Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:15]([NH2:21])C(OCC)=O)=[N:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:3])=[O:2].CN(C)[CH:29]=[O:30]>>[N+:1]([C:4]1[C:5]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:6][C:7]2[C:8]3[N:9]([C:29](=[O:30])[NH:21][N:15]=3)[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(=O)[nH]c2cc([N+](=O)[O-])c(N3CCCC3)cc12
Product: O=c1[nH]nc2c3cc(N4CCCC4)c([N+](=O)[O-])cc3[nH]c(=O)n12
Temperature: 25 °C
Yield: 78 %

Procedure:
500 mg (1.38 mmol) of ethyl (7-nitro-2-oxo-6-pyrrolidin-1-yl-1,2-dihydro-quinazolin-4-yl)-carbazate in 30 ml of dry dimethylformamide were heated at reflux for 3 hrs. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue was triturated with a small amount of acetone and the red precipitate was filtered off and dried in a vacuum. 342 mg (78%) of 8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were obtained as a red powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CN1C=CN=C1.CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2)C(=O)O)cs1
Yield: 52.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 21.15 g.), 1 N sodium hydroxide aqueous solution (94 ml.), 1-methylimidazole (1.02 g.), methanol (220 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetic acid (syn isomer, 10.13 g.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C(Cl)(Cl)Cl>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:1]=[C:2]3[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)c2sc3nc(-c4ccccc4)cn3c2C1

Procedure:
A 0.08 m. quantity each of 2-amino-5,5-dimethyl-7-keto-4,5,6,7-tetrahydrobenzothiazole and α-bromoacetophenone are mixed in 150 ml. of chloroform and heated at reflux for 4 hours. The slurry is filtered hot and the insoluble intermediate product is suspended in 600 ml. of water containing 25 g. of sodium acetate. This suspension is heated slowly to boil over 21/2 hours, then allowed to cool. The product is filtered off, washed well with water and dried yielding 12.5 g. of product melting at 175°-178° C. and having the structure: ##STR9##
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:19]=[C:18]([B:29]2[O:33][C:32](C)(C)C(C)(C)[O:30]2)[C:15]=1C=O>C1COCC1.[Zn]>[Cl:13][C:14]1[C:15]2[CH:32]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:33][B:29]([OH:30])[C:18]=2[CH:19]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:21]=1
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)cc(Cl)c2C=O)OC1(C)C
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(Cl)c21
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a suspension of powdered zinc dust (1.0 g, 2.73 mmol) in THF (3 mL) was added trimethylsilyl chloride (0.21 mL, 2.73 mmol) at 40° C. The mixture was stirred at 55° C. for 15 min. After cooled to 37° C., ethyl bromoacetate (1.21 mL, 13.65 mmol) was added slowly while maintaining the temperature between 37˜40° C. The resulting mixture was stirred at ambient temperature for an additional 30 min. To a solution of 2-chloro-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)benzaldehyde (1 g, 2.73 mmol) in anhydrous THF (3 mL) cooled at −78° C., was added above freshly prepared zinc reagent. Upon completion of addition, the reaction mixture was warmed to room temperature and stirred for 30 min before quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was used directly in the next step reaction without further purification. MS (ESI) m/z=355 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH2:33]([OH:38])[CH2:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:37][CH2:36][CH2:35][CH2:34][CH2:33][OH:38])[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCCCO

Procedure:
By reacting p-tert-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide with the monosodium salt of 1,4-butanediol, there was obtained p-tert-butyl-N-[6-(4-hydroxybutoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide as a white foam.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:7])C.Cl>CC(C)=O>[C:16]1([C:6]([C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])([CH3:7])[CH2:5][CH:4]=[O:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(CC(C)(C(=O)C1CCCCC1)c1ccccc1)OCC
Agent: Cl
