Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](C)([C:14]([O-])=O)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.Cl>O>[CH3:14][CH:8]([C:9]([OH:11])=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
In a 200 ml round-botton flask is placed 15.03 g (~43.7 mmol) of ethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate, 62 ml of glacial acetic acid, and 22 ml of 6 N aqueous hydrochloric acid. The mixture is refluxed under nitrogen for 24 hours. On cooling to room temperature, the solution is diluted with 250 ml of water and the mixture is extracted with 4×50 ml of methylene chloride. The combined extracts are washed with 2×100 ml of water and then with 8×40 ml (0.2 N) of aqueous potassium hydroxide solution. Extracts 1-4 are combined, acidified to pH <1 with concentrated hydrochloric acid, and the resulting solution is extracted with 3×50 ml of methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in vacuo to give 7.13 g (38.8% overall) crude flurbiprofen. Extract 5 is backwashed with 3×15 ml methylene chloride, acidified with concentrated hydrochloric acid, and the resulting mixture is extracted with 3×20 ml methylene chloride to give 1.84 g (10.0%) crude flurbiprofen. Fractions 6-8 are combined and the pH is adjusted to ~9.0. After washing with 3×30 ml methylene chloride, the aqueous is acidified with concentrated hydrochloric acid and is then extracted with 3×50 ml of methylene chloride. Drying and concentration of the extracts gives 0.53 g (4.0%) crude flurbiprofen Ib.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9](OCC)=O)[C:4]([O:6]CC)=[O:5].[CH3:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1.[OH-].[K+]>C(O)C.O>[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:9][CH:3]([CH3:2])[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1.[C:4](=[O:6])=[O:5]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Cc1ccc(CBr)cc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CC(C)C(=O)O)cc1
Product: O=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a three-necked round-bottom 2000 ml flask equipped with a reflux condenser, a pressure-equalizing dropping funnel, and magnetic stirring bar, 18.9 g (0.82 mol) of sodium metal was dissolved in 450 ml of dry ethanol. To the resulting solution, 137 g (0.79 mol) of diethyl 2-methylmalonate was added dropwise within 15 minutes. This mixture was stirred for 15 minutes; then, 146 g (0.79 mol) of p-methylbenzyl bromide was added with vigorous stirring at a rate that allowed the reaction mixture to maintain a gentle reflux. Additionally, this mixture was refluxed for 4 hours, then cooled to room temperature. A solution of 151 g of potassium hydroxide in 500 ml of water was added. This mixture was refluxed for 2 hours to saponificate the ester formed. Ethanol and water were distilled off. To the residue, 500 ml of water, and then 12 M HCl (to pH 1) were added. Crude 2-(4-methylphenyl)-2-methylmalonic acid precipitated along with potassium chloride. This precipitate was filtered off and washed with 500 ml of CH2Cl2. The solution obtained was evaporated to dryness to give crude substituted methylmalonic acid. This acid was decarboxylated by heating for 2 hours at 180° C. to form crude 3-(4-methylphenyl)-2-methylpropionic acid (and CO2 as a byproduct). The crude 3-(2-bromophenyl)-2-methylpropionic acid was used without further purification. A mixture of this acid and 200 ml of SOCl2 was refluxed for 3 hours. Then, thionyl chloride was distilled off in vacuum. Fractional distillation gave the title product, b.p. 93-95° C./1 mm Hg. Yield, 181 g (72%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>CC(O)C>[CH3:18][NH:17][S:14]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])=[C:2]([NH:1][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:3]=1)(=[O:15])=[O:16]
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(N)c1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of 3-amino-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (3.0 g, 10.7 mmol) in i-PrOH (100 mL) was treated with 4-chloro-6-(methyloxy)-7-[(phenylmethyl)oxy]quinazoline (3.2 g, 10.7 mmol, prepared according to J. Med. Chem. (1999) 42 5369) and stirred at 80° C. for 2 hours before being concentrated. The residue was washed with petroleum ether and dried to give N-methyl-3-({6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}amino)-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (4.2 g, 72%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (br. s., 1 H), 8.75 (s, 1 H), 8.20 (s, 1 H), 7.80-7.84 (m, 2 H), 7.49-7.57 (m, 4 H), 7.35-7.49 (m, 4 H), 5.34 (s, 2 H), 4.91 (q, J=8.82 Hz, 2 H), 3.99 (s, 3 H), 2.45 (d, J=5.07 Hz, 3 H). MS (m/z) 549.1 (M+H+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[N:7]1([C:11]([C:13]2[N:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[C:22]([CH:33]=[C:34]([O:36][CH:37]4[CH2:41][CH2:40][O:39]C4=O)[CH:35]=3)[C:23]([NH:25][C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[O:24])=[CH:15][CH:14]=2)=[O:12])[CH2:10][CH2:9][CH2:8]1.[CH2:43](O)[CH3:44]>>[N:7]1([C:11]([C:13]2[N:18]=[CH:17][C:16]([O:19][C:20]3[CH:35]=[C:34]([CH:33]=[C:22]([C:23](=[O:24])[NH:25][C:26]4[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=4)[CH:21]=3)[O:36][CH:37]([CH2:41][CH2:40][OH:39])[C:1]([O:2][CH2:43][CH3:44])=[O:4])=[CH:15][CH:14]=2)=[O:12])[CH2:8][CH2:9][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCOC3=O)c2)cn1
Reactant: CCO
Agent: [K+]
Product: CCOC(=O)C(CCO)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (113 mg, 0.82 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-N-(5-methylpyrazin-2-yl)-5-(2-oxooxolan-3-yl)oxy-benzamide (Intermediate 29) (800 mg, 1.6 mmol) in ethanol (80 mL) at 0° C. under nitrogen. The reaction was allowed to warm to RT and stirred for 4 hours. The reaction mixture was filtered through silica, washing well with ethyl acetate, and concentrated to afford crude product which was used directly in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.N1C=CC=CC=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:15][C:12]1[CH:11]=[CH:10][C:9]2[C:3]3[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=3[NH:1][C:23](=[O:25])[C:14]=2[CH:13]=1
Reactant: Cc1nn(C)c(N)c1-c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nn(C)c2[nH]c(=O)c3cc(F)ccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 146 %

