Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[CH3:18].[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12>>[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:6]4[CH:7]5[CH2:8][CH:3]([CH2:4][CH:5]=4)[C:2]5([CH3:1])[CH3:19])=[C:10]([CH3:18])[CH:11]=3)=[O:14])[CH2:25][C:24]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CCC2CC1C2(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCC2CC1C2(C)C
Yield: 86.2 %

Procedure:
4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-3-methyl-benzoic acid of Step B (0.360 g, 1.40 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.284 g, 1.54 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from ethyl acetate afforded the title compound (0.510 g) as white crystals, m.p. 187° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[CH2:16][N:17]=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][N:20]=1)[CH3:13].[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][C@H:31]([CH:34]([CH3:36])[CH3:35])[CH2:32]Br)=[CH:28][C:27]=1[O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][C@H:31]([CH:34]([CH3:36])[CH3:35])[CH2:32][C@@H:16]2[C:15]([O:14][CH2:12][CH3:13])=[N:20][CH2:19][C:18]([O:21][CH2:22][CH3:23])=[N:17]2)=[CH:28][C:27]=1[O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44].[CH2:12]([O:14][C:15]1[CH2:16][N:17]=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][N:20]=1)[CH3:13]
Reactant: COCCCOc1cc(C[C@@H](CBr)C(C)C)ccc1OC
Agent: CCOC1=NCC(OCC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC1=N[C@H](C[C@H](Cc2ccc(OC)c(OCCCOC)c2)C(C)C)C(OCC)=NC1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
1 6M n-butyllithium in hexane (788 ml, 1.26 mol) is added dropwise at -40° C. under an inert atmosphere over a period of 20 minutes to a solution of 3,6-diethoxy-2,5-dihydro-pyrazine (229.8 g, 1.35 mol) in tetrahydrofuran (3.0 liters). The batch is stirred for a further 15 minutes at -40° C. and then a solution of 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide (323.4 g, 0.90 mol) in tetrahydrofuran (1.0 liter) is added dropwise thereto over a period of 20 minutes. When the addition is complete, the temperature of the mixture is allowed to rise to -20° C. and the mixture is then stirred at that temperature over a period of 18 hours. The reaction mixture is concentrated and the residue is partitioned between ethyl acetate (1 liter) and water (1 liter). The organic phase is washed with 2×1 liter of water, and the aqueous phases are each back-extracted with 1 liter of ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution (1 liter) and dried over magnesium sulfate. After concentration, the residue is dried under a high vacuum over a period of 1 hour at 35° C. The crude title compound is obtained in admixture with a small amount of epimeric 2(R)-{2(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]3-methylbutyl}-3,6-diethoxy-2,5-dihydro-pyrazine (approx. 95:5 diastereoisomeric mixture) and excess 3,6-diethoxy-2,5-dihydro-pyrazine in the form of a colourless oil (472 g): Rf (ethyl acetate/hexane 1:2)=0.20. The 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide used as starting material can be prepared, for example, as described below:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:7]=1[N+:18]([O-])=O>[Fe].C(OCC)(=O)C>[NH2:18][C:7]1[CH:8]=[C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)Nc1ccc(F)c(N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A mixture of 63.1 g (1.13 mol) of iron powder and 120 ml of an aqueous solution of 5% acetic acid was heated to 80° C., and a mixed solution of 28.0 g (0.113 mol) of N-(4-fluoro-3-nitrophenyl)ethanesulfonamide, 116 ml of acetic acid and 116 ml of ethyl acetate was slowly added dropwise to the resultant mixture. After the reaction was continued for 3 hours, the insolubles were filtered out and washed with ethyl acetate. Thereafter the filtrate was distilled to remove the solvent, and the product was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate, water and saturated saline solution. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 22.0 g of the objective product (yield: 89%) in the form of light yellow crystals.
Reaction SMILES: [N:1]1([CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].I[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[Cl-].[NH4+]>CN(C)C=O>[N:1]1([CH:14]([CH2:17][CH3:18])[CH2:15][O:16][CH2:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:28][CH2:29]2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(CO)n1cnc2cnc3ccccc3c21
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(COCCC1CCN(C(=O)OC(C)(C)C)CC1)n1cnc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 18.1 %