Solvent: CC(C)=O
Product: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
1,1-Diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane (74.4 g, 224 mmol) was dissolved in acetone (800 mL) followed by addition of 3.0 N HCl (800 mL). The reaction mixture was stirred for one hour at room temperature. It was then concentrated under vacuum to less than ½ its original volume and then extracted with methylene chloride (800 mL). The organic extract was then washed with brine (300 mL), dried over anhydrous magnesium sulfate, suction filtered and concentrated under vacuum to provide crude 3-phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g). Alternatively, the dried and filtered methylene chloride solution can be used directly in the next step without concentration.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12](S(C)(=O)=O)=[CH:11][C:10]=3Cl)[N:7]=[CH:6][C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.[NH2:23][C:24]([NH2:26])=[NH:25]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:10]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[N:7]=[CH:6][C:5]=2[C:20]([NH:25][C:24]([NH2:26])=[NH:23])=[O:22])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C(=O)O)c2C2CC2)c(Cl)c1
Reactant: N=C(N)N
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
coupling said 5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([OH:40])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:33]([OH:40])[CH:32]=1
Reactant: OB(O)c1ccc(Cl)cc1O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (80 mg, 0.179 mmol), (4-chloro-2-hydroxyphenyl)boronic acid (30.9 mg, 0.179 mmol), potassium carbonate (124 mg, 0.897 mmol) and Pd(Ph3P)4 (20.73 mg, 0.018 mmol) was added dioxane (897 μl) and Water (299 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. m/z (ESI) 537.9 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.[CH2:15]([N:17]([CH2:37][CH3:38])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[CH:24][CH:23]=1)[CH3:16]>O>[C:1]([C:32]1[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:15][CH3:16])[CH2:37][CH3:38])=[CH:23][CH:24]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 1.02 g. (0.006 mol.) of p-anisoyl chloride in 75 ml. of methylene chloride was added 2.0 g. (6.2 mmol.) of the hydrochloride salt of 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran. The reaction mixture was cooled to 0°, 3.3 ml. (0.024 mol.) of stannic chloride was added and the resulting mixture was stirred for 10 minutes at 0° then for 2.75 hours at 25°. The mixture was then poured into water and stirred vigorously. The layers were separated and the organic phase was washed with 10% aqueous sodium carbonate solution and water, dried (MgSO4) and concentrated to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]([CH3:8])([CH2:6][O:7][C:14]1[CH:15]=[CH:16][C:11]([C:10]([F:19])([F:18])[F:9])=[CH:12][N:13]=1)[C:3](=[O:5])[CH3:4]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(=O)C(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)C(C)(C)COc1ccc(C(F)(F)F)cn1
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
3,3-Dimethyl-4-hydroxybutan-2-one (11.2 g) was dissolved in 50 ml of dimethyl sulfoxide, and nitrogen gas was passed therethrough for 20 minutes. Then, 18.2 g of 3-trifluoromethyl-6-chloropyridine and 15 g of anhydrous potassium carbonate were added thereto, and the solution was gradually heated to 115° C. and reacted under stirring for 4 hours at that temperature. After completion of the reaction, the product was put into ice water, extracted with methylene chloride, washed with water and dried over Glauber's salt. The solvent was distilled off to give 24.8 g of oily 3,3-dimethyl-4-(5-trifluoromethylpyridine-2-yloxy)butan-2-one.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@@H]3[C@@H]1CCC2=C(F)F
Yield: 95.7 %

Procedure:
A suspension of 1.2 g of 17-difluoromethylene-3-tetrahydropyranyloxy-8α-estra-1,3,5(10)-triene in 25 ml of methanol and 2.5 ml of water is refluxed with 1.2 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.9 g of 17-difluoromethylene-8α-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 119-120° C., [α]D22 =-10.6° (c=0.5% in pyridine).