Procedure:
A solution of 5-amino-4-(4-fluorophenyl)-1,3-dimethylpyrazole (20.0 g) and pyridine (23.6 mL) in dichloromethane (150 mL) was added dropwise over 30 min to a solution of triphosgene (11.6 g) in dichloromethane (100 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction solution was added dropwise to a solution of aluminum chloride (97.5 g) in dichloromethane under ice-cooling, and the mixture was stirred at room temperature for 2 days. After the completion of the reaction, the reaction solution was poured into ice-water. The precipitated crystals were collected by filtration and washed with water to give 7-fluoro-1,3-dimethyl-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one (13.2 g).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:19])[N:11]([CH3:18])[C:12](=[O:17])[N:13]([CH3:16])[C:14]=1[CH3:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=O)[CH3:29].CC1[O:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>[Cl-].[Zn+2].[Cl-]>[CH3:36][C:35]1[O:38][C:29]([CH:28]2[NH:27][C:22]3[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]3[C:15]2=[C:14]2[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH3:18])[C:10](=[O:19])[C:9]2=[C:1]3[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CC(=O)Nc1ccccc1N
Reactant: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1ccc(C2Nc3ccccc3-n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1

Procedure:
Synthesis of PPQ-102—Synthesis of PPQ-102 was achieved in six steps as illustrated in FIG. 2B. Commercially available 6-methyluracil 1 was methylated using dimethylsulfate to produce 1,3,6-trimethyluracil 2, which upon Friedel-Crafts acylation using zinc chloride as a catalyst yielded 5-benzoyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione 3 as a white powder. Bromination of 3 followed by reaction with N-(2-aminophenyl)acetamide generated amino-protected intermediate 5. The acetamido function of 5 was hydrolyzed and resultant intermediate 6 was cyclocondensed with 5-methylfurfural to yield yellowish-white racemic PPQ-102 7. Aromatic compound 8, which lacks a stereocenter, was prepared from 7 by oxidation with potassium permanganate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(CCCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Yield: 63.7 %

