Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:5][C:3]=1[NH2:4].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: COC(=O)COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)nc(Nc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 360 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylpyrimidine and 2 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 5 hours at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 98 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylamino}-6-methoxy-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-67].
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:5].[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31](N2C=CN=C2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([NH:5][CH:4]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[C:3]([O:2][CH3:1])([O:19][CH3:20])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NCCCc1ccccc1)n1ccnc1
Reactant: COC(OC)(c1ccncc1)C(N)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine (51.12 g, 0.185 mol) and N-(3-phenylpropyl)-1H-imidazole-1-carboxamide (42.42 g, 0.185 mol) in toluene (300 mL) under N2, was stirred and heated to reflux temperature for 3 h. The solution was cooled to room temperature and the dark brown solution was diluted with ethyl acetate (200 mL). The mixture was washed with water (2×200 mL), brine (200 mL), and dried with Na2SO4. The solvents were removed in vacuo to yield a brown solid which was recrystallized from a solvent mixture of ethyl acetate/hexane (1:1) to yield an off-white solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:19]([O:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1cc(C(C)O)on1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
5.55 g of ethyl 5-(1-hydroxyethyl)-isoxazole-3-carboxylate was dissolved in 30 ml of N,N-dimethylformamide, and 2.38 g of imidazole and 5.28 g of t-butyldimethylsilyl chloride were then added. The mixture was stirred at room temperature for 10 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 8.95 g of ethyl 5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazole-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:33](CC)CC)C.C([O-])(=O)C.[NH4+]>C(O)CCC.C(OCC)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:33]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[NH:15][CH:16]=2)=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
A mixture of 4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (2900.00 mg; 6.71 mmol; 1.00 eq.), triethylamine (0.94 ml; 6.71 mmol; 1.00 eq.), and ammonium acetate (3618.76 mg; 46.95 mmol; 7.00 eq.) in 20 ml of n-butanol was placed in microwave (150° C.) for 20 min. after cooling to rt, the reaction mixture was diluted with 150 ml of ethyl acetate and washed with water, 5% NaHCO3aq, then brine and concentrated. The residue was treated with ether and collected whit solid as title compound (1500 mg, 54% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:28](=[O:30])[CH3:29])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(F)cc1F
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}carbamate (3.94 g, 10.0 mmol) and N,N-dimethylpyridine-4-amine (1.22 g, 10 mmol) in pyridine (20 mL) was added dropwise acetyl chloride (0.94 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (4.36 g, quantitatively) as a pale-yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Reactant: CCn1cc(Br)cn1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Yield: 36 %

Procedure:
To a stirred solution of 6-chloro-7-fluoro-1H-indole 8 (400 mg, 2.36 mmol) in toluene (10 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (Step 3 above; 414 mg, 2.36 mmol), potassium phosphate (1.25 g, 5.91 mmol), N,N′-dimethylethylenediamine (84 mg, 0.95 mmol) and Cu(I)I (45 mg, 0.24 mmol) at RT under inert atmosphere. The resulted solution was purged with argon and sealed the tube. The reaction mixture was then heated to 140° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, diluted with hexane (10 mL) and filtered through a short pad of celite. The filtrate was washed with water (2×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 8-10% EtOAc/Hexanes) to afford compound 9 (224 mg, 36%) as a light brown thick liquid. 1H NMR (500 MHz, CDCl3): δ 7.64 (s, 1H), 7.61 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.12-7.07 (m, 2H), 6.60-6.59 (m, 1H), 4.22 (q, J=7.5 Hz, 2H), 1.55 (t, J=7.5 Hz, 3H); LC-MS (ESI): 94.7%; m/z 264.1 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 3.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:17]1[CH2:18][CH3:19]
Reactant: Nc1cnc2ccccc2c1NCCCCl
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCl
Yield: 71.2 %

Procedure:
Using the general method of Example 1 Part D, N4-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using triethyl orthopropionate (7.96 g, 45.2 mmol) in the presence of pyridine hydrochloride (0.43 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.33 g of 1-(3-chloropropyl)2-ethyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>CN(C)C=O>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2ccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(Oc3cc(N)cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Yield: 70.5 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 36.5 g (0.0747 mol) of 1,4-bis(3-nitro-5-trifluoromethylphenoxy)benzene, 250 mg of N,N-dimethylformamide and 1.8 g Pd-alumina were charged and reacted in a hydrogen atmosphere at 50° C. for 6 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 1,4bis(3-amino-5-trifluoromethylphenoxy)benzene as colorless crystals. The product was 36.5 g (70.5% yield) and had a melting point of 157.4°~158.0 ° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:8][CH:9]=1
Reactant: OCCc1ccc(OC(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A solution of 2-(4-difluoromethoxyphenyl)-ethanol (0.582 g, 3.09 mmol, from step (iii) above) in methylene chloride (8 mL) was cooled to 0° C. Triethylamine (0.52 mL, 3.7 mmol) was added followed by a solution of methanesulfonyl chloride (0.26 mL, 3.4 mmol) in methylene chloride (2 mL) and the reaction mixture was stirred at 0° C. for 90 min. The reaction mixture was diluted with methylene chloride (40 mL) and the organic phase was washed with water (2×30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give 0.78 g (95%) of the title compound as a colourless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-:26].[Na+].O.Cl>C(#N)C>[C:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:24])([CH3:25])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:26])[NH2:23]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C#N)c1)N2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
A mixture of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), sodium hydroxide (1.8 g, 44.9 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 4 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.58 g, 20%) as a white solid which was used for next step without further purification: MS (ESI) M+1=325.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1>C(O)C.O.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate (700 g, 2.27 mol) and iron (1272.7 g, 22.7 mol) in ethanol (5 L) and water (1 L) was stirred at room temperature for 10 h. The mixture was filtered, the filtrate was concentrated in vacuo, and the crude product was crystallized using EtOAc to give tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate. Preparative Example 2.3 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([NH:28][CH2:27][CH2:26][N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncc3c(Cl)ccnc32)cc1
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2ncc3c(NCCN4CCOCC4)ccnc32)cc1
Temperature: 150 °C
Yield: 56.2 %

Procedure:
1-(4-methoxybenzyl)-4-chloro-1H-pyrazolo[3,4-b]pyridine (0.200 g, 0.731 mmol) was charged to a pressure tube in 5 mL of NMP. 2-morpholinoethanamine (0.144 ml, 1.10 mmol) was added and the reaction was heated to 150° C. for 72 hours. After cooling, the reaction mixture was diluted with 25 mL of EtOAc and washed with water (2×15 mL) and then dried with brine and Na2SO4. Purification via flash Si 10 g eluting with 1-5% MeOH/DCM with NH4OH to afford 151 mg (55%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H), 7.92 (s, 1H), 7.30 (t, 2H), 6.83 (m, 2H), 6.14 (d, 1H), 5.56 (s, 2H), 5.41 (s, 1H), 3.75 (m, 7H), 3.44 (m, 2H), 2.73 (t, 2H), 2.51 (bs, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][C:24]1[S:28][C:27]([C:29](Cl)=[O:30])=[C:26]([CH2:32][CH2:33][Cl:34])[CH:25]=1>C1COCC1>[CH3:14][N:13]([CH3:15])[C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:27]3[S:28][C:24]([Br:23])=[CH:25][C:26]=3[CH2:32][CH2:33][Cl:34])=[O:30])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1sc(Br)cc1CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3sc(Br)cc3CCCl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of [(R)-1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amine (349 mg) and triethylamine (0.25 mL) in THF (4 mL) a solution of 5-Bromo-3-(2-chloro-ethyl)-thiophene-2-carbonyl chloride (489.6 mg) in THF (3 mL) added dropwise. The mixture was stirred for 2 h at room temperature. Then the solvent was removed in vacuum and then water and ethyl acetate were added to the residue. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 456.84 (C19H23BrClN3OS); MS (ESI): 456, 458 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:18][C:16]([N:12]1[CH2:13][CH2:14][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:11]1=[O:15])=[O:17]
