Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C(O)CCC>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][NH:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)CC1
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A mixture of 69 (0.2 g, 0.57 mmol), 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 1.13 mmol) and DIEA (0.20 mL, 1.14 mmol) in 1-butanol (5 mL) was heated to 120° C. for 1.5 h. After concentration, the residue was purified by silica gel chromatography using 2-5% MeOH/DCM, to give 4-[2-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-ylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester 71 (0.20 g). Compound 71 was subjected to 20 mL of 20% TFA/DCM at rt for 2 h, then the reaction was concentrated almost to dryness under reduced pressure, and purified by silica gel column chromatography using 0.1% MeOH/DCM containing 1 mL ammonium hydroxide, to give 72 (0.15 g). MS: 400.2(M+1). 1HNMR (DMSO-d6) ppm 8.36 (s, 1H), 7.61-7.33 (m, 10H), 5.49 (t, 1H, J=4.48 Hz), 3.45 (dd, 2H, J1=5.10 Hz, J2=5.84 Hz), 2.33 (t, 2H, J=5.80 Hz), 2.13 (br, 4H), 1.95 (br, 1H) (note: some peaks overlapped with water peak in DMSO-d6). 1HNMR (CCl3-d) ppm 8.43 (s, 1H), 7.60-7.50 (m, 6H), 7.50-7.26 (m, 4H), 5.39 (t, 1H), 3.54 (dd, 2H, J1=5.05 Hz, J2=6.20 Hz), 2.73 (t, 4H, J=4.71 Hz), 2.44 (t 2H, J=5.91 Hz), 2.28 (br, 4H), 1,87 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([CH2:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([CH2:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CCc1nc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (65 mg, 0.20 mmol) and 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine (60 mg, 0.24 mmol) in anhydrous DMF (1.0 mL) at room temperature was added anhydrous K2CO3 (66 mg, 0.48 mmol). The resulting suspension was stirred at 80° C. The reaction progressed slowly, and additional 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine (60 mg, 0.24 mmol) and K2CO3 (66 mg, 0.48 mmol) were added after 1.5 h. After stirring for additional 5 h, the same amounts of 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine and K2CO3 were again added. The reaction mixture was stirred at 80° C. for 1 h more before a few drops of diisopropylethylamine were added. The resulting black reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The EtOAc layer was washed with water twice, then saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (0-70%) in hexanes to afford the title compound (95% pure) as a yellow foam. This was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 35 mg (34%) of the title compound as a light yellow powder. HPLC/MS: retention time=3.07 min, [M+H]+=510.2. 1H NMR (CDCl3, 400 MHz): δ 8.55 (dd, J=1.8, 6.2 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.16 (d, J=1.8, 6.2 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.66 (d, J=7.5 Hz, 1H), 5.26 (s, 2H), 3.04 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[CH:8]=[CH:9][CH:10]=[O:11])#[N:2].[CH3:14][O:15][CH2:16]Cl.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][O:15][CH3:16])=[C:7]([CH:12]=1)[CH:8]=[CH:9][CH:10]=[O:11])#[N:2]
Reactant: N#Cc1ccc(O)c(C=CC=O)c1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(C#N)cc1C=CC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 5-cyano-2-hydroxycinnamaldehyde (2.3 g) in N,N-dimethylformamide (25 ml) were added methoxymethyl chloride (1.5 ml) and triethylamine (2.8 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (2.8 g, yield 98%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1.O>[CH2:28]([N:27]([CH3:26])[C:2]1[N:3]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CNCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and N-methylbenzylamine (76 mg, 0.625 mmol) in dioxane (5 mL) was heated to reflux for 5 min and cooled. The mixture was diluted with water to give a white precipitate, which was recrystallised from EtOH to give N-benzyl-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 147-150° C.; 1H NMR (CDCl3) (rotamers) δ 8.45 and 8.22 (2d, J=7.6 and 7.9 Hz, 1H), 7.90 and 7.85 (2d, J=8.3 and 7.7 Hz, 1H), 7.68 and 7.44 (2t, JHF=53.7 and 53.6 Hz, 1H), 7.43-7.25 (m, 7H), 4.92 and 4.90 (2s, 2H), 3.95-3.73 (m, 8H), 3.22 and 3.20 (2s, 3H); Anal. Calc. for C23H23F2N7O: C, 61.2; H, 5.1; N, 21.7. Found: C, 61.45; H, 5.2; N, 21.95%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Br[C@H:19]([CH3:41])[C:20]([N:22]1[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:21]>C(#N)C>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:19]([CH3:41])[C:20]([N:22]1[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:21])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
Introduce 123 g of ethyl (2S)-2-aminopentanoate, 160 ml of triethylamine and 160 ml of acetonitrile into a reactor, and then bring the mixture to 60° C., slowly add the solution obtained in Step A and reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield benzyl (2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]-propionyl}octahydro-1H-indole-2-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[C:38]([CH3:40])[CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[C:38]([CH3:40])[CH:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-n2cc(C)cn2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cc(C)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(4-methyl-1H-pyrazol-1-yl)benzoic acid. MS (ESI) 327 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[C:13]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:24][CH2:25][O:26][C:27]([C:29]([CH2:31]Br)=O)=[O:28]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:19][CH:31]=[C:29]([C:27]([O:26][CH2:25][CH3:24])=[O:28])[N:18]=4)=[C:13]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Temperature: 100 °C

