Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=1.[K+].[C:20]([C:22]1[N:23]=[C:24]([C:35]([O-])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=1)#[N:21]>CO.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:35]([C:24]2[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[C:22]([C:20]#[N:21])[N:23]=2)=[O:36])=[C:3]([C:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C(N)=O)ccc2N)CC1
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 94 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-benzamide (as prepared in the previous step, 51.0 mg, 0.209 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 70.2 mg, 0.230 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (91 mg, 94%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C26H35N5O3Si, 494.3 (M+H), found 494.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CN(C)[CH:20]=[O:21].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:21]
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhydrous tetra-hydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithium-hexane solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformamide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)=cyclohexanol (150 mg), and sodium hydride (43 mg, 60% dispersion in oil) and n-octyl bromide (180 ml) in dry N,N-dimethylformamide (1 ml) was stirred for 3 hrs at room temperature. The mixture was allowed to cool to 0° C., and the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)=cyclohexyl octyl ether (222 mg, 89% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino)-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-chlorobenzylamine (19 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was then slurried in a 1:1 methanol-dichloromethane solution, and the solid collected by vacuum filtration to afford the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl [trans-4-(4-{[(benzyloxy)carbonyl]amino}phenyl)cyclohexyl]acetate (3.34 g, 8.76 mmol) in THF (42 mL) and MeOH (42 mL) was added 0.6M aqueous lithium hydroxide (43.6 mL, 26.27 mmol) and the mixture stirred at ambient temperature for 18 hours. The mixture was partitioned between EtOAc (200 mL) and 1M HCl (100 mL). The organic phase was concentrated in vacuo and the residue partitioned between EtOAc (300 mL) and brine (20 mL). The organic phase was dried (MgSO4), filtered and evaporated to give the title compound (3.19 g, 99%) as a white solid; 1H NMR (CDCl3) δ 1.05-1.15 (2H, m), 1.36-1.46 (2H, m), 1.74-1.87 (5H, m), 2.22 (2H, d), 2.34-2.41 (1H, m), 5.13 (2H, s), 6.58 (1H, s), 7.07 (2H, d), 7.21 (3H, t), 7.28-7.35 (4H, m); MS m/e (MH)+ 368
Reaction SMILES: [C:1](OOC(=O)C1C=CC=CC=1)(=[O:8])C1C=CC=CC=1.[Br-].[Br-].O1CCOCC1.[CH3:27][C:28]1[C:33](C)=[CH:32][C:31]2[N:35]([CH2:45][CH:46]([O:62]C(C)=O)[CH:47]([O:58]C(C)=O)[CH:48]([O:54]C(C)=O)[CH2:49][O:50]C(C)=O)[C:36]3[C:43](=[N:44][C:30]=2[CH:29]=1)[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]=3>O1CCOCC1>[CH3:27][C:28]1[C:33]([CH2:1][OH:8])=[CH:32][C:31]2[N:35]([CH2:45][C@@H:46]([OH:62])[C@@H:47]([OH:58])[C@@H:48]([OH:54])[CH2:49][OH:50])[C:36]3[C:43](=[N:44][C:30]=2[CH:29]=1)[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]=3
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(Cn1c2nc(=O)[nH]c(=O)c-2nc2cc(C)c(C)cc21)OC(C)=O
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@@H](O)[C@@H](O)[C@@H](O)CO)c2cc1CO