Procedure:
A mixture of 7-methyl-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.24 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-methyl-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2,3-dihydro-isoindol-1-one (0.063 g, 64%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.24-2.77 (m, 18H), 4.15 (s, 2H), 4.72 (s, 2H), 7.08 (d, 1H), 7.28 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)NCc1cncnc1-2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2Cc3cncnc3-c3ccc(Cl)cc3C2c2ccccc2Cl)cc1

Procedure:
A solution of 14.5 g (42 mmole) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepine, 14.5 g (76 mmols) of p-toluene-sulfonyl chloride, 30 ml of pyridine and 0.3 g of 4-dimethylaminopyridine in 300 ml of methylene chloride was stirred at room temperature for 24 hr. The mixture was washed with an excess of dilute ice cold hydrochloric acid and dilute aqueous sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methylene chloride and ether to give the product as a white solid, mp 200°-201° C. Recrystallization from a mixture of ether and methylene chloride gave the pure product as colorless prisms, mp 200°-201° C.
Reaction SMILES: [Na].[CH2:2]([SH:6])[CH2:3][CH2:4][CH3:5].Cl[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C([OH:15])C>>[CH2:2]([S:6][CH:9]1[CH2:10][CH2:11][CH2:12][C:8]1=[O:15])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCS
Reactant: ClC1CCCC1
Reactant: CCO
Agent: [Na]
Product: CCCCSC1CCCC1=O
Reaction time: 8 h

Procedure:
Absolute ethanol (600 ml) was added with metal sodium (13.8 g) and butylmercaptan (64.8 g). A solution of 2-chlorocyclopentane (71.1 g) in absolute ethanol (600 ml) was added to the mixture and then was allowed to stand overnight at a low temperature. The ethanol was removed from the mixture, and the residue was dissolved in ether. The resulting solution was neutralized with aqueous acetic acid solution, the solvent was evaporated, and the resultant was then subjected to distillation, thereby giving 2-buthylthiocyclopentanone (90 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]#[CH:16])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])[CH3:3].I[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.C(NCC)C.C(OCC)(=O)C>C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]#[C:15][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][CH3:13])=[O:11])=[CH:19][CH:20]=1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@H](CC#Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
A solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 1.020 g, 4.49 mmol), prepared by an analogous procedure to the one described hereinabove, 4-Iodo-bromobenzene (1.524 g, 5.38 mmol), diethylamine (2.28 ml, 1.62 g, 22.12 mmol), CuI (84 mg, 0.441 mmol) and Pd(PPh3)2Cl2 (156 mg, 0.22 mmol) in diethyl ether (10 ml) was stirred at room temperature for 24 h. Ethyl acetate was added and the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified via flash chromatography using a gradient of cyclohexanes and ethyl acetate (98:2 to 80:20) to afford the title compound (1.199 g, 69%). MS: (ES/+) m/z: 404, 406 [MH+], C17H20BrNO4 requires 404. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.56 (d, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 4.30 (m, 1H), 3.67 (s, 3H), 2.82 (m, 2H), 1.40 and 1.38 (2xs, 9H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O.[CH:32]1C=CC2N(O)N=NC=2[CH:37]=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:24]([C:23]2[C:22]3[C:30](=[CH:31][CH:32]=[CH:37][CH:21]=3)[CH:29]=[CH:28][CH:27]=2)=[O:26])[CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 2(S)-benzyl-1-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethylbenzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol), EDC.HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil. 1HNMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m).
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1.[C:12]1([C:18]#[C:19][C:20](O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Na+]>C(O)CO>[Br:3][C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:20](/[CH:19]=[C:18](/[Cl:1])\[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:6]=2[CH:5]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: Cl
Reactant: O=C(O)C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cl/C(=C/c1nc2cc(Br)ccc2[nH]1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-benzene-1,2-diamine dihydrochloride (1.3 g, 5 mmol), phenylpropiolic acid (0.73 g, 5 mmol) in 4 mL of ethylene glycol was heated to reflux for 5 h. The mixture was cooled to rt and poured into water. The mixture was neutralized with 2N sodium hydroxide and filtered. The solid was suspended in water and extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield a red oil. The residue was purified using preative TLC plates twice (silica gel, 20×20 cm, 2000 microns, EtOAc:hexanes 3:7 and silica gel, 20×20 cm, 2000 microns, EtOAc:dichloromethane 3:97) to provide a mixture of cis and trans isomers of the title Compound 30a (0.345 g). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.59 (m, 1H), 7.86-7.78 (m, 3H), 7.64-7.56 (m, 1H), 7.54-7.49 (m, 3H), 7.46 (s, 1H), 7.40-7.34 (m, 1H). Mass Spectrum (LCMS, APCl pos.) Calcd. For C15H10BrClN2:333.0 (M+H), Found 333.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:21])[F:22])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
562 mg (4 mmol) of 2-(4-fluoro-phenyl) ethyl amine were added to 733 mg (4 mmol) of 4-trifluoromethyl benzaldehyde dissolved in 40 ml methanol. The reaction mixture was stirred at rt over night under nitrogen. 151 mg (4 mmol) of sodium borohydride were added in portions and the reaction mixture was stirred for 2 h at rt. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with water and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (60 g silica gel; DCM/methanol 19:1) to yield 1.16 g (98%) of [2-(4-fluoro-phenyl)-ethyl]-(4-trifluoromethyl-benzyl)-amine as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.65 (d, 2H), 7.52 (d, 2H), 7.21 (dd, 2H), 7.06 (dd, 2H), 3.79 (s, 2H), 2.70 (s, 4H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[S:10][C:9]([C:11](=[NH:13])[NH2:12])=[N:8][CH:7]=1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[NH:12][C:11]([C:9]2[S:10][C:6]([F:5])=[CH:7][N:8]=2)=[N:13]1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ncc(F)s1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Yield: 81.1 %