Procedure:
6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide (20) (30 mg, 0.08 mmol) and ethyl bromo pyruvate (0.17 mmol, 2 equiv.) were taken in DMF (5 mL) and heated at 100° C. for 3 h. The reaction mixture was then concentrated under reduced pressure to remove excess of DMF. The residue was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc twice. The organic layers were collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH:CHCl3 as eluent to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=20.00 Hz, 6H), 1.43 (t, J=7.20 Hz, 3H), 3.75-3.77 (m, 1H), 4.41 (q, J=7.20 Hz, 2H), 6.16 (s, 1H), 7.54 (dd, J=2.00, 8.8 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.21 (s, 1H), 8.43 (s, 1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 2.131 min; LCMS (ES-API), m/z 440.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.409 min; Purity: 98%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, dissolved in DCM and cooled to 0 centigrade is added a corresponding benzaldehyde, then NaBH(OAc)3 and 5 drops of HOAc. The mixture is warmed to room temperature and stirred overnight. The mixture is diluted with DCM, washed with brine, and dried. After removal of solvent, the crude 4-(benzylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained (33) and used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:25]2[N:26]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccccc1

Procedure:
(S)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]phenyl}-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (48%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H), 7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H), 4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]([C@@H:17]1[CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:27]3[CH2:33][C:32]4[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=4[O:30][CH2:29][CH2:28]3)[C:20]=2[CH2:19][CH2:18]1)[CH3:16].[NH2:41][C:42]1[C:47]([S:48]([N:51]2[CH2:55][CH2:54][C:53]([NH:57]C(=O)OC(C)(C)C)([CH3:56])[CH2:52]2)(=[O:50])=[O:49])=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[NH2:57][C:53]1([CH3:56])[CH2:54][CH2:55][N:51]([S:48]([C:47]2[C:42]([NH2:41])=[N:43][CH:44]=[C:45]([C:35]3[CH:36]=[CH:37][C:31]4[O:30][CH2:29][CH2:28][N:27]([C:21]5[C:20]6[CH2:19][CH2:18][C@H:17]([CH2:15][CH3:16])[CH2:26][C:25]=6[N:24]=[CH:23][N:22]=5)[CH2:33][C:32]=4[CH:34]=3)[CH:46]=2)(=[O:49])=[O:50])[CH2:52]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5CCC(C)(N)C5)c4)cc3C2)C1