Reaction SMILES: CC(C)([O-])C.[K+].[I:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[CH:28][N:27]=1>CN(C=O)C.O>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[N:31][C:26]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:12]=3)[C:8]([I:7])=[CH:9]2)=[N:27][CH:28]=1
Reactant: Fc1ccccc1-c1cnc(Cl)nc1
Reactant: O=C(c1ccc2c(I)c[nH]c2c1)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(I)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)N1CCOCC1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (236 mg, 2.106 mmol, 1.5 eq), compound 354a) (500 mg, 1.404 mmol, 1.0 eq) and 2-chloro-5-(2-fluorophenyl)pyrimidine (292 mg, 1.404 mmol, 1.0 eq) in DMF (10 mL) were stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography [100-200 mesh silica; ethyl acetate/pet ether=7:3]. Yield: 400 mg (53% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:21]=1)[CH2:10][O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O:3][CH3:4])=[O:2].[Br:22]Br>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:21]=1)[CH2:10][O:11][CH:12]([Br:22])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O:3][CH3:4])=[O:2]
Reactant: BrBr
Reactant: COC(=O)c1cccc(COCC(=O)c2ccccc2)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(COC(Br)C(=O)c2ccccc2)c1

Procedure:
g 20 of 5-carbomethoxy-2-benzyloxy-acetophenone, m.p.=86°-88° C. dissolved in methylene chloride (ml 200) were reacted with bromine (9.8 g) at 10° C. for 15 minutes. After treatment with 10% sodium sulphite and water, the organic phase was evaporated to dryness. The residue, crystallized from isopropyl ether, gave 5-carbomethoxy-2-benzyloxy-ω-bromo-acetophenone (17 g), m.p.=84°-86° C., which was dissolved in dimethylformamide (85 ml) and reacted with anhydrous potassium acetate (5.6 g) at 50° C. for 2 hours. After cooling, and dilution with water, the precipitate was filtered and washed with cold methanol so obtaining 5-carbomethoxy-2-benzyloxy-ω-acetoxy-acetophenone (12.9 g), m.p.=86°-87° C., which was dissolved in tetrahydrofuran (40 ml) and ethanol (20 ml); few drops of concentrated HCl were added and then the solution was hydrogenated at atmospheric pressure and room temperature in the presence of 5% Pd/C (2.5 g) to the theoretical hydrogen consumption. The mixture was filtered to remove the catalyst and the organic solution was evaporated to dryness so obtaining crude 5-carbomethoxy-2-hydroxy-ω-acetoxy-acetophenone (9.2 g), which was dissolved in dioxane (20 ml) and pyridine (10 ml) and reacted with trans-cinnamoyl-chloride (9.4 g) at room temperature for 8 hours. The reaction mixture was diluted with water and acidified to pH 4. The precipitate was filtered, dried and dissolved in methyl-ethyl-ketone (100 ml); anhydrous K2CO3 (9.3 g) was added and the mixture was vigorously stirred under reflux for 5 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)=[O:16])=[CH:10][CH:9]=1
Reactant: C1=CCNCC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,2,3,6-tetrahydropyridine (82 mg) in tetrahydrofuran (2 ml) was added 4-fluorophenyl-isocyanate (0.112 ml) at ambient temperature. After stirring at ambient temperature for 10 hours, the solvent was removed by evaporation under reduced pressure, and the residue was triturated with diisopropyl ether to give 1-(4-fluorophenylcarbamoyl)-1,2,3,6-tetrahydropyridine (117 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]([O:35][C:36](=[O:56])[CH2:37][C@H:38]([NH:42][S:43]([C:46]1[C:51]([CH3:52])=[CH:50][C:49]([O:53][CH3:54])=[CH:48][C:47]=1[CH3:55])(=[O:45])=[O:44])[C:39](O)=[O:40])([CH3:34])([CH3:33])[CH3:32].[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60][NH2:61]>C(Cl)Cl>[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60][NH:61][C:39](=[O:40])[C@@H:38]([NH:42][S:43]([C:46]1[C:51]([CH3:52])=[CH:50][C:49]([O:53][CH3:54])=[CH:48][C:47]=1[CH3:55])(=[O:44])=[O:45])[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:56]
