Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[Sn](CCCC)(CCCC)CCCC)[C:9]1=[O:29].[Cl:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.[OH-].[NH4+].[Cl-].[Na+]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[C:9]1=[O:29]
Reactant: Clc1ccc(I)cc1
Reactant: CCCC[Sn](/C=C/C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](C/C=C/c2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-tributylstannyl-2-propene-1-yl)-4-methylazetidin-2-one (0.92 g, 1.79 mmol) in 3 mL of dimethylformamide is added 4-chloroiodobenzene (470 mg, 1.97 mmol) and triphenyphosphine palladium (II) dichloride (63 mg, 0.09 mmol). The resulting solution is heated at 80° C. for 16 h, then 0.5 mL ammonium hydroxide is added. The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted with 1:1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3:1 hexanes-ethyl acetate) to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-(4-chlorophenyl)-2-propene-1-yl)-4-methylazetidin-2-one as an oil (370 mg, 61% yield).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][O:6][C:7]1[C:8]([N+:14]([O-])=O)=[N:9][C:10](Br)=[CH:11][CH:12]=1)C.BrC1N=C([N+]([O-])=O)[C:22]([OH:28])=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OCC)=O>CC(C)=O.CCOCC>[O:17]=[C:4]1[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:22]=[O:28])=[N:9][C:8]=2[NH:14]1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
(6-Bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester. To a suspension of 6-bromo-2-nitro-pyridin-3-ol (3.07 g, 14.0 mmol) in acetone (20 mL) was added K2CO3 (3.93 g, 28.0 mmol) and ethyl bromoacetate (1.55 mL, 14.0 mmol). The mixture was heated to reflux and stirred for 20 h. The resulting suspension was cooled to RT, diluted with Et2O (100 mL) and filtered. The filtrate was concentrated to afford 3.14 g (74%) of the title compound, which was used without further purification. MS (ESI): exact mass calculated for C9H9BrN2O5, 303.97; m/z found, 305.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.67 (d, J=8.6, 1H), 7.35 (d, J=8.7, 1H), 4.78 (s, 2H), 4.27 (q, J=7.1, 2H), 1.30 (t, J=8.5, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[C:11]([CH2:12][Br:17])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)C(C)(C)CCC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(F)cc21
Temperature: 25 °C
Yield: 124.4 %

Procedure:
To a solution of 10.0 g (45.4 mmol) of 2-fluoro-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 91 mL of carbon tetrachloride was added 8.48 g (47.7 mmol) of N-bromosuccinimide and 0.330 g (1.36 mmol) of benzoyl peroxide. The solution was heated at reflux for 35 minutes and then cooled to room temperature. 200 mL petroleum ether was added and the solution filtered and concentrated in vacuo to afford 16.9 g of 2-fluoro-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.[F:14][C:15]([F:51])([F:50])[C:16]1[CH:17]=[C:18]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:19][N:20]([C:37]1[O:41][N:40]=[C:39]([CH3:42])[CH:38]=1)[C@H:21]1[CH2:27][CH2:26][CH2:25][NH:24][C:23]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:22]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:24]2[CH2:25][CH2:26][CH2:27][CH:21]([N:20]([CH2:19][C:18]3[CH:43]=[C:44]([C:46]([F:48])([F:49])[F:47])[CH:45]=[C:16]([C:15]([F:14])([F:50])[F:51])[CH:17]=3)[C:37]3[O:41][N:40]=[C:39]([CH3:42])[CH:38]=3)[C:22]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][C:23]2=3)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(C=O)CC1
Reactant: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc(C(F)(F)F)c(C)cc32)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)CC1CCC(CN2CCCC(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3cc(C)no3)c3cc(C)c(C(F)(F)F)cc32)CC1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Add (4-formyl-cyclohexyl)-acetic acid methyl ester (68 mg, 0.368 mmol) to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (80 mg, 0.122 mmol) in acetic acid (0.5 mL) and 1,2-dichloroethane (5 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (103 mg, 0.488 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless semi-solid (73 mg, 85%). 1H NMR (CDCl3, 300 MHz) δ 0.72-2.34 (m, 21H), 2.60-2.65 (m, 1H), 2.82-2.90 (m, 1H), 3.00-3.10 (m, 2H), 3.89 (s, 3H), 4.60-4.89 (m, 3H), 5.12-5.18 (m, 1H), 6.89 (s, 1H), 7.15 (s, 1H), 7.68-7.71 (m, 3H), 7.82 (s, 1H); ESI MS m/z 720 [C35H38F9N3O3+H]+; HPLC 96.1%, tR 22.1 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].ClCC1C=C(NC(N2C3C(=CC(OC4C5CCN(C(OC(C)(C)C)=O)CC=5N=CN=4)=CC=3)C=C2)=O)C=C(C(F)(F)F)C=1>C(Cl)Cl.CCOC(C)=O>[CH3:52][S:53]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CO)cc(C(F)(F)F)c3)c2)C1
Agent: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CCl)cc(C(F)(F)F)c3)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate (0.211 g, 0.361 mmol) in 6 mL of DCM with DIEA (0.19 mL, 1.08 mmol) at 0° C., methanesulfonyl chloride (0.037 mL, 0.469 mmol) is added and the reaction stirred for 3 h. At that point the reaction is diluted with EtOAc, washed with saturated sodium bicarbonate, brine and the organic layer is dried over sodium sulfate. Concentration provides a mixture of the title compound and tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate (3:7), which is carried on to next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:3]1>CO>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:3]1
Reactant: CN1CCC(N2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CN1CCC(N2CC(C)(C)c3ccc(N)cc32)CC1
Reaction time: 8 h