Procedure:
Prepared as dihydrochloride salt according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)-3-methylpyrrolidin-3-ylcarbamate (reagent preparation 25) in step 1 followed by Boc deprotection. 1H NMR (400 MHz, methanol-d4): 8.50 (m, 3H), 7.70 (s, 1H), 7.50 (d, 1H), 7.07 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.57 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 4.21 (m, 1H), 3.70 (m, 3H), 3.55 (m, 1H), 3.45 (m, 1H), 2.98 (m, 2H), 2.73 (m, 1H), 2.41 (m, 1H), 2.19 (m, 2H), 2.05 (m, 1H), 1.82 (m, 1H), 1.48 (m, 4H), 1.24 (m, 1H), 1.02 (t, 3H); MS (EI) for C29H37N7O3S: 564 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Cl)c(F)c2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2c(ccc(Cl)c2F)/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 72.8 %

Procedure:
To the mixture of 6-chloro-7-fluoroindolin-2-one (1.1 g, 5.9 mmol) (Natrochem) and 3-chloro-2-fluorobenzaldehyde (1.4 g, 8.9 mmol) (Aldrich) in methanol (50 mL) was added piperidine (1.5 g, 17.8 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to half its volume. The mixture was filtered and resulting precipitate was collected, dried to give the first batch of desired product (1.4 g). The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product (0.44 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.84 g, 89%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([O:21][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C=O)C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A mixture of 2-fluoro-benzaldehyde (0.85 mL; 8.06 mmol; 1 eq.), 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.54 g mg; 8.86 mmol; 1.1 eq.) and K2CO3 (2.23 g; 16.11 mmol; 2 eq.) in DMF (20 mL) was stirred at 120° C. for 16 hours. 3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester (279 mg; 1.61 mmol; 0.2 eq.) was added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with DCM, washed with water then brine, dried over magnesium sulfate and concentrated in vacuo. Recrystallization from Et2O afforded the title compound (1.03 g, 46%) as a yellow solid. HPLC (max plot) 99.4%; Rt 4.07 min.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCCl>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([N:18]2[CH2:19][CH2:20][C:14]3[NH:13][C:12]4[N:11]=[CH:10][CH:9]=[C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:16]=4[C:15]=3[CH2:17]2)=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1cccc(Cl)c1)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), 3-chlorobenzoyl chloride (32 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 9 (16 mg, 26% yield) as a tan solid. LC-MS (M+H=403, obsd.=403).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH:20]=[N:19][C:18]([CH3:21])=[N:17]1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[N:33]=[C:34](Cl)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1>C(#N)C>[Cl:31][C:32]1[N:33]=[C:34]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[N:16]2[CH:20]=[N:19][C:18]([CH3:21])=[N:17]2)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: CNCCCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN(C)c2nc(Cl)nc3c2CCC3c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a solution of N-methyl-3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation L, 1.20 g, 4.15 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (0.731 g, 5.66 mmol) followed by 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation R, 1 g, 3.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-N-methyl-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (1.2 g, 61.2%) as a light yellow solid. LC-MS (M+H)+=518.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 7.30-7.11 (5H, m), 4.35-4.31 (2H, m), 4.18-4.14 (1H, m), 3.87-3.70 (2H, s), 3.28 (3H, s), 3.21-3.07 (2H, m), 2.54-2.50 (1H, m), 2.27-2.24 (2H, m), 2.01-1.98 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([S:18]([CH3:19])=[O:33])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(F)c1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(F)c1
Reaction time: 0.5 h

Procedure:
In DCM (50 mL) was dissolved ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (2.2 g, 6.3 mmol). m-CPBA (3-chloroperbenzoic acid, 1.1 g, 6.4 mmol) was added. The reaction was conducted at ambient temperature for 30 min. The reaction mixture was washed with water. The organic phase was dried over sodium sulfate and concentrated to give ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxylate. The product was used in the subsequent procedure without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH:29][CH2:30][CH2:31][CH3:32])[CH3:28]>C(#N)C>[CH2:27]([N:29]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1)[CH2:30][CH2:31][CH3:32])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCC
Solvent: CC#N
Product: CCCN(CC)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-ethylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 282 (5), 101 (8), 100 (bp), 72 (6), 58 (9).