Procedure:
Synthesis of 8α-hydroxyriboflavin was carried out by the method of McCormick (21). Briefly, riboflavin was added to a solution of acetic acid: acetic anhydride (1:1) and the yellow solution was stirred at room temperature for 24 hours. Tetra-acetylriboflavin (TAR) was extracted from the aqueous reaction mixture with CHCl3, followed by extraction with water and evaporation to give a yellow residue of essentially pure TAR. Dibenzoyl peroxide and dioxane dibromide in dioxane were added to a solution of TAR in dioxane, and the solution was refluxed. The crude bromo-TAR was separated from the reaction mixture on a C-18 Semi-Prep HPLC column (Beckman). The bromo-TAR was hydrolyzed to yield 8α-hydroxyriboflavin, which was separated by HPLC (System Gold, Beckman) through a linear gradient from 0.5% trifluoroacetic acid (TFA) in water to 0.5% TFA in acetonitrile for 50 minutes at a flow rate of 4 ml/minute.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCOC
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: COCCN(C)C(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-methoxy-N-methylethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[O:20]=[C:21]1[C:26]2[CH:27]=[CH:28][C:29](O)=[C:30]([CH2:31][CH2:32][CH3:33])[C:25]=2[O:24][C:23]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(N(CC)CC)C>[O:20]=[C:21]1[C:26]2[CH:27]=[CH:28][C:29]([O:14][CH2:13][CH2:12][O:11][C:1]3[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[CH:4]=[CH:3][CH:2]=3)=[C:30]([CH2:31][CH2:32][CH3:33])[C:25]=2[O:24][C:23]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22]1
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reactant: OCCOc1cccc2c1CCCC2
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of 202 mg (1.05 mmol) of the title product of Example 59 in 10 ml of CH2Cl2 was cooled with stirring to 0° C. and treated sequentially with 370 mg (3.70 mmol) of triethylamine and 362 mg (3.15 mmol) of methanesulfonyl chloride. After one hour, the mixture was treated with another 370 mg of triethylamine and 362 mg of methanesulfonyl chloride. After one-half hour, the mixture was washed successively with water, aqueous sodium bicarbonate solution, dilute aqueous hydrochloric acid, and water. The organic phase was dried (MgSO4), filtered, and the solvent removed under reduced pressure. The residue was taken up in 10 ml of dimethylformamide. To the resulting solution was added 406 mg (1.00 mmol) of the title product of Example 1 and 290 mg (2.10 mmol) of anhydrous potassium carbonate. The mixture was stirred overnight at room temperature. Another 290 mg of potassium carbonate was then added, and stirring was continued at 60° C. for six hours. The mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed successively with water and with brine, dried (Na2SO4), filtered, and the solvent removed under reduced pressure. The residue was chromatographed over silica gel. Elution with 15% ethyl acetate/toluene produced 152 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][CH:11]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH2:14][CH2:13][NH:12]1>>[CH3:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:13][CH2:14][C:15]3[CH:19]=[CH:18][S:17][C:16]=3[CH:11]2[CH3:10])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: CC1NCCc2ccsc21
Reactant: Cc1cc(O)nc(Cl)n1
Product: Cc1cc(O)nc(N2CCc3ccsc3C2C)n1
Yield: 70.4 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 6-methyl-2-chloro-4-hydroxypyrimidine(6 g, 37.5 mmol) prepared in Step 1 of Example 57, and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (12.07 g, 78.75 mmol) prepared in preparation 1 were used as starting materials, 6.9 g of the titled compound was prepared.
Reaction SMILES: O.NN.C1(=O)[N:8](C(N)=O)[C:7](=O)[C:6]2=CC=CC=C12.O=C1C2C(=CC=CC=2)C(=O)N1CC[C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([C:40]([NH2:42])=[O:41])=[CH:35][CH:34]=2.CN1C(N)=NC(=O)C1.S([O-])([O-])(=O)=O>C(O)C.O>[NH2:8][CH2:7][CH2:6][C:39]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:40]([NH2:42])=[O:41])[CH:37]=2)[NH:32][CH:31]=1
Reactant: NC(=O)c1ccc2[nH]c(CCN3C(=O)c4ccccc4C3=O)cc2c1
Reactant: NC(=O)N1C(=O)c2ccccc2C1=O
Agent: CN1CC(=O)N=C1N
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: NCCc1c[nH]c2ccc(C(N)=O)cc12

Procedure:
Hydrazine hydrate (30 ml) was added to the crude phthalimido carboxamide prepared in (ii) above (1.5 g) in ethanol (60 ml). The mixture was refluxed for 2.5 hours and cooled. The solvent was evaporated off and the residue stirred with 2 N sodium carbonate solution (60 ml) and the resulting solution was evaporated to dryness. The residue was extracted with ethanol and the combined extracts were evaporated to give a yellow solid that was dissolved in hot ethanol (45 ml) and treated with a solution of creatinine sulphate (1.6 g) in water (20 ml) and ethanol (10 ml). The solution obtained was diluted with ethanol to 85 ml. The title compound (1.8 g) precipitated as an off-white solid m.p. 205°-210° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][C:35]#[N:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:36][CH2:35][CH2:34][C:33]#[N:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: N#CCCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 55.4 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 48 (500 mg, 1.12 mmol) and 3-aminopropionitrile (0.41 mL, 5.6 mmol) were reacted to give the desired product 270 mg (55%). LC-MS: 436.0 (MH+, m/z), 2.17 (Rt, min).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20FN5O2, 417.2
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7]Cl.[I-:16].[Na+]>CC(C)=O>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][I:16]
Reactant: [I-]
Reactant: CON=C(CCCCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CON=C(CCCI)c1ccc(F)cc1
Yield: 99.8 %

Procedure:
4-Chloro-1-(4-fluorophenyl)butan-1-one O-methyl oxime (0.78 g, 3.40 mmol) and sodium iodide (0.76 g, 5.09 mmol) in acetone (10 mL) were heated at reflux overnight. The mixture was evaporated, the residue diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (gradient to 10% ethyl acetate/hexanes) to give product as an oil (1.09 g, quant.); MS for C11H13FNO m/z 322 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][Br:26])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Temperature: 77 °C
Yield: 99.2 %