Reactant: COC(CN)OC
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NCC(OC)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Diisopropylethylamine (2.5 eq) followed by HOBT (1.0 eq) and EDCI (1.5 eq) was added to a solution of (S)-4-tert-butoxy-2-(4-methoxy-2,6-dimethylphenyl-sulfonamido)-4-oxobutyric acid (1.91 mmol, 1.0 eq) in DCM (10 ml/mmol) at 0° C. The resulting solution was stirred for 15 min at 25° C., cooled to 0° C. again and 2,2-dimethoxyethanamine (1.2 eq) was added. The reaction mixture was stirred for 16 h at 15° C. It was then diluted with DCM and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated to low volume under vacuum. The crude product was processed by column chromatography. Yield: 70%
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium methoxide in methanol (82.65 mL of a 1 M solution) is added slowly to a stirred solution of methyl 6-chloro-5-nitronicotinate (17 g) in anhydrous methanol (250 mL) and the mixture stirred for 8 hours. The mixture is concentrated, the residue treated with water and then extracted into ethyl acetate. The extracts are washed with water, treated with decolourising charcoal and dried (MgSO4). Concentration afforded methyl 6-methoxy-5-nitronicotinate (9.8 g) as an orange solid. Recrstallisation from cyclohexane afforded white needles, m.p. 118–9° C.
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:7]([C:9]1[S:13][C:12]([NH:14][C:22](=[O:23])[C:21]([OH:20])([CH3:26])[CH3:25])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)C(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Compound 136 (150 mg, 0.555 mmol) was dissolved in DMF (2.5 mL), and 2-hydroxy-2-methylpropanoic acid (116 mg, 1.11 mmol), EDC hydrochloride (313 mg, 1.11 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.11 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 137 (158 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[NH:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[NH:12][C:13]1[CH:18]=[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccc(Cl)cc21
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCOc2ccc(Cl)cc21
Yield: 15.4 %

Procedure:
A solution of 6-chloro-N-(5-fluoro-2-(methylsulfonyl)phenyl)chroman-4-amine (143.0 mg, 0.4 mmol), piperazine (694.0 mg, 8.00 mmol) and N,N-diisopropylethylamine (0.52 mL, 4.00 mmol) in acetonitrile (5 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo. The crude product was purified by silica chromatography (5% methanol in dichloromethane) to yield 26.0 mg (15% yield) of desired product. 1H NMR (400 MHz, CD3OD): δ 7.64 (d, 1H) 7.25 (d, 1H), 7.15 (dd, 1H), 6.81 (d, 1H), 6.45 (d, 1H), 6.35 (dd, 1H), 6.20 (d, 1H), 4.65 (m, 1H), 4.26 (m, 2H), 3.31 (m, 4H), 3.03 (m, 4H), 2.98 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30](Cl)=[O:31].O>C(#N)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30]([NH:20][C:12]1([C:10]([O:9][CH3:8])=[O:11])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:31]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: COC(=O)C1(N)CCN(OC)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To 5.4 g of potassium carbonate and 2 g of 4-Amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride in 10 ml of acetonitrile, 1.94 g of (2,5-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile are added at a temperature of 0-5° C. After stirring for 22 h at room temperature the reaction mixture is poored on cold water and extracted with ethyl-acetate. The organic phase is dried over sodium sulfate, filtered and evaporated to yield 2.13 g of methyl 4-[2-(2,5-dimethyl-phenyl)acetylamino]-1-methoxy-piperidine-4-carboxylate as beige cristalline solid. 1H-NMR (CDCl3): □ 1.95-2.30 (br signals, total 4H), 2.27 (s, 3H), 2.33 (s, 3H), 2.77-3.23 (br signals, total 4H), 3.48 (s, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 5.40 (br s, 1H), 7.02 (s, 1H), 7.04 (d, 1H), 7.11 (d, 1H).