Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]([O:15]CC)=O)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]([NH2:18])=[O:15])(=[O:9])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)CNS(=O)(=O)c1cncc(Br)c1
Reactant: N
Solvent: CO
Product: NC(=O)CNS(=O)(=O)c1cncc(Br)c1
Yield: 66 %

Procedure:
A solution of ethyl 2-(5-bromopyridine-3-sulfonamido)acetate (0.50 g, 1.7 mmol) and ammonia in methanol (2M, 10 mL) was heated to 60° C. in a sealed tube for 4 h. The cooled reaction mixture was concentrated under reduced pressure to yield 2-(5-bromopyridine-3-sulfonamido)acetamide (300 mg, 66%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (d, 1H, J=2.4 Hz); 8.90 (d, 1H, J=2 Hz); 8.39 (t, 1H, J=2 Hz), 8.21 (br s, 1H), 7.35 (br s, 1H), 7.07 (br s, 1H), 3.5 (s, 2H). LCMS Method D: retention time 0.945 min; [M+1]=294, 296.0.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19]([S@@:22]([N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:23])([CH3:21])[CH3:20]>C1COCC1>[CH3:21][C:19]([CH3:18])([S@@:22]([NH:24][C@:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[O:23])[CH3:20]
Reactant: COC(C)=O
Reactant: CC(=N[S@@](=O)C(C)(C)C)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A solution of i-Pr2NH in THF (25 mL) was cooled to −78° C., n-BuLi (2.5M, 2 mL) was added and the solution was stirred for 1 h. Then methyl acetate (4.48 mmol, 278 mg) was added and the mixture was stirred for 30 min. To this solution Ti(Oi-Pr)3Cl (1 M, 9.4 mL) was added. After 0.5 h, (S)-2-methyl-N-(1-phenylethylidene)propane-2-sulfinamide (500 mg, 2.24 mmol) dissolved in THF (1 mL) was added. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with NH4Cl and warmed to rt. The mixture was diluted with water and filtered. The solid was washed with H2O/EtOAc and filtered. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC to afford (R)-methyl 3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoate (305 mg, 46%). 1H NMR (CDCl3): 1.24 (s, 9H), 1.68 (s, 3H), 3.08 (s, 2H), 3.53 (s, 3H), 5.46 (s, 1H), 7.15-7.18 (m, 1H), 7.23-7.30 (m, 2H), 7.30-7.36 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1Br.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[F:37]
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(F)c(OC)ccc3c2)cc1
Temperature: -78 °C
Yield: 62.8 %

Procedure:
To a solution of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene (1.28 g, 3.72 mmol) in THF (25 mL) at −78° C. was slowly added n-butyl lithium (1.9 mL of 2.5 N in hexanes). The resulting solution was stirred at −78° C. for thirty minutes and a solution of N-fluorobenzenesulfonimide (1.40 g, 4.5 mmol) in THF (10 mL) was added. After 2 additional hr at −78° C., the reaction was warmed to room temperature, poured in water, and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica chromatography (5% THF-hexanes) yielded 0.66 g (63%) of a white solid: Mfp 150–155° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.04 (3H, s), 7.02 (2H, d, J=8.69 Hz), 7.28–7.34 (1H, m), 7.62–7.67 (3H, m), 7.74 (1H, dd, J=1.60 Hz, J=8.79 Hz), 7.93 (1H, s), 8.09 (1H, d, J=8.77 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][C:25]([NH2:28])=[N:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH:27]=[N:26][C:25]([NH:28][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:24]2)=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(-c2ccc(Cl)cc2)n1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-chloro-phenyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=18%). MS ISP (m/e): 376.2 (100) & 378.2 (35) [(M+H)+].
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:26]=[CH:25][C:24]([C@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][C@@H:27]([C:24]4[CH:25]=[N:26][C:21]([C:20]([F:31])([F:19])[F:30])=[CH:22][CH:23]=4)[CH3:28])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Cl)cn1)CC2)c1ccc(C(F)(F)F)nc1
Temperature: 200 °C
Yield: 20.1 %

