc1ccccc1)C(C(=O)OC)C2

Procedure:
Methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine 6-carboxylate hydrochloride and benzyloxycarbonyl-acetic acid are treated in the same manner as in Example 8-(1) to give methyl 2-n-butyl-5-benzyloxycarbonylacetyl-3 -{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetra-hydroimidazo[4,5-c]pyridine-6-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](I)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[CH2:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:37]3[CH:38]=[CH:39][C:34]([CH2:32][CH3:33])=[CH:35][CH:36]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(I)c(C)c2)s1
Product: CCc1ccc(-c2c(C)cc(OC(CCC(F)(F)F)c3ccc(C(=O)NCCC(=O)OC)s3)cc2C)cc1

Procedure:
This compound is made by the general method as exemplified in Preparation 77 using 3-({5-[4,4,4-trifluoro-1-(4-iodo-3,5-dimethyl-phenoxy)-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester - chiral Isomer 1 and 4-ethyl-phenyl boronic acid as the starting materials. MS(ES): 548.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20]CC4C=CC=CC=4)=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10](C(OC)=O)[C:9]=2[C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:4][N:3]=1>C(O)(=O)C.O1CCOCC1.[C].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[CH:10][C:9]2([C:32]([O:34][CH3:35])=[O:33])[C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(OC)cc2c(-c2ccnc(Cl)c2)c1C(=O)OC
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)C1(C(=O)OC)C=Cc2cc(O)c(OC)cc2C1c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a suspension of 1-(2-chloro-4-pyridyl)-2,3-bis(methoxycarbonyl)-6-benzyloxy-7-methoxynaphthalene (6.6 g) in a mixture of acetic acid and dioxane (1:1, 1000 ml) is added 10% palladium-carbon (2 g), and the mixture is subjected to medium-pressure catalytic hydrogenation at room temperature overnight with using, a Parr-reduction apparatus. To the reaction solution is added a mixture of acetic acid and dioxane (1000 ml), and thereto is added 10% palladium-carbon (2 g). The mixture is subjected to medium-pressure catalytic hydrogenation at room temperature for 18 hours with using a Parr-reduction apparatus. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from ethanol to give 1-(2-chloro4-pyridyl)-2,2-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (3.35 g, yield; 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.Br[C:18]1[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=1.O1CCCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:18]2[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: Cc1cc(C)cc(S)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Sc2nnc(C(F)(F)F)s2)c1
Yield: 94.9 %

Procedure:
8.5 g (0.061 mole) of 3,5-dimethylthiophenol, 6.2 g (0.061 mole) of triethylamine and 14.3 g (0.061 mole) of 2 -bromo-5-trifluoromethyl-1,3,4-thiadiazole in 150 mole of tetrahydrofuran were stirred for 30 minutes under reflux. The salt (by-product) which had precipitated was filtered off and washed thoroughly with tetrahydrofuran. After distilling off the solvent in vacuo, a colorless oil passed over on distillation. 16.8 g (95% of theory) of 2-(3',5'-dimethylphenylthio)-5-trifluoromethyl-1,3,4-thiadiazole of boiling point 107°-108° C/10.2 mm Hg were obtained. 22.8 g (0.201 mole) of hydrogen peroxide (30% strength) in 100 ml of glacial acetic acid were added thereto and the reaction mixture was stirred for 15 hours at 60° C, and poured onto ice water. The precipitate was filtered off and recrystallized from ethanol. 12.7 g (54% of theory) of 2-(3',5'-dimethylphenylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 110° C were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:12]=2)[CH:10]=1)=O)C.[CH3:47][NH2:48]>>[CH3:47][NH:48][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:12]=2)[CH:10]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 65 °C

Procedure:
A mixture of 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.07 g, 0.112 mmol) and 40% aqueous methyl amine solution (3 ml) is heated to 65° C. for 12 h. The reaction mixture is concentrated in vacuo and purification of the crude residue by chromatography on silica eluting with 4% methanol in chloroform yields the title compound.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[H][H]>C(O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
The crude Boc-Asn-Leu-Gly-OBzl was suspended in 2.0 l 50% ethanol. Addition of 10 g 10% Palladium on carbon and hydrogenation for one hour at 3 bar hydrogen pressure under stirring. The crude solution was filtrated and pH adjusted to 3.0 with a 1N sodium hydrochloric acid solution. Removal of ethanol under vacuum at 40° C. resulted in crystallisation of product. Filtration and drying under vacuum at 40° C. for 2 days gave the pure product. Yield 72.3 g (58%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.Cl>CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1ccc(C=C2CCc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 83.6 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dimethoxybenzaldehyde 1.23 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for 5.5 hours under reduced pressure to obtain the desired compound 1.60 g.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:7]1[C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Br
Temperature: 100 °C
Yield: 8588.6 %

