Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[CH:11]([N-]C(C)C)(C)C.[Li+].IC.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:11][CH:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1
Reactant: O=C1CCCc2sccc21
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCc2sccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 6,7-dihydro-1-benzothiophen-4(5H)-one (1.63 g) in tetrahydrofuran (90 ml) at −78° C. under N2 was added lithium diisopropyl amide (5.89 ml, 2 M). After 30 min, iodomethane (0.732 ml) was added and the reaction was allowed to warm to ambient temperature. After 2 h, the reaction mixture was poured into saturated sodium bicarbonate (100 ml), extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated. MPLC was run on a biotage 40M column with 4-6% ethyl acetate/heptane to provide the title compound as an oil (560 mg, 32%): 1H NMR (300 MHz, CDCl3) δ) 7.41, 7.08, 3.15-2.99, 2.61-2.53, 2.33-2.25, 2.06-1.92, 1.28; HRMS (FAB) calcd for C9H10OS+H 167.0531, found 167.0527.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[C:5]=1[F:11]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cccc(N)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N=Cc2cccc(Br)c2)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-2-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-2-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. A mixture solution of 3-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+]336.0 & 338.0.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:14])[CH2:5][C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[S:8][C:7]=1[Cl:13].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][NH:3][CH:4]([CH3:14])[CH2:5][C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[S:8][C:7]=1[Cl:13]
Reactant: CON=C(C)Cc1c(Cl)sc(Cl)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CONC(C)Cc1c(Cl)sc(Cl)c1Cl
Temperature: 15 °C
Reaction time: 7 h

Procedure:
In a sulfonation flask 299 mg (1.1 mmol) 1-(2,4,5-trichlorothiophene-3-yl)propan-2-one O-methyl oxime were dissolved in 3.5 ml acetic acid and the resulting mixture was cooled to a temperature of 15° C. Then 138 mg (2.2 mmol) sodiumcyanoborohydride was added and the reaction mixture was stirred for 7 hours at ambient temperature. The mixture was then carefully diluted with 20 ml of water and the pH was adjusted to ca.10 by slowly adding 16 ml of 4N sodiumhydroxide solution. The mixture was extracted 3 times with ethylacetate and the combined organic phase was washed 2 times with water. After drying and evaporation of the solvent, the residue was purified by column chromatography (eluent: ethylacetate/heptane 1:9). Yield: 304 mg (100% of theory) of a colourless liquid (NMR-data see table 9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]([O:12]CC)=O.Cl.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(O)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:10](=[O:12])[CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:25]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Temperature: 135 °C
Reaction time: 3 h

Procedure:
Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.5 g, 12 mmol) and 2-fluorophenyl hydrazine hydrochloride (1.5 g, 12 mmol, 1.0 equiv) were dissolved in acetic acid (24 mL) and placed into a preheated oil bath at 120° C. for 3 hours and then heated for an additional 2 hours at 135° C. The mixture was cooled to ambient temperature, concentrated in vacuo and then concentrated once from toluene (1×25 mL). The residue was suspended in dichloromethane, filtered and the solid was washed once with dichloromethane and dried in vacuo, providing the titled compound. The resulting filtrate was concentrated in vacuo and purified by silica gel gradient chromatography (100:0 to 65:35; hexanes:ethyl acetate), providing additional titled compound as a light brown solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31]([C:30]1[CH:29]=[N:28][C:27]([Cl:26])=[CH:35][CH:34]=1)=[O:32])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-N,N-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxamide (intermediate C, 200 mg, 0.562 mmol), 6-chloronicotinoyl chloride (109 mg, 0.618 mmol), triethylamine (0.157 mL, 1.13 mmol) and methylene chloride (30 mL) was stirred at room temperature. The crude material was purified by flash chromatography (10% ethyl acetate in hexanes ramped to 70% ethyl acetate in hexanes) to give 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.C([O-])(=[S:28])C.[K+].O>CC(N(C)C)=O>[SH:28][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC([O-])=S
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCI)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCS)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.6 g (0.015 mol) of 1-[4-(3-Iodopropylamino)phenyl]-2-dimethylamino-2-benzyl-propan-1-one are dissolved in 50 ml of dimethylacetamide. To the solution are added 2.42 g of potassium thioacetate and heated up to 50° C. After the reaction mixture is stirred at 50° C. for 2 h, it is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is dissolved in 70 ml of ethanol and the solution is bubbled by nitrogen for 30 min. to remove oxygen. To the solution are added 7 ml of 2 N sodium hydroxide solution and stirred at 0° C. for 30 min. After the reaction mixture is neutralized by adding 2 N hydrochloric acid solution, the resulting solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:2) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 1.14 (s, 3H), 1.43 (t, 1H), 1.97 (m, 2H), 2.33 (s, 6H), 2.68 (q, 2H), 2.96 (d, 1H), 3.34-3.39 (m, 2H), 3.42 (d, 1H), 4.18 (br, 1H), 6.57 (d, 2H), 6.89-6.92 (m, 2H), 7.10-7.12 (m, 3H), 8.46 (d, 2H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[N:27]=[C:26]([NH:28]N)[CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>CCO>[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:24][CH:23]=1
Reactant: NNc1cccc(Cl)n1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccncc2)ccc1=O
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1ccn(-c2ccncc2)nc1-c1ccnn1-c1cccc(Cl)n1
Yield: 11.6 %