Procedure:
4-Bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (250 mg, 0.768 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (219 mg, 1.15 mmol), N,N-diisopropylethylamine (401 μL, 2.30 mmol), and acetonitrile (0.75 mL) were added to a 0.5-2 mL microwave vial. The reaction was heated in the microwave reactor at 200° C. for 2.5 hours. The solids were filtered from solution and washed with acetonitrile (2×0.5 mL) and ether (2×3 mL) (219 mg of a light yellow solid). The filtrate was evaporated and the residue was redissolved in CH2Cl2 (10 mL) and washed with 1M NaH2PO4 (2×8 mL). The organic layer was dried with Na2SO4, filtered and evaporated to give an orange solid. The crude product was purified by column to give 67 mg of a light yellow solid. The 2 products that were obtained were combined (219 mg+67 mg). To remove some of the yellow colored impurity, ethyl ether (3 mL) was added and the mixture was stirred for about 1 hour then the solution was decanted from the solids. The solids were washed with ethyl ether (2×2 mL) to yield a light beige solid (264 mg, 79% yield).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13](Cl)=[O:14])[N:5]=1)(=[O:3])[CH3:2].Cl.[CH3:17][NH:18][CH3:19].N1C=CC=CC=1>ClCCl>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13]([N:18]([CH3:19])[CH3:17])=[O:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)n(CCOC(=O)Cl)n1
Reactant: CNC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cc(C)n(CCOC(=O)N(C)C)n1
Reaction time: 1.5 h

Procedure:
3-Acetyl-1-[2-(chlorocarbonyloxy)ethyl]-5-methylpyrazole (prepared in Example 22, Preparation 1) in dry dichloromethane (20 ml) was treated with dimethylamine hydrochloride (367 mg) and pyridine (712 mg) and the mixture stirred for 1.5 h. The mixture was then partitioned between ethyl acetate and 1M aqueous HCl. The organic phase was separated, washed with 1M aqueous HCl, saturated aqueous NaHCO3 and brine then dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give 3-acetyl-1-[2-(N,N-dimethylaminocarbonyloxy)ethyl]-5-methylpyrazole (222 mg); νmax (KBr) 1697 and 1683 cm−1; δH (CDCl3) 2.31 (3H,s), 2.53 (3H,s), 2.82 (3H,s), 2.91 (3H,s), 4.4 (4H,m); Found m/z 239.1273 C11H17N3O3 requires 239.127.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C1OCCOCCOCCOCCOC1>O1CCOCC1>[N:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(CN=[N+]=[N-])cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-bromomethylphenyl)-proprionic acid (1.5 g) in 1,4-dioxane was added NaN3 (5 g) and 15-crown-5 (100 mg). The mixture was heated to 80° C. for 16 h, then cooled. The solvent was removed under reduced pressure, and the residue chromatographed on silica to yield 2-(4-azidomethylphenyl)-proprionic acid as an off white solid.
Reaction SMILES: Cl.[C:2]([CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][NH:6]1)(=[O:4])[NH2:3].CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:2]([CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:25]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34])(=[O:4])[NH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNC(C(N)=O)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Ethyl 2-carbamoylpiperidine-4-carboxylate hydrochloride (2 g, 7.86 mmol) was slurried in dichloromethane (25 mL) and DIPEA (3.43 mL, 19.65 mmol) was added followed by benzyl carbonochloridate (1.161 mL, 8.25 mmol) dropwise. The reaction was stirred for 1 h then washed with 25 mL of 2 M HCl and water, dried over Na2SO4 and evaporated. The crude product was purified on a 100 g Biotage column with heptane/EtOAc over 4 CV followed by 100% EtOAc over 10 CV. 1-Benzyl 4-ethyl 2-carbamoylpiperidine-1,4-dicarboxylate (1.99 g, 76%) was isolated. 1H NMR (400 MHz, dmso) δ 1.16 (t, 3H), 1.57-1.69 (m, 1H), 1.81-1.92 (m, 1H), 1.95-2.07 (m, 1H), 2.21-2.32 (m, 1H), 2.58-2.67 (m, 1H), 3.29-3.45 (m, 1H), 3.69-3.77 (m, 1H), 3.92-4.06 (m, 2H), 4.34 (t, 1H), 4.99-5.08 (m, 2H), 6.95 (s, 1H), 7.25-7.38 (m, 6H). MS m/z 335 (M+H)+
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2].C=O.[CH:29](O)=O.O>C(OCC)(=O)C>[CH:1]([N:4]([CH3:29])[CH2:5][C:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:17]=2)[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: CC(C)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 60 °C
Yield: 65 %