Procedure:
Under a nitrogen atmosphere, 2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (6.5 g, 26.9 mmol) was added in three portions to a suspension of sodium hydride (1.4 g of 60%, 35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture was allowed to stir for 45 minutes by which time gas evolution had ceased. Tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was allowed to stir at ambient temperature for 2.5 hrs; then it was heated to 100° C. and stirred overnight. Analysis by HPLC showed that the reaction was about 35% complete. Saturated ammonium chloride solution was added, the resulting mixture was allowed to stir for 20 minutes and then it was extracted with ethyl acetate (2×). The ethyl acetate extracts were washed with water (2×) and then with brine, combined, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography (silica gel eluting sequentially with 30% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide 2.2 g of tert-butyl 4-{2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH2:27][OH:28])[CH:24]=[CH:25][CH:26]=1.[H-].[Na+]>CS(C)=O>[NH:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([O:28][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=3)=[CH:3][CH:4]=2)=[O:9])=[CH:11]1
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(c1ccc(OCc2cccc(C(F)(F)F)c2)nc1)c1c[nH]c2ncccc12
Temperature: 60 °C

Procedure:
To (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 in DMSO was added (3-trifluoromethyl-phenyl)-methanol 72. Sodium hydride was added and the reaction was heated to 60° C. for two hours. The reaction was quenched with water and extracted with ethyl acetate. The organic portion was dried with magnesium sulfate and concentrated to provide (1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone 73, which was used in the next step without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](N)=[O:7])=[CH:4][N:3]=1.P(=O)(O)(O)[OH:12]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:12])=[O:7])=[CH:4][N:3]=1
Reactant: NC(=O)c1ccc(N)nc1
Reactant: O=P(O)(O)O
Product: Nc1ccc(C(=O)O)cn1
Temperature: 100 °C

Procedure:
6-Aminonicotinamide, 200 g, was dissolved in warm 85% phosphoric acid, 700 ml. The clear solution was heated to 100° C. for 8 hours. The solution was then diluted with 1.5 Kg of ice water. The white crystals thus obtained were separated by filtration, and washed with ice water followed with an acetone wash. The yield of 6-aminonicotinic acid phosphoric salt was 310 g. This product in its phosphoric salt form may be directly incorporated into the therapeutic compositions of the present invention.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[CH:6][CH:7]=[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=12.C(N(C(C)C)CC)(C)C.[CH2:27]([OH:30])[CH2:28][OH:29]>>[CH3:15][O:14][C:12]1[C:11]([O:16][CH3:17])=[CH:10][C:9]2[CH:3]([CH2:2][O:29][CH2:28][CH2:27][OH:30])[O:4][CH2:5][CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: OCCO
Reactant: COc1cc2c(cc1OC)=C(CBr)OC=CC=2
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)C(COCCO)OCCC2
Yield: 89 %

Procedure:
A mixture of 3.67 g (12.2 mmoles) of 1-bromomethyl-7,8-dimethoxy-2-benzoxepin, 2.12 ml (12.2 mmoles) of diisopropylethylamine, and 15 ml of ethylene glycol is heated at 100° for 7 hours. The reaction mixture is then cooled and extracted with methylene chloride, then with water and finally with brine. The organic layer is filtered through Na2SO4, taken to dryness, and chromatographed on silica gel to give 3.06 g (89%) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol: mass spectrum: M+ (m/e=282).
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO[CH:11]([N:14]([CH3:16])[CH3:15])OC>>[CH3:11][N:14](/[CH:16]=[C:3](/[C:2](=[O:1])[CH3:8])\[C:4]([O:6][CH3:7])=[O:5])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(C)=O
Product: COC(=O)/C(=C\N(C)C)C(C)=O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask, was placed methyl 3-oxobutanoate (10.8 g, 92.6 mmol) and (dimethoxymethyl)dimethylamine (12.7 mL, 95.3 mmol). The resulting solution was stirred for 2.5 h at 80° C., then concentrated under reduced pressure to yield 14.5 g (crude) of the title compound as a red solid.
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[N:15][N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:17]=1.ClC1C=CC=CC=1C1N(C2CCCCO2)N=NN=1.[CH2:42]([O:44][CH:45]([O:54][CH2:55][CH3:56])[C:46]1[CH:51]=[CH:50][C:49]([Mg]Br)=[CH:48][CH:47]=1)[CH3:43]>COC(C)(C)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH2:55]([O:54][CH:45]([O:44][CH2:42][CH3:43])[C:46]1[CH:51]=[CH:50][C:49]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[N:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:17]=2)=[CH:48][CH:47]=1)[CH3:56]
Reactant: Clc1ccccc1-c1nnn(C2CCCCO2)n1
Reactant: CCOC(OCC)c1ccc([Mg]Br)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Clc1ccccc1-c1nnnn1C1CCCCO1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(OCC)c1ccc(-c2ccccc2-c2nnn(C3CCCCO3)n2)cc1
Temperature: 0 °C