Procedure:
A solution of 3-((E)-3-dimethylamino-acryloyl)-1-pyridin-4-yl-1H-pyridazin-4-one (A-1; 0.075 g; 0.3 mmol) in EtOH (2 ml) was treated with (6-chloropyridin-2-yl)-hydrazine (0.048 g; 0.3 mmol) in a sealed tube and irradiated at 100° C. for 30 min. Acetic acid (0.5 ml) was added and the mixture again irradiated at 100° C. for 15 min. The solvent of the reaction mixture was removed and the crude product purified by preparative HPLC yielding 0.0122 g (12%) of the final product. MS: M=351.1 (M+H)−
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH2:18][S:19][CH2:20][C:21]=2[C:22]([O:24]C)=O)=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:24])[C:21]3[CH2:20][S:19][CH2:18][C:17]=3[NH:16][C:14]2=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)NC2=C(C(=O)OC)CSC2)ccc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-{3-[4-(methoxycarbonyl)-2,5-dihydro-thien-3-yl]ureido}-benzoate with sodium ethylate in ethanol there is obtained ethyl 2-chloro-5-{1,2,5,7-tetrahydro-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 194°-196° C.,
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:12].[C:13]([O:16][CH2:17][CH2:18]Br)(=[O:15])[CH3:14]>>[NH2:12][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][N:8]([CH2:18][CH2:17][O:16][C:13](=[O:15])[CH3:14])[CH2:7][C:6]=2[CH:1]=1
Reactant: CC(=O)OCCBr
Reactant: Nc1ccc2c(c1)CNCCS2
Product: CC(=O)OCCN1CCSc2ccc(N)cc2C1
Yield: 85.1 %

Procedure:
Following the procedure of 521a, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.28 g, 0.0015 mol) and 2-bromoethyl acetate (0.40 g, 0.0023 mol) were reacted to give acetic acid 2-(2-amino-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl)-ethyl ester (0.34 g, 83%) as an oil. LC/MS (ESI+): 266 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:11]2[N:12]=[CH:13][N:14]=[C:15]([OH:16])[C:10]2=[N:9]1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)=[C:11]2[N:12]=[CH:13][N:14]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:15](=[O:16])[C:10]2=[N:9]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ncnc2c(-c3ccc(C(F)(F)F)cc3)n(-c3ccccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(C(F)(F)F)cc3)c2ncn1CC(F)(F)F
Reaction time: 8 h

Procedure:
To a stirred mixture of 2-(2-chlorophenyl)-3-(4-(trifluoromethyl)phenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-2A-2b: 100 mg, 0.26 mmol) and Cs2CO3 (85 mg, 0.26 mmol) in DMF (1.5 ml) was added a DMSO solution (0.1 ml) of 2,2,2-trifluoroethyl trifluoromethanesulfonate (60 mg, 0.26 mmol). After stirring overnight, the reaction mixture was extracted from water with ethyl acetate. The organic solution was washed with half saturated aqueous NaCl and then concentrated in vacuo. The crude residue was purified on a Biotage™ Flash 12S column using 20% ethyl acetate in hexanes as eluant to give the title compound 2A-2 (65 mg, 53%) as a solid: +ES MS (M+1) 473.4; 1H NMR (CD3OD) δ 8.17 (s, 1H), 7.73-7.52 (m, 8H), 4.83 (q, J=9.1 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[CH:11]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](CC4C=CC=CC=4)[CH2:15][CH2:14]3)[O:10][CH2:9][CH2:8][C:7]=2[CH:26]=1.CO>[Pd].O>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[CH:11]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:10][CH2:9][CH2:8][C:7]=2[CH:26]=1
Reactant: COc1cc2c(cc1OC)C(CN1CCN(Cc3ccccc3)CC1)OCC2
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)C(CN1CCNCC1)OCC2