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCN1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(S(=O)(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 80 parts by weight of 1-benzenesulphonyl-2-oxo-imidazolidine, 69 parts by weight of phosgene, 31.6 parts by weight of pyridine and 350 parts by volume of dichloromethane, brought together at 0°C, was stirred overnight at room temperature and subsequently evaporated to dryness. Thereafter the material was suspended in 500 parts by volume of ice water and filtered off, the residue was taken up in 500 parts by volume of dichloromethane, the solution was dried over MgSO4, filtered and again evaporated to dryness, and the residue was recrystallized from acetone/petroleum ether.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(NC(C)C)(C)C>C1COCC1.Cl[Cu]>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]#[C:1][C:3]2[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:5][CH:4]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Brc1ccc(C#Cc2ccc(OCCN3CCCC3)cc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 9.6 g (44.6 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine, 10.6 g (44.6 mmol) 2,5-dibromopyridine, 626 mg (0.9 mmol) tetrakis-triphenylphosphane-palladium, 170 mg (0.9 mmol) CuCl and 12.6 mL diisopropylamine in 500 mL THF is heated for 3 h at 40° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in EtOAc, the organic phase is washed with water and saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH:30](Cl)[CH3:31]>CN(C=O)C>[Cl:29][CH2:30][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: CC(Cl)Cl
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCl
Temperature: 70 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
7-Hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (85 g, 270 mmol, several batches pooled together) was dissolved in DMF (400 mL), potassium carbonate (77 g, 550 mmol) and dichloroethane (400 mL, 5130 mmol) were added and the reaction mixture was stirred overnight at 70° C. The solid was removed by filtration and washed with DMF. The solvent was evaporated and the solid so obtained was washed with water and dried at 50° C. over P2O5. The crude product was purified by flash chromatography using dichloromethane/ethyl acetate (85/15 up to 75/25). Evaporation of the solvent gave 7-(2-chloroethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (65.6 g, 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22](O)=[S:23])=[N:14]1.C(N(CC)CC)C.C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:46]=[N+:47]=[N-:48])=[S:23])=[N:14]1
Reactant: OC(=S)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=S)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Temperature: 5 °C
Yield: 90.9 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole-3-carboxylic acid (5.6 g) was dissolved in dry N,N-dimethylformamide (50 ml) and triethylamine (1.33 g) added. After cooling to 5° C., a solution of diphenylphosphorylazide (3.63 g) in N,N-dimethylformamide (20 ml) was added. When the solution had reached ambient temperature, it was heated to 35° C. for 21/2 hours. After evaporation in vacuo at a temperature kept below 40° C., a solution of sodium chloride (5 g) in water (100 ml) was added, and the suspension extracted with ether (3×100 ml). The combined extracts were washed with water (50 ml), dried over anhydrous magnesium sulphate and evaporated to give 1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylthiopyrazole-3-carboxylic acid azide (5.4 g). A solution of this in dry toluene (200 ml) was heated under reflux with stirring for 1.5 hours, tert-butanol (35 ml) was added, and reflux continued for 4 hours. After evaporation in vacuo the residue was purified by chromatography eluting with dichloromethane to give the title compound (3.3 g) as an off-white solid, m.p. 122°-125° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:32].[K+]>CO.O>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])(=[O:32])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (37.3 mg, 0.84 mmol) in methanol (4 mL) at 0° C. was added a solution of potassium permanganate (13.3 mg, 0.084 mmol) in water (2 mL) dropwise. After stirring for 2 h at 0° C., the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silica gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo to give the residue. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfonyl-1H-pyrrolo[2,3-b]pyridine (8 mg, 21%): LC/MS m/e calcd for C23H28N2O4S2 [M+H]+ 461.62, observed 461.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.59 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.88-7.92 (m, J=8.3 Hz, 2H), 7.59-7.63 (m, J=8.3 Hz, 2H), 6.62 (s, 1H), 4.36 (t, J=8.0 Hz, 1H), 3.25 (q, J=7.4 Hz, 4H), 3.07-3.13 (m, 4H), 2.26-2.34 (m, 1H), 2.11-2.19 (m, 1H), 1.61-1.71 (m, 2H), 1.46-1.53 (m, 2H), 1.23 (t, J=7.3 Hz, 5H).