Procedure:
In another flask, dichloro[1,3bis(diphenylphosphino)propane]nickel(II) (0.027 g; 0.05 mmol) is suspended in tert-butyl methyl ether (3.8 mL) and cooled to about 0° C. before a 0.5 M solution of zinc chloride in tetrahydrofuran (0.50 mL; 0.25 mmol) and a solution of a mixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (1.32 g; 5.0 mmol) in tert-butyl methyl ether (1.3 mL) are added. To the vigorously stirred resulting suspension is added at about 0° C. 13 mL of the above 0.46 M 4-(diethoxymethyl)phenylmagnesium bromide solution (6.0 mmol) over one hour. The resulting black-yellow solution is stirred at about 0° C. for 5 hours, allowed to warm up and further stirred at room temperature for 19 hours. The mixture is cooled to about 0° C. and quenched with a 7.5% solution of ammonium chloride in water (10 mL). The aqueous phase is separated and extracted with ethyl acetate (25 mL). The combined organic phases are washed with water (10 mL), a 7.5% solution of sodium carbonate in water (10 mL) and a 10% solution of sodium chloride in water (10 mL). The combined organic phases are evaporated in vacuo. A solution of the resulting brown-yellow oil in a small amount of ethyl acetate is filtered and evaporated. The resulting oil (2.68 g) is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.2 volume-% of triethylamine) to afford the main isomer (N2-isomer) 5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazole as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[C:38]([O:41][CH2:42][C:43](Cl)=[O:44])(=[O:40])[CH3:39]>O1CCCC1>[C:38]([O:41][CH2:42][C:43](=[O:44])[NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:12]=3)=[N:6][N:5]2[CH:30]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 80.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.725 mmol), triethylamine (152 μL, 1.08 mmol), 2-chloro-2-oxoethyl acetate (94 μL, 0.870 mmol) and tetrahydrofuran (7 mL) as starting materials and in the same manner as in Example 388, the title compound (299 mg, 80%) was obtained as a white powder.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13].C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.[C:37]([NH:44][C@@H:45]([C:50](O)=[O:51])[CH2:46][CH2:47][S:48][CH3:49])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[NH:44]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:45]([C:50]([NH:13][C@H:12]([C:11]([O:10][CH3:9])=[O:15])[CH3:14])=[O:51])[CH2:46][CH2:47][S:48][CH3:49]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
N-methylmorpholine (5.6 g), L-alanine methyl ester hydrochloride (3.9 g), HOBT (4.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.3 g) was added to a solution of Boc-(D)-Methionine (7 g, 0.028 mol) in dry DMF (50 ml). The mixture was stirred overnight. Solvent was removed by evaporation and the residue was partitioned between dichloromethane (100 ml) and 5% aqueous acetic acid (50 ml). On standing HOBT crystallised and was removed by filtration, and the organic layer was separated and washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue (8.5 g) was purified by flash chromatography in a sinter funnel eluting with a mixture of dichloromethane and ether (0% to 100% ether). The fractions containing product were combined and evaporated to give Boc-(D)-Met-(L)-Ala-OMe (7.2 g) as a gum which crystallised on standing; NMR (CDCl3): 1.4 (d, 3H), 1.45 (s, 9H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1 (m, 1H), 2.6 (m, 2H), 3.75 (s,3H), 4.3 (bs, 1H), 4.6 (m, 1H), 5.3 (m, 1H), 6.9 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26]C(=O)C[CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.CCN(S(F)(F)F)CC.[C:50](O)([C:52]([F:55])(F)[F:53])=O>C([O-])(O)=O.[Na+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:52]([F:55])([F:53])[CH2:50][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(F)(F)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 6 %