Procedure:
3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole (600 mg, Step E) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (100 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford the title compound as an oil. MS: 260 (M+1). Calc'd. for C16H25N313 259.39.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH3:24])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:38](OCCBr)(=[O:40])[CH3:39].CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:23]=2[CH3:24])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:39][CH2:38][OH:40])[CH2:11][CH2:10]1)#[N:2]
Reactant: CC(=O)OCCBr
Reactant: Cc1c(C(=O)Nc2ccc(N3CCCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(N3CCCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
N-[3-Cyano-4-(homopiperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (1.5 g), potassium carbonate (0.6 g) and 2-bromoethyl acetate (0.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. To the residue were added 2N aqueous sodium hydroxide solution (10 ml) and ethanol (20 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure and dilute hydrochloric acid was added. The obtained crystals were recrystallized from hydrous ethanol to give the title compound (1.1 g), melting point: 124° C.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Cc1ccc(O)cc1
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 4-methylphenol:
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([O:23]C)[C:8]2=[S:25])[CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=[S:25])[CH:2]=1
Reactant: COc1c(CCCCCc2c[nH]nn2)ccn(-c2cccc(C)c2)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(-n2ccc(CCCCCc3c[nH]nn3)c(O)c2=S)c1
Yield: 55.2 %

Procedure:
Reaction of 165b (0.10 g, 0.271 mmol) and 1M BBr3 (0.33 mL) in CH2Cl2 (8 mL) within 48 h as described for the synthesis of 148a gave compound 167b (0.053 g, 56%) as olive green solid. 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.61 (s, 1H), 7.55 (m, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.92 (m, 2H), 4.55 (m, 2H), 4.44 (t, J=6.7 Hz, 2H), 2.36 (s, 3H), 2.01 (m, 4H), 1.41 (m, 2H). 13C NMR (100 MHz, CD3OD) δ 149.29, 140.05, 131.87, 131.78, 130.38, 130.20, 127.90, 127.63, 124.13, 122.51, 51.40, 31.07, 30.93, 28.97, 24.49, 22.02. HRMS (EI) calcd for C19H22N4OS [M]+ 354.151. found 354.1523.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][CH2:13][CH2:14]Cl)[C:5]([O:7][CH3:8])=[O:6].[I-].[Na+]>CC(=O)CC>[S:12]1[CH2:13][CH2:14][NH:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]1=2
Reactant: COC(=O)c1ccc(SCCCl)c(N)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2c(c1)NCCS2
Temperature: 70 °C
Yield: 50 %

Procedure:
To a solution of methyl 3-amino-4-(2-chloroethylthio)benzoate (19.7 mg, 0.080 mmol) in 2-butanone (2 mL) was added sodium iodide (36 mg, 0.240 mmol). The reaction mixture was heated to 70° C. and stirred over night at that temperature. The reaction mixture was cooled to room temperature. TLC and LCMS analysis of the reaction mixture indicated product formation. The product was purified by flash column chromatography [gradient elution with Hexanes and 5-50% EtOAc]. To provide methyl 3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (8.6 mg, 0.040 mmol, 49.6% overall 3 steps) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 180 °C