Procedure:
A mixture of 53 g of 1-[(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]-4-(phenylmethyl)piperazine, 150 ml of methanol, 150 ml of water and 5 g of 5% Pd on activated charcoal was acidified with 36% hydrochloric acid and hydrogenated at 50 psi until absorption of hydrogen was finished. The catalyst was filtered and the solvent evaporated, after which the residue was basified with sodium hydroxide and extracted with dichloromethane. The dichloromethane phase was washed, dried and evaporated and the product precipitated under diisopropyl ether to obtain 1-[(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:37]=[CH:36][C:13]([CH2:14][N:15]([C:23]3[CH:35]=[CH:34][C:26]4[O:27]C(C)(C)[O:29][C:30](=[O:31])[C:25]=4[CH:24]=3)[C:16]([C:18]3[O:22][N:21]=[CH:20][CH:19]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:16]([C:18]3[O:22][N:21]=[CH:20][CH:19]=3)=[O:17])[C:23]3[CH:35]=[CH:34][C:26]([OH:27])=[C:25]([CH:24]=3)[C:30]([OH:31])=[O:29])=[CH:36][CH:37]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)c3ccno3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)C(=O)c2ccno2)ccc1O

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-chlorophenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)isoxazole-5-carboxamide and NaOH as a yellow solid (55%). M− (ESI): 470.7; M+ (ESI): 472.6. HPLC, Rt: 4.56 min (Purity: 71.3%).
Reaction SMILES: [CH3:1][C@:2]12[O:7][C@H:6]1[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3]2.[OH-].[NH4+:19]>O1CCOCC1>[NH2:19][C@@H:6]1[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][C@:2]1([OH:7])[CH3:1]
Reactant: C[C@@]12CN(C(=O)OCc3ccccc3)C[C@@H]1O2
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@]1(O)CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 100 °C

Procedure:
A mixture of (1R,5S)-benzyl 1-methyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.50 g, 19.29 mmol) and concentrated ammonium hydroxide (16 mL, 411 mmol) in dioxane (8 mL) in a sealed vessel was heated to 100° C. for 15 h. The resulting mixture was concentrated to afford (3R,4R)-benzyl 4-amino-3-hydroxy-3-methylpyrrolidine-1-carboxylate along with its regioisomer (4.8 g, 85:15 ratio), which was used in the next step without purification. MS (ES+) m/z: 218.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[F:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1c([N+](=O)[O-])cc(C#N)c(F)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])c(O)c(O)c1F
Reaction time: 1.5 h

Procedure:
550 mg of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile are dissolved in 30 ml of methylene chloride, whereupon the solution is treated with 0.44 ml of boron tribromide. After stirring at 23° for 6 hours an additional 0.1 ml of boron tribromide are added thereto, whereupon the mixture is stirred at 23° for an additional 1.5 hours. Thereupon, 3 ml of ethanol are added thereto at -15°. The reaction mixture is evaporated and the residue is dried in a high vacuum at 23°. By recrystallization from ether/hexane there is obtained 2-fluoro-3,4-dihydroxy-5-nitrobenzonitrile of m.p. 154°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:22][O:23][CH2:24][C@H:25]1[CH2:29][O:28]C(C)(C)[O:26]1)=[O:21].C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:22][O:23][CH2:24][C@H:25]([OH:26])[CH2:29][OH:28])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOC[C@H]2COC(C)(C)O2)c(=O)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOC[C@H](O)CO)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(R)-6-(2-chloro-4-iodophenylamino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 26, 140 mg, 0.24 mmol, 1 eq) was dissolved in 3 ml of MeOH and 3 ml of THF then p-toluenesulfonic acid (24 mg, 0.5 eq) was added. After stirring at RT for 6 hours the reaction was complete. Evaporation in vacuo, followed by HPLC purification gave the title compound as a white solid. (31 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.89 (s, 3 H) 3.21 (s, 3 H) 3.28-3.40 (m, 2 H) 3.65-3.74 (m, 2 H) 3.93 (dd, J=14.15, 6.82 Hz, 1 H) 4.61 (t, J=5.68 Hz, 1 H) 4.99 (d, J=4.04 Hz, 1 H) 7.14 (d, J=8.34 Hz, 1 H) 7.70 (dd, J=8.34, 1.77 Hz, 1 H) 7.98 (d, J=1.77 Hz, 1 H) 12.03 (s, 1 H) 12.50 (s, 1 H) [M+H] calc'd for C16H18ClIN4O6, 525; found, 525.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[NH2:18])=[O:6])C.[C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:20]>>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:19]1[NH:20][C:5](=[O:6])[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][S:9][C:8]=2[N:18]=1)[CH3:26]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: CCOC(=O)CC#N
Agent: Cl
Product: CCOC(=O)Cc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Reaction time: 18 h