Procedure:
A suspension of compound 1D (79 mg, 0.30 mmol), NBS (59 mg, 0.33 mmol) and benzoyl peroxide (5 mg, 0.02 mmol) in CCl4 (2 mL) was heated at 77° C. for 3 hours. After cooling to room temperature, the reaction was purified by a short silica gel column (eluted with CH2Cl2) to give compound 16A as a yellow solid (102 mg, 99%). B. 4-Chloro-3-cyano-5-hydroxymethyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (16B)
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:51]=[C:52]([S:57](Cl)(=[O:59])=[O:58])[CH:53]=[C:54]([Cl:56])[CH:55]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([C:52]1[CH:51]=[C:50]([Cl:49])[CH:55]=[C:54]([Cl:56])[CH:53]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3cc(Cl)cc(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step6, Example 1) was added 3,5-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [Li].[CH3:2][Si:3](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.II.[F:19][C:20](F)=[CH2:21]>O1CCCC1>[F:19][C:20]([Si:3]([CH3:2])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:21]
Reactant: C[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C(F)F
Agent: II
Agent: [Li]
Solvent: C1CCOC1
Product: C=C(F)[Si](C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium wire (2.08 g, 300 mmol) in dry tetrahydrofuran (150 ml) was added methyldiphenylsilyl chloride (15.8 ml, 75 mmol) and a catalytic amount of iodine. The reaction mixture was sonicated for 40 min and then stirred overnight at room temperature. The reaction mixture was cooled to −78° C. and 1,1-difluoroethylene (approx. 225 mmol) was passed through the mixture for 30 min. The mixture was stirred at −78° C. for 2 h and then warmed to room temperature.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH2:12](Br)[CH:13]=[CH2:14]>>[N+:1]([CH:4]=[C:5]1[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:14][CH:13]=[CH2:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCCCN1
Reactant: C=CCBr
Product: C=CCN1CCCCNC1=C[N+](=O)[O-]

Procedure:
Method B, reacting hexahydro-2-(nitromethylene)-1H-1,3-diazepine with allyl bromide. Melting point: 82° - 83°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:3]=1.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH:9]([O:8][C:6]1[N:7]=[C:2]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CCCCNCCCC
Reactant: CC(C)Oc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(CCCC)c1nc(OC(C)C)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 16 h

Procedure:
12.5 g of 2-chloro-4-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine and 5.5 g of dibutylamine are dissolved in 100 ml of xylene. After addition of a solution of 1.8 g of sodium hydroxide in 10 ml of water, the water is slowly removed by distillation in a water separator under a weak flow of nitrogen. The contents of the flask are subsequently stirred at 135° for about 16 hours. The mixture is allowed to cool somewhat, 50 ml of water are added to the contents of the flask and the mixture is stirred vigorously for 10 minutes. The aqueous phase is separated off and the organic layer is washed four times, each with 50 ml of water, dried over sodium sulfate and completely evaporated in vacuo. The 2-isopropyloxy-4-dibutylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine obtained is a weakly yellowish resin.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]1[C:21](OC)=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=1I)([O-:3])=[O:2].C(Cl)(=O)[C:34](Cl)=[O:35].COC1C=C(C(I)=CC=1OC)C(O)=O.[N+](C1C=CC=C2C=1N=CC=C2NCCN(C)C)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:20]1[C:19]([O:35][CH3:34])=[CH:18][C:17]2[C:10]3[C:9](=[C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:13]4=[N:12][CH:11]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(I)c(C(=O)N(CCN(C)C)c2ccnc3c([N+](=O)[O-])cccc23)c1OC
Agent: CN(C)CCNc1ccnc2c([N+](=O)[O-])cccc12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cccc([N+](=O)[O-])c4ncc3c2cc1OC
Yield: 85 %

Procedure:
N-(8-Nitroquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8a). Oxalyl chloride (762 mg, 6.0 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (570 mg, 1.85 mmol) in anhydrous methylene chloride (20 mL), and the stirred mixture was refluxed for 3 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 20 mL of anhydrous methylene chloride, and this solution was added to a solution of 7a (400 mg, 1.54 mmol) and triethylamine (1.14 g, 11.3 mmol) in methylene chloride (20 mL), and the resulting mixture was stirred at reflux overnight. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×100 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 722 mg of the amide, in 85% yield; 1H NMR (CDCl3) δ 2.30 (s, 6H), 2.69 (m, 2H), 3.32 (s, 3H), 3.74 (s, 3H), 3.95 (m, 1H), 4.57 (m, 1H), 6.41 (s, 1H), 7.02 (s, 1H), 7.75 (m, 2H), 8.05 (d, 1H, J=6.6), 8.44 (d, 1H, J=8.4), 8.95 (d, 1H, J=4.4); 13C NMR (CDCl3) δ 45.4, 47.3, 55.7, 56.1, 56.5, 82.7, 110.7, 121.9, 123.3, 124.0, 126.1, 126.9, 127.2, 133.1, 140.9, 147.4, 148.4, 149.0, 150.1, 153.0, 169.9; IR (CHCl3) 1362, 1536, 1655.