Procedure:
To isopropyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}-amine (258 mg, 0.71 mmol) was added formaldehyde (37% w/w solution in H2O, 1 mL) and formic acid (1.5 mL). The resulting mixture was heated to 60° C. overnight. After cooling, H2O and ethyl acetate were added. The aqueous layer was separated, basified with 30% NaOH and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as an oil (170 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.76 (m, 2H), 3.50 (m, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.44 (m, 1H), 2.38 (s, 2H), 2.08 (m, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.85 (s, 3H), 1.79 (m, 4H), 0.84 (d, 6H).
Reaction SMILES: CN(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][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[NH:36][NH2:37])[CH:29]=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)[CH:29]=[CH:28][CH:27]=1
Reactant: NNc1cccc2cccnc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2cccnc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and quinolin-8-yl-hydrazine according to the method described for example 43. MS: M=450.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:16][C:17]3[CH:28]=[CH:27][C:20]4[N:21]=[C:22](S(C)=O)[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[OH:39].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:16][C:17]3[CH:28]=[CH:27][C:20]4[N:21]=[C:22]([NH:32][C@@H:33]5[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]5[OH:39])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 138 °C
Yield: 59.5 %

Procedure:
A stirred mixture of 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.48 g, 3.4 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol hydrochloride (1.29 g, 8.5 mmol), and DIEA (2.19 g, 17 mmol) in DMA (44 mL) was heated at 138° C. for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 6% MeOH in DCM to afford (1R,2R)-2-((6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (0.98 g, 59%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.43-7.46 (m, 3H), 7.29-7.39 (m, 4H), 7.25 (s, 1H), 7.13-7.16 (m, 2H), 6.96 (m, 1H), 5.75 (br s, 1H), 5.31 (s, 2H), 5.09 (s, 2H), 3.46-3.56 (m, 2H), 2.07-2.18 (m, 2H), 1.71-1.77 (m, 2H), 1.26-1.40 (m, 4H); LCMS (ESI) m/z 485 (M+H)+.
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O=P(Cl)(Cl)[Cl:23]>>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[Cl:23])=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Yield: 50 %

Procedure:
2-[(4-Bromophenylamino)methylene]malonic acid diethyl ester (5 g) was heated with POCl3 (phosphoryl chloride, 31.5 mL) at 150° C. in a sealed tube for about 6 h. The excess POCl3 was removed by rotavapor and the crude mixture was diluted with dichloromethane. The dichloromethane extract was washed with 10% NaOH solution, dried over sodium sulphate and purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20) to give 2.3 g (50%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H, aromatic), 8.60 (d, 1H, J=2.1 Hz, aromatic), 8.04 (d, 1H, J=9 Hz, aromatic), 7.95-7.85 (m, 1H, aromatic), 4.53 (q, 2H, J=7 Hz, —CH2—), 1.50 (t, 3H, J=7 Hz, —CH3); LC-MS (m/z) 315.8 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[CH:10]1([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:17]=3[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:10]1([N:14]2[CH2:15][CH2:16][C:17]3[CH:24]=[CH:23][C:22]([O:25][C:2]4[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=4)=[CH:21][C:18]=3[CH2:19][CH2:20]2)[CH2:13][CH2:12][CH2:11]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: O=[N+]([O-])c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-nitrothiophene (478 mg, 2.3 mmol), 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (500 mg, 2.3 mmol) and potassium carbonate (765 mg, 5.5 mmol) in dimethylformamide (10 ml) was stirred at 80° C. for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water, brine and dried (sodium sulfate). Concentration in vacuo and purification of the resulting residue by column chromatography 0.880 ammonia:methanol:dichloromethane (1:8:300) afforded the title compound (E211); MS (ES+) m/e 345 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCC(F)(F)C2)ncn1