Procedure:
Hydrogen chloride gas was bubbled through a stirred reaction mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (4.94 g, 0.02 mol) in ethyl cyanoacetate (50 ml) for 2 hours. A thick suspension formed initially which slowly dissolved on gentle warming. The mixture was allowed to stand at ambient temperature for 18 hours. Excess hydrogen chloride was removed by bubbling nitrogen through the reaction mixture and most of the excess ethyl cyanoacetate was distilled out at reduced pressure. The solid residue was recrystallised from ethanol to give (4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester (3.64 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12]>>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH3:12])=[O:5]
Reactant: O=C(O)c1ccncc1F
Reactant: CCO
Product: CCOC(=O)c1ccncc1F

Procedure:
3-fluoro-isonicotinic acid and ethyl alcohol were processed according to the method of Example 128A to provide the product. MS (ESI+) m/z 170 (M+H)+;
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:20]=[O:21])=[CH:16][NH:17]3)=[CH:13][CH:12]=2)=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[OH:21][CH2:20][C:15]1[C:14]2[C:18](=[CH:19][C:11]([C:9]([N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[O:10])=[CH:12][CH:13]=2)[NH:17][CH:16]=1
Reactant: O=Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc2c(CO)c[nH]c2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (2.2 g, 58.34 mmol) was added at 0° C. portion wise to a suspension of 6-(morpholine-4-carbonyl)-1H-indole-3-carbaldehyde (5 g, 19.44 mmol) in methanol (106 mL) and the mixture was stirred at room temperature for 3 h. The methanol was removed under vacuum whereby the temperature was kept below <35° C. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Washing of the remnant with ether provided the product as white solid. Yield: 4 g (79% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20].N1CCCCC1>C(O)C>[NH2:22][C:21]1[O:1][C:2]2=[C:3]3[C:8](=[CH:9][CH:10]=[C:11]2[CH:17]([C:16]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:18]=1[C:19]#[N:20])[CH:7]=[N:6][CH:5]=[CH:4]3
Reactant: COc1ccc(C=C(C#N)C#N)cc1OC
Reactant: Oc1cccc2cnccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2ccc2cnccc32)cc1OC
Temperature: 25 °C

Procedure:
To a stirred suspension of 5-hydroxyisoquinoline (2.90 g) and 3,4-dimethoxy benzylidenemalononitrile (4.28 g) in ethanol (11 ml) was added dropwise piperidine (1.70 g). The suspension was then heated at reflux temperature for one hour forming a red solution. This was then allowed to cool to room temperature, depositing a brown solid. This was filtered off and washed with ethanol and ether and dried in vacuo at 60° C., yielding 2-amino-4-(3,4-dimethoxyphenyl)- 4H-pyrano[2,3-f] isoquinoline-3-carbonitrile as a yellow-brown solid, m.p. 225°-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:18]Br>ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[Br:18]
Reactant: BrBr
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(N)c(Br)c3)sc2c1
Yield: 85.2 %

Procedure:
2-(4'-Aminophenyl)-6-methylbenzothiazole (0.6 g, 2.5 mmol) was treated with bromine (0.403 g, 2.5 mmol) in dichloromethane according to the above-described general procedure for bromination. Crude product was purified by flash chromatography on silica gel, using ethyl acetate-hexane (1:3) as eluent, to give brown small crystals (0.68 g, 85.3%), m.p. 187.9-189.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenol (31.5 g, 160 mmol) in DMSO (200 ml) was added K2CO3 (46.5 g, 337 mmol) at room temperature under nitrogen. After 5 minutes stirring, 4-fluorobenzonitrile (19.4 g, 160 mmol) was added to the mixture in one portion and the resulting mixture was stirred at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into ice-cold 1N aqueous NaOH solution with vigorous stirring. The precipitated solid was collected by filtration and under vacuum to afford 50 g of the title compound.