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline (256 mg, 1 mmol), 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine prepared as in STEP 1 above (194 mg, 1.0 mmol) in DMSO (3 mL) was added DIPEA (0.52 mL, 3 mmol). The resulting mixture was sealed and heated at 180° C. for 1.5 h under microwave irradiation. The resulting mixture was poured into H2O (30 mL) and the aqueous layer was extracted with 30% CH2Cl2/Et2O (30 mL×5). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield the title compound, 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)indoline.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:35][CH2:36][CH2:37][NH:38][C:39]1[N:47]=[C:46]([Cl:48])[N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl.O>[Cl:48][C:46]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:39]([NH:38][CH2:37][CH2:36][NH:35][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[N:47]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: CSc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg of 4-(methylthio) benzoic acid, 205 mg of 1-hydroxybenzotriazole hydrate, 290 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 280 mg of the product obtained in Stage 1 of Example 7 is added and the reaction medium is agitated for 4 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 336 mg of expected product is collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:21][CH2:22][C@@H:18]([NH:17][C:16](=[O:23])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19]2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cc2C=O)C1
Temperature: 120 °C
Yield: 83.3 %

Procedure:
5-Bromo-2-fluorobenzaldehyde (1.55 mL, 13.0 mmol) and tert-butyl-(3R)-pyrrolidin-3-ylcarbamate (2.90 g, 15.6 mmol) in DMF (70 mL) were treated with potassium carbonate (2.25 g, 16.3 mmol). The solution was heated to 120° C. for 18 h under nitrogen. The solution was allowed to cool to ambient temperature and was diluted with ethyl acetate (150 mL) and washed with water (100 mL). The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (30% ethyl acetate/hexanes) to afford product 22-A as a yellow solid (4.00 g, 83%). 1H NMR (500 MHz, CD3OD): δ 10.02 (s, 1H), 7.81 (d, J=2.9 Hz, 1H), 7.51 (dd, J=11.2, 2.4 Hz, 1H), 6.88 (d, J=9.27 Hz, 1H), 4.20 (m, 1H), 3.60–3.51 (m, 2H), 3.42 (m, 1H), 3.21 (m, 1H), 2.22 (m, 1H), 2.00 (m, 1H), 1.46 (s, 9H); LCMS found for C16H21N2O3Br (M+H)+: m/z=370.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[C:7]2[OH:15].[Cl-].[NH4+].C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH2:21])=[O:13])[CH:8]=[C:7]2[OH:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(O)cc(C(N)=O)nc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid (115 mg, 0.45 mmol) and ammoniumchloride (36 mg, 0.68 mmol) were dissolved in DMF (4 mL). HATU (342 mg, 0.9 mmol) and NMM (159 mg, 1.58 mmol) were added and the mixture was stirred at r.t. overnight. An additional amount of ammoniumchloride (72 mg, 13.5 mmol) was added and heated to 53° C. for 18 h. The reaction mixture was cooled to r.t. and concentrated to give 8-chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid amide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1F
Product: O=C(C=Cc1ccc(Br)cc1F)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-bromo-2-fluorobenzaldehyde and acetophenone, 3-(4-bromo-2-fluorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH:9]1[CH2:15][CH:14]([OH:16])[CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:15][CH:14]([OH:16])[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: OC1CNCCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC1CNCCN(c2cccc(Br)n2)C1
Temperature: 100 °C

Procedure:
To a mixture of 2-bromo-6-fluoropyridine (845 mg, 4.83 mmol) and 1,4-diazepan-6-ol (560 mg, 4.83 mmol) in EtOH (20 mL) was added DIPEA (5 mL). The reaction mixture was heated at 100° C. for 15 hours, which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was used in the next step without further purification. MS (ESI) m/z: 272 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5][CH2:4]1
Reactant: OCC(CO)(CBr)CBr
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: BrCC1(CBr)COC(c2ccccc2)OC1
Reaction time: 6 h
Yield: 88.6 %

Procedure:
2,2-Bis(bromomethyl)propane-1,3-diol (250 g) and benzaldehyde (110 g) were added to benzene (500 cm3) containing concentrated sulphuric acid (2 cm3) and the mixture boiled. Water was removed using a Dean Stark apparatus. After about 6 hours the reaction was complete. The mixture was cooled and the sulphuric acid neutralised by the addition of excess sodium bicarbonate. The resulting solution was filtered and the benzene removed under reduced pressure to give an oil which solidified on standing. Recrystallisation from petroleum ether gave the 1,3-dioxane (296 g) as a white solid (m.p. 66° C.).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 98.4 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (536 mg, 1 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 12 h. The mixture was then diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (390 mg, 98.5%) as a white solid: LC/MS m/e calcd for C22H24N2O3S [M+H]+ 397.51, observed 397.2.