Procedure:
5-fluorothiazole-2-carboximidamide acetate (0.25 g, 1.22 mmol) was reacted with 2,4-dichlorobenzaldehyde (0.21 g, 1.22 mmol) and ethyl 3-oxobutanoate (0.16 g, 1.22 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (0.41 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[S:4][C:3]=1[S:15]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=1)(=[O:17])=[O:16].C(Cl)(Cl)Cl>C(O)(=O)C.[Fe]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:2]([Br:1])=[C:3]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=3)(=[O:16])=[O:17])[S:4][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(cc([N+](=O)[O-])c[n+]3[O-])c2Br)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
3-Bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-5-nitro-thieno[2,3-b]pyridin-N-oxide (1.0 g, 2.18 mmol) was suspended in acetic acid (12 ml) and Fe powder was added (0.73 g, 13 mmol). The reaction mixture was stirred at 60-70° C. for 60 minutes. Chloroform (45 ml) was added and after filtration through celite the filtrate was evaporated, the crude residue was treated with methanol (3 ml). The product was filtered, washed with methanol. It was obtained (0.69 g, 76.7%) as a yellow powder. LC-MS: (M+H)+ 413.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C[CH2:19][N:20](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN>C1COCC1.C(Cl)CCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([NH:20][CH3:19])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(CCC(=O)O)cc1OCC
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOc1ccc(CCC(=O)NC)cc1OCC
Temperature: 70 °C

Procedure:
To a solution of 0.72 g of 3-(3,4-diethoxy-phenyl)-propionic acid in 10 mL THF were added 1.6 mL of DIPEA, 0.45 g of HOBt, 0.63 g of EDC and 10 mL of MeNH2 (2M in THF). The reaction mixture was heated in a closed vessel overnight at 70° C. Further additions of MeNH2 were done during the next 12 h. The mixture was then concentrated in vacuo, the residue was taken up in sat. aq. NaHCO3 and washed with EtOAc (2×). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC with EtOAc yielded 0.16 g of 3-(3,4-diethoxy-phenyl)-N-methyl-propionamide as solid.