Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:27][C:28]1[C:29]([C:35]([NH2:37])=[O:36])=[N:30][CH:31]=[CH:32][C:33]=1Cl>CS(C)=O.O>[Cl:27][C:28]1[C:29]([C:35]([NH2:37])=[O:36])=[N:30][CH:31]=[CH:32][C:33]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a mixture of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (356 mg, 1.1 mmol) in DMSO (4 mL) in a microwave vial was added NaH (88 mg, 2.2 mmol, 60% dispersed in mineral oil) at rt. The reaction was stirred at rt for 30 minutes, then 3,4-dichloropicolinamide (191 mg, 1.0 mmol) was added. The mixture was microwaved at 160° C. for 2 hours, then cooled to rt, and diluted with water (10 mL). The resulted mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (140 mg, 29%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@@H:23]1OS(=O)(=O)[N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1>CN(C=O)C>[C:33]([O:32][C:30]([NH:25][CH2:24][C@H:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A stirred suspension of 60% NaH (371 mg, 9.3 mmol) in DMF (10 mL) is cooled in an ice bath, and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 2.6 g, 10.1 mmol) in DMF (10 mL) is added. The mixture is stirred for 20 min, then a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.0 g, 8.4 mmol) in DMF (10 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and then warmed to room temperature and stirred for 48 h. The reaction is poured into ice water and the resultant solid is removed by filtration. The filtrate is acidified to pH 3 with 1N aqueous HCl and extracted with EtOAc. The combined extracts are washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (2.7 g, crude) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:49])[CH2:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:49])[CH2:35][O:36][C:37](=[O:48])[C:38]4[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[CH:39]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: COc1cc(OC)cc(C(=O)OC[C@H](C)NC(C)C)c1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3cc(OC)cc(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and 3,5-dimethoxy-benzoic acid (S)2-isopropylamino-propyl ester as described for example 1.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][N:26]=1>O1CCCC1>[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:25]2[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH2:31])=[CH:27][N:26]=2)=[CH:18][CH:17]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add potassium tert-butoxide (4.28 g, 36.2 mmol) to a stirred solution of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (6.40 g, 27.0 mmol) and anhydrous tetrahydrofuran (120 mL). Stir for 30 minutes under nitrogen at room temperature. Add 6-chloronicotinamide (4.27 g, 27.2 mmol) and beat to reflux for 18 h under nitrogen. Cool to room temperature pour the reaction mixture into 150 mL), and extract with diethyl ether (3×150 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 4.46 g (46%) of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester: mass spectrum (ion spray): m/z=358.1 (M+1); 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (dd, 1H), 8.02 (br s, 1H), 7.46 (br s, 1H), 7.23 (d, 2H), 7.06-7.02 (m, 3H), 6.92-6.89 (m, 1H), 3.17-3.12 (m, 2H), 2.69 (t, 2H), 1.35 (s, 9H).
Reaction SMILES: [BrH:1].N[C:3]1[C:11]2[C:10](=[O:12])[N:9]3[CH2:13][CH2:14][S:15][C:8]3=[N:7][C:6]=2[N:5]([CH3:16])[N:4]=1.N([O-])=O.[Na+]>O>[Br:1][C:3]1[C:11]2[C:10](=[O:12])[N:9]3[CH2:13][CH2:14][S:15][C:8]3=[N:7][C:6]=2[N:5]([CH3:16])[N:4]=1
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(Br)c2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
In a mixture of 52 ml of an aqueous solution of hydrogen bromide and 36 ml of water was dissolved 4.00 g (17.9 mmol) of Compound 13 prepared in Example 10, and 1.24 g (17.9 mmol) of sodium nitrite was added to the solution under ice-cooling, followed by stirring for 30 minutes. Then, a solution of 3.08 g (21.5 mmol) of cuprous bromide in 36 ml of an aqueous solution of hydrogen bromide was added thereto and the temperature of the mixture was raised slowly to room temperature, followed by stirring for one hour. The precipitated crystals were collected by filtration and washed with water. The crystals were then subjected to silica gel column chromatography and eluted with chloroform to give 3.51 g (68%) of Compound 25. The compound was recrystallized from chloroform/ethanol for purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:16]([O:17]COCC[Si](CC)(CC)CC)=[CH:15][CH:14]=[CH:13][N:12]=2)[OH:10])=[CH:5][CH:4]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[OH:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2ncccc2OCOCC[Si](CC)(CC)CC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C(O)c2ncccc2O)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a solution of 4-ethylphenyl-[3-[2-(triethylsilyl)ethoxymethoxy]]pyridin-2-yl-methanol (2.35 g, 6.54 mmol) in THF-water (25:1; 60 mL), p-toluenesulfonic acid monohydrate (2.8 g, 16.4 mmol) was added and stirred at room temperature for 20 hours and at 40° C. for 4 hours. After cooling the reaction mixture to room temperature, saturated sodium bicarbonate solution (100 mL) was added and the resulting mixture was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 4-ethylphenyl-3-hydroxypyridin-2-yl-methanol (0.62 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccncc1