Procedure:
To a 10 mL round bottomed flask was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from Example 137). The vessel was purged with nitrogen. DCM (1 mL) was added and the solution was cooled to 0° C. DAST (0.071 mL, 0.535 mmol) was added and the stirred reaction mixture was allowed to slowly warm to ambient temperature. After 18 h, saturated aqueous NaHCO3 (200 mL) was carefully added, and the mixture was extracted with EtOAc (300 mL). The organics were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (8.2 mg, 6% yield) as a TFA salt. LC-MS (M+H)+ 489.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.14 (1 H, br. s.), 8.11 (1 H, s), 7.03-7.45 (7 H, m), 4.59 (1 H, br. s.), 4.26-4.46 (2 H, m), 3.87 (3 H, s), 2.29-2.84 (4 H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Cc1cc(C2CC2)nc(Cl)n1
Solvent: CCO
Solvent: O
Product: Cc1cc(C2CC2)nc(NN)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.0 g of 2-chloro-4-methyl-6-cyclopropylpyrimidine are dissolved in 30 ml of ethanol; 3.8 ml of hydrazine hydrate are added and the mixture is stirred for 20 hours at room temperature. The solvent is then evaporated off in vacuo and the residue is recrystallised with ethyl acetate. M.p. 98°-99° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[C:24]4=[CH:27][S:28][CH:29]=[C:23]4[NH:22][C:21]3=[O:30])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CN([CH:36]=[O:37])C>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[C:24]4=[CH:27][S:28][CH:29]=[C:23]4[N:22]([CH2:23][CH2:24][C:25]([O:37][CH3:36])=[O:26])[C:21]3=[O:30])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: COC(=O)CCn1c(=O)n(CCCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)c2cscc21
Yield: 41 %

Procedure:
The title compound was produced following the procedure of Example 1 using 12.0 g (26 mmol) of 3-[5-[4-(3-trifluoromethylphenyl)piperazin-1-yl]pentyl]thieno[3,4-d]pyrimidine-2,4-dione in DMF at 50° C. for 24 hours to produce methyl 3-[3-[5-[4-(3-trifluoromethylphenyl)piperazin-1-yl]pentyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate in 41% yield (5.78 g) after recrystallization from ether/hexane, mp 99.5°-101° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].Cl>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 60 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (+)-2-[2-[(dipropylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 60% of theory. Colourless crystals, m.p. 164°-165° C. (acetonitrile); [α]D20 =+7.24° (dilute aqueous hydrochloric acid).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[Na+].Cl>CCOCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 19.6 %

Procedure:
Formation of compound (b): To a mixture of 3,5-dimethylphenol (a) (25 g, 205 mmol) and NaNO3 (26.1 g, 307 mmol) in ether (200 mL) and water (200 mL), at 0° C., 250 mL of conc.HCl solution was added dropwise within 1 hour under stirring. The reaction mixture was kept under stirring overnight and the temperature was allowed to warm to room temperature. The organic phase was seperated and the aqueous phase was extracted with ether (3×100 mL). The combined organic phase was washed with 3N HCl (2×100 mL), saturated NaHCO3 solution (3×100 mL) and finally with brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. The obtained residue was purified by chromatography over silica gel by using ethyl acetate and hexane (2:8) as eluent. The collected fractions were further recrystalized in ether/hexane to afford compound (b), 3,5-dimethyl-4-nitrophenol (6.7 g, 19% yield) as a yellow solid. MS: m/e 167
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](Br)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Br)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccn23)CC1

Procedure:
To a solution of 1.15 g of 1-tert-butoxycarbonyl-4-(1-bromo-formylmethyl)piperidine (from Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. After refluxing for 18 h, the solvent was evaporated. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes, followed by 100% ethyl acetate to give the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 1.70 (m, 2H), 2.06 (d, J=13 Hz, 2H), 2.93–3.02 (m, 3H), 4.26 (br, 2H), 6.87 (t, J=6.8 Hz, 1H). 7.21(m, 1H), 7.44(s, 1H), 7.69(d, J=9.2 Hz,1H), 7.99 (d, J=6.9 Hz, 1H).