Procedure:
4,5-Dichloro-2-nitroaniline (41.0 g, 1.98 mmol), N-bromosuccinimide (42.86 g, 2.41 mmol) and N,N-dimethylformamide were combined and heated to 100° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into a flask containing ice water (1 L). The yellow solid was collected and was dissolved in dichloromethane (2 L), resulting in two phases. The organic layer was collected and was dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure using a rotary evaporator to leave 48.62 g (86%) of a brown solid. Anal. Calcd. for C6H3BrCI2N2O2: C, 25.21; H, 1.06; N, 9.80. Found: C, 25.32; H, 1.13; N, 9.68.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(F)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 2-fluoro-6-methoxybenzaldehyde (0.63 g) in tetrahydrofuran (5 mL) were added water (0.5 mL) and sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and the solvent was removed under reduced pressure to give the title compound (0.58 g).
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][CH2:14][NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)C)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:9][NH:11][CH2:13][CH2:14][NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(NCCN(C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNCCNc1ccc(C(=O)OC)cc1
Yield: 78.3 %

Procedure:
To a stirred solution of methyl 4-[2-(N-benzyloxycarbonyl-N-methylamino)ethylamino]benzoate (1.26 g, 3.68 mmol) in MeOH (20 mL) was added 5 wt. Pd—C (700 mg), and the mixture was hydrogenated (3 atm) for 4 hr at room temp. The mixture was filtered, and the filtrate was evaporated under a reduced pressure to give 600 mg (78%) methyl 4-[2-(N-methylamino)ethylamino]benzoate as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ2.46 (s, 3H), 2.88 (t, 2H, J=5.5 Hz), 3.27 br s, 2H), 3.85 (s, 3H), 6.57 (d, 2H, J=8.8 Hz), 7.85 (d, 2H, J=8.8 Hz); MS (FAB) m/z 209 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].CO[CH2:13][Cl:14].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH2:13][Cl:14])=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(F)cc1Cl
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(CCl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
17.6 g (0.11 mol) of 2-chloro-4-fluoroanisole was dissolved in a dichloromethane solution of 1N titanium tetrachloride, and 88.3 g (1.10 mol) of methoxymethyl chloride was dropwise added thereto at room temperature, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction solution was poured into water, followed by stirring at room temperature for 2 hours, and then the aqueous phase was removed The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Then, the obtained residue was purified by silica gel column chromatography to obtain 15.5 g (yield: 68%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=O>C(O)(=O)C>[CH3:7][C:4]1[C:3]([C:8]#[N:9])=[C:2]2[N:1]=[CH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:6]2[N:5]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Product: Cc1nn2c(-c3ccncc3)ccnc2c1C#N
Yield: 52.5 %

Procedure:
A mixture of 6.1 g of 5-amino-3-methyl-4-pyrazole carbonitrile and 8.81 g of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one in 50 ml of glacial acetic acid is stirred and heated at reflux for 5 hours. The reaction mixture is cooled and the precipitate which forms is collected by filtration and washed with water and a little dichloromethane to give a solid. The solid is partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer is dried over anhydrous sodium sulfate and passed through a short column of hydrous magensium silicate. The addition of hexane to the eluate crystallizes the product which is collected by filtration to give 6.17 g of the desired product, mp 220°-221° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccc(C23CC4CC(CC(C4)C2)C3)c1
Product: C=CCOC(=O)c1ccc(OC(=O)c2cccc(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 65.5 %

Procedure:
In a manner analogous to Example 9(a) by reacting 1.5 g (5.5 mmoles) of 3-(1-adamantyl)benzoyl chloride with 980 mg (5.5 mmoles) of allyl 4-hydroxybenzoate, 1.5 g (68% yield) of the expected ester in the form of a colorless oil are obtained.