Procedure:
100 mg (0.8 mmol) of the compound from Example 12A, 57 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine were initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 13 mg (12% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([O:19][CH3:20])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)[C:14]2=[O:21])=[C:9]1[C:31]([O:33]C)=[O:32])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([O:19][CH3:20])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)[C:14]2=[O:21])=[C:9]1[C:31]([OH:33])=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c2c(c(C(=O)O)n(CC(=O)OC(C)(C)C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.49 g, 0.96 mmol) and lithium hydroxide monohydrate (0.12 g, 2.9 mmol) in a mixture of tetrahydrofuran (3 mL) and water (2 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. This was used in the following step without further purification. ES MS M+1=495
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@@H:6]([NH:10][C:11]([C@H:13]([NH:25][C:26](=[O:42])[O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]C=C)=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])[CH:2]=[CH2:3]>ClCCl>[CH:7]([C@@H:6]1[NH:10][C:11](=[O:12])[C@H:13]([NH:25][C:26](=[O:42])[O:27][CH2:28][CH:29]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:14][C:15]2=[CH:16][CH:17]=[C:18]([CH:19]=[CH:20]2)[O:21][CH2:22][CH:3]=[CH:2][CH2:1][O:4][CH2:5]1)([CH3:9])[CH3:8]
Reactant: C=CCOC[C@@H](NC(=O)[C@@H](Cc1ccc(OCC=C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Yield: 86.6 %

Procedure:
A solution of 1.25 g (2.20 mmol) of 9H-fluoren-9-ylmethyl [(R)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)-2-(4-allyloxyphenyl)ethyl]carbamate and 0.40 g (0.659 mmol) of dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (Hoyveda-Grubbs catalyst) in 610 ml of dichloromethane was stirred at 40° C. for 24 h. The reaction mixture was then concentrated, and the residue was purified by chromatography on silica gel. 1.03 g of the desired compound were obtained as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.[NH3:23]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[CH2:14][NH:13][C:7]1[C:6]2[C:11](=[C:2]([NH2:23])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(N)c2n1
Yield: 52 %

Procedure:
(8-Bromo-2-methylquinolin-4-yl)-(3,4-dichlorobenzyl)-amine (500 mg, 1.26 mmole), copper(II)sulphate pentahydrate (316 mg, 1.27 mmole) and ammonia (20% in water/ethanol 1:1, 20 mL) were stirred in a microwave oven at 150° C. for 5 hrs. The reaction mixture was dissolved in water and extracted with dichloromethane. The resulting organic phases were dried and purified using silica gel chromatography, eluting with dichloromethane:water 99:1. Precipitation in isopropyl ether gave a brownish solid (220 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][N:18]=[C:19]=[O:20]>N1C=CC=CC=1.C1COCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:12])=[C:5]2[C:10]=1[C:2]([NH:1][C:19]([NH:18][CH3:17])=[O:20])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[NH:4]2
Reactant: CN=C=O
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24 %

Procedure:
A mixture of 0.6 g (2.75 mmol) of methyl 3-amino-4,7-dimethylindole-2-carboxylate, one drop of pyridine and 15 ml of anhydrous THF was prepared and 5.0 ml of methyl isocyanate was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2.5 hours. The crystals precipitated were separated by filtration, washed with ethyl acetate and air-dried to provide 180 mg of white crystals. Yield: 24%
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][NH:20][C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]=O>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC1
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 1-aminocyclopropanecarboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO d6) 0.90-1.00 (m, 2H); 1.10-1.20 (m, 2H); 3.93 (s, 2H); 3.96 (s, 3H); 7.14 (s, 1H); 7.28 (m, 1H); 7.40-7.55 (m, 2H); 8.29 (s, 1H); 8.40 (s, 1H); Mass Spectrum: (M+H)+ 417. 1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid reacted with para-formaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.08 (m, 2H); 1.21 (m, 2H); 2.43 (s, 3H); 3.94 (s, 3H); 4.08 (s, 2H); 7.17 (s, 1H); 7.28 (t, 1H); 7.52 (m, 2H); 8.21 (s, 1H); 8.42 (s, 1H); 9.73 (s, 1H); Mass Spectrum: (M+H)+ 431