Reactant: CCCCC#CCCCCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccc(C)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 4-picoline (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 4-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (87%). 1HNMR (300 MHz, CDCl3, ppm), 9.28 (d, 2H), 7.92 (d, 2H), 4.92 (t, 2H), 2.68 (s, 3H), 1.96-2.18 (m, 6H), 1.32-1.50 (br, 10H), 0.88 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:22][NH2:23]>>[CH2:13]([C:12]1[C:6]2[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8](=[O:9])[NH:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(Cc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(phenylacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([O:15][CH2:16][CH:17]([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH3:20]O>>[Cl:5][C:6]1[C:7]([O:15][CH2:16][CH:17]([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([O:13][CH3:20])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cnc(OCC(F)F)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc(OCC(F)F)c(Cl)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
Thionyl chloride (1.38 ml, 18.9 mmol) is added to a solution of 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (1.5 g, 6.31 mmol, Step-1) in methanol (100 ml) at 0° C. Then the reaction mixture is refluxed with stirring for 2 hours. After removing solvent to give 1.57 g (>99% yield) of the title compound as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[CH:10][C:9]=2[C:24]#[N:25])=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[C:24]([C:9]1[CH:10]=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)=[CH:3][CH:4]=1)#[N:25]
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(Br)cc2)cc1F
Reactant: OB(O)c1ccco1
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(-c3ccco3)cc2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 5 using 5-(4-bromophenyl)-4-cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide, 2-furanboronic acid instead of 3-thienylboronic acid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)/[CH:3]=O.[C:15]([O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(#N)C>[CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)/[CH:3]=[CH:22]/[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C/C(C=O)=C\c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CC(/C=C/C(=O)OC(C)(C)C)=C\c1ccc([N+](=O)[O-])cc1
Temperature: 65 °C
Yield: 53.2 %

Procedure:
(E)-2-Methyl-3-(4-nitrophenyl)prop-2-enal (3.0 g, 15.6 mmol), (tert-butoxycarbonyl methylene)triphenylphosphorane (8.85 g, 23.4 mmol) and dry acetonitrile (60 ml) were stirred and heated at 65° C. until reaction was complete (ca. 1 h, HPLC monitoring). The mixture was cooled, filtered to remove some insoluble by-product, and the filtrate concentrated in vacuo to ca. 15 ml volume. On cooling the product deposited, was collected by filtration and washed with cold acetonitrile to give a yellow solid (2.4 g), mp 120-122° C. The mother liquors were evaporated to dryness, the residue stirred in ether (20 ml) and the insoluble material removed by filtration. The filtrate was concentrated in vacuo and the residue crystallised from acetonitrile (5 ml) to give a second crop of product (1.3 g). Total yield=3.7 g (87%)
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:26])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:25])[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=O)[CH2:12][CH2:11]1.[NH2:33][C:34]1[CH:46]=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:36][CH:35]=1>>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:25])[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][NH:33][C:34]2[CH:46]=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:36][CH:35]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCNc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 82.7 %

Procedure:
The compound (130 mg, 0.297 mmol) obtained in Example 33b and tert-butyl 4-aminobenzoate (92 mg, 0.475 mmol) were used to give the title compound (151 mg; yield, 83%) as a white solid according to the method described in Example 18b.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[BH4-].[Na+]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:27][CH:28]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(C=O)cc4)nn23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(CO)cc4)nn23)c1
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of 4-(5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzaldehyde (450 mg, 1.15 mmol) in tetrahydrofuran was added sodium borohydride (22 mg, 0.57 mmol) at 24° C. After 3 hr, the reaction mixture filtered through Celite. The solvent was removed in vacuo to provided the crude product which was purified by preparative thin layer chromatography to afford the desired product (300 mg, 67% yield). LCMS (ESI) m/z: 395.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)[CH3:2].[NH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[OH:22])=[S:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCc1ccc(N=C=S)cc1
Solvent: CO
Product: CCc1ccc(NC(=S)Nc2cc([N+](=O)[O-])ccc2O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Ethylphenyl isothiocyanate (3.48 mmol, 1 eq) was added to 2-amino-4-nitrophenol (3.48 mmol, 1 eq) dissolved in 10 mL of methanol, and stirred at room temperature for 24 hours. The organic solvent was removed by evaporation under reduced pressure, and then the precipitate was filtered under reduced pressure with hexane to yield the title compound (a). Yellow-green powder (79%), mp 137-138° C.; 1H NMR (Acetone-d6 400 MHz) δ 9.475 (s, 1H), 9.351 (s, 1H), 8.755 (s, 1H), 7.968 (d, J=9.8 Hz, 1H), 7.464 (d, J=8.0 Hz, 2H), 7.282 (d, J=8.8 Hz, 2H), 7.089 (d, J=9.2 Hz, 1H), 2.658 (q, J=7.6 Hz, 2H), 1.225 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=3)=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(C(=O)O)cc1/C=C/c1csc2c(N)ncnc12
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1/C=C/c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
(E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid (30 mg, 0.096 mmol) was dissolved in DMF (1 mL), 3-(trifluoromethyl)benzeneamine (16 mg, 0.096 mmol), HATU (110 mg, 0.289 mmol) and TEA (67 μL, 0.48 mmol) was added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (36 mg, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCOCC1c1ccc(F)c(F)c1
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)COC2

Procedure:
3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Y(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Y(3)). LC-MS (M+H)+=282.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.08-7.20 (m, 3H) 4.67 (d, J=15.26 Hz, 1H) 4.46 (dd, J=15.56, 2.14 Hz, 1H) 3.98-4.10 (m, 2H) 3.67 (br. s., 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Cl:29])=[N:9][NH:10]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Cl)c2c1COC(C)=O)C(=O)OCC
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-bromo-1H-indazol-5-yl)methyl)succinate(400 mg, 0.879 mmol) was dissolved in N,N-dimethylformamide (5.0 ml). N-Chlorosuccinimide (130 mg, 0.974 mmol) was added to the solution. Mixture was warmed to 150° C. and held with stirring for 1.5 hours. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed twice with water and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 88% yield. MS (M+H)+=491.0.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH2:7]([NH2:10])[CH:8]=[CH2:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:7]([NH:10][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH:8]=[CH2:9]
Reactant: C=CCN
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CCNC(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-pentanone (1 g, 11.61 mmol) in anhydrous 1,2-dichloroethane (45 ml) is added allylamine (0.872 ml, 11.61 mmol) followed by NaBH(OAc)3 (3.44 g, 16.254 mmol) at ambient temperature and under nitrogen. The reaction is stirred at room temperature overnight. The reaction mixture is quenched with 1N NaOH and extracted with dichloromethane. The extract is dried over Na2SO4 and concentrated in vacuo to allyl-(1-ethyl-propyl)-amine
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:47]=[CH:46][C:17]([C:18]([O:20][CH2:21][N:22]2[C:31]3[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[CH:23]2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][N:22]2[C:31]3[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)=[CH:23]2)=[O:19])=[CH:46][CH:47]=1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)c3ccc(OCc4ccccc4)cc3)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)c3ccc(O)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
10% palladium/carbon (260 mg) was added to a THF (30 ml) and ethanol (15 ml) solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-benzyloxybenzoate (2.6 g, 4.6 mmol). The mixture was subjected to hydrogen substitution and stirred at room temperature for 3 hours. After completion of the reaction, the catalyst was removed by conducting filtration using Celite, and the mixture was concentrated to dryness under reduced pressure, giving a pale yellow powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-hydroxybenzoate (2.22 g, yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].[ClH:16]>O>[ClH:16].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:6][CH:7]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(CC(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-(4-aminophenyl)acetamide (19.5 g) in concentrated hydrochloric acid (43 ml) was added an ice cold solution of sodium nitrite (9.43 g) in water (25 ml) at such a rate that the temperature of the mixture remained between -5° and +5° C. When the addition was complete the solution was stirred at 0° C. for 15 min. This was then added to a stirred solution of stannous chloride (146.3 g) in concentrated hydrochloric acid (86 ml) at -10° C. The mixture was stirred for 30 min., poured into ice cold ethanol (750 ml) and the suspension was stirred for a further 30 min. Collection of the solid by filtration and washing with ethanol followed by ether gave the title compound as a white powder (20.6 g). This material was 62% pure but was contaminated with sodium chloride. It was used in the next stage without further purification.