Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]([Mg][Cl:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[ClH:14].[NH2:5][CH:1]([CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(C)C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(N)Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 13.8 g(0.2 mol) of isobutyronitrile dissolved in 50 ml of absolute tetrahydrofuran(THF) was added 2.0M solution of benzyl magnesium chloride(110 ml, 0.22 mol) at room temperature. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. 200 ml of methanol and 11.4 g(0.3 mol) of NaBH4 were added to the resulting solution and the whole mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding 300 ml of 1N hydrochloric acid and the solvent was removed by distillation under a reduced pressure. The reaction mixture was adjusted to pH 11 with 1N NaOH solution, extracted with chloroform, dried over anhydrous Na2SO4, and 50 ml of 5N hydrochloric acid in methanol was added thereto. The resulting solution was purified by column chromatography using dichloromethane: methanol(10:1) as an eluent to give 37.5 g of the title compound(yield:94%).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([I:28])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[I-:28].[CH2:1]([S+:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCCCCCI
Reactant: CCSCC
Product: CCCCCCCCCCCCCCCCCCCCCC[S+](CC)CC
Product: [I-]

Procedure:
Diethyl sulphide is quaternized by docosyl iodide in order to obtain diethyldocosylsulphonium iodide. This iodide is then placed in an alcoholic solution with an equivalent of the TCNQ lithium salt. This gives crystals, which are recrystallized in alcohol. These crystals are constituted by the simple tetracyanoquinodimethane diethyl docosyl sulphonium salt of formula: ##STR4##
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added acetanilide (50 g, 370 mmol), succinic anhydride (37 g, 370 mmol), and 200 mL carbon disulfide. The reaction vessel was cooled with an external ice bath while aluminum (III) trichloride (185 g, 1390 mmol) was added over 1 hour. Additional carbon disulfide (75 mL) was added, the reaction stirred for 1 hour with external ice bath, and then stirred at room temperature for 18 hours. The reaction vessel was cooled with an external ice bath and ice (75 mL) was added to the reaction to quench. The mixture was transferred to a 2 L beaker and ice was added until the final volume was 1400 mL. The insoluble material was collected by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 1000 mL of 8% aqueous sodium bicarbonate and stirred for 3 hours, diluted with an additional 200 mL of water, and filtered to remove insoluble impurities. The filtered solution was acidified with 1 M aqueous hydrochloric acid until pH=2. The crude product precipitate was collected by filtration and was re dissolved in hot (80-85° C.) water (1250 mL), insoluble material removed by decanting and the mixture cooled to 4° C. The product (8.45 g, 10%) was isolated by filtration as yellow off-white crystals. Found: C, 61.20, H, 5.63%, N, 5.94%; C12H23NO4 requires C, 61.27; H, 5.58%, N, 5.96%; 1H NMR (d6-DMSO): δ 12.2, s, 1H (COOH); δ 10.3, s, 1H(NH); δ 7.9, d, 2H (aryl H's); δ 7.7 d, 2H (aryl H's); 3.2, t, 2H(CH2 α to carbonyl); δ 2.6, t, 2H(CH2 α to COOH); δ 2.1, s, 3H(CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]#[N:21])[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.Cl.[NH2:23][OH:24].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20](=[N:23][OH:24])[NH2:21])[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(Cl)c2)C1
Reaction time: 5 h
Yield: 96.3 %

Procedure:
A solution of tert-butyl 1-(3-chloro-4-cyanobenzyl)azetidine-3-carboxylate (0.133 g, 0.434 mmol) in isopropanol (1.2 mL) with hydroxylamine hydrochloride (0.060 g, 0.868 mmol) and sodium bicarbonate (0.146 g, 1.74 mmol) was stirred at 90° C. for 6.5 hrs. HPLC and LCMS indicated the reaction was only 33% complete after 20 minutes. Additional hydroxylamine hydrochloride (0.060 g) and sodium bicarbonate (0.146 g) were added and heating was continued for 5 hrs. The isopropanol was removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate and washed with water (2×), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded tert-butyl 1-(3-chloro-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (142 mg) of a tan viscous taffy. The compound had an HPLC ret. time=0.795 min.−Column. PHENOMENEX® S5 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=340.11.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1.[C:18](Cl)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([NH:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
As shown in step 10-ii of Scheme 10, to Compound 1033 (10.0 g) in pyridine (80 mL) was added acetyl chloride (4.2 mL). After stirring at 50° C. for 30 min, water (200 mL) was added. The resulting solid was collected by filtration and washed with water (2×) gave tert-butyl 2-acetamido-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (Compound 1034, 10.873 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].I[CH:13]([CH3:15])[CH3:14]>CS(C)=O.O>[CH:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: CC1(C)OCC(CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (2 g), in DMSO (50 mL), powdered potassium hydroxide was added portionwise at 0° C. then warmed to room temperature. 2-Iodo-propane (43 mL) was added to the mixture at 0° C. then stirred for 72 h at room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine (×2) and dried (MgSO4), filtered and evaporated to give the subtitle compound as clear, colourless oil. Yield: 2 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>>[C:23]([NH:22][CH2:21][CH2:20][NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])(=[O:25])[CH3:24]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-(2-Acetylamino-ethyl)-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.44 mmol N-(2-amino-ethyl)-acetamide LC/MS [8.38 min; 4.59 (M+1)]
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][S:22]([CH:19]5[CH2:21][CH2:20]5)(=[O:24])=[O:23])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=S(=O)(NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)C1CC1
Yield: 40 %

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (53.2 mg, 0.19 mM) was reacted with cyclopropane sulfonylchloride (2.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per general procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 16.7 mg of 376 after RP-HPLC purification (40% yield). MS (Q1) 471.3 (M)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(OC)c1)OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester (Example 132, Step A) (0.080 g, 0.31 mmol) in acetonitrile (10 mL) was added 4-(3-bromo-propoxy)biphenyl (Example 132, Step D) (0.101 g, 0.35 mmol) and potassium carbonate (0.115 g, 0.945 mmol). The resulting suspension was stirred at 85° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (10 mL), and water (10 mL) was added. The organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), and concentrated. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate, 7:3) to produce 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic acid ethyl ester (0.086 g, 59%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.26 (m, 7H), 6.98 (d, 2H, J=8.6), 6.87–6.73 (m, 3H), 4.25–4.17 (m, 6H), 3.91 (dd, 1H, J=7.0, 5.6), 3.83 (s, 3H), 3.35 (s, 3H), 2.97–2.93 (m, 2H), 2.31 (qn, 2H, J=5.9), 1.24 (t, 3H, J=7.3).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[C:7]([C:9]1[CH:25]=[CH:24][C:12]2[CH2:13][CH2:14][N:15](C(=O)C(F)(F)F)[CH2:16][CH2:17][C:11]=2[C:10]=1[S:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])#[N:8].O.C(Cl)Cl>CO>[C:9]([O:2][C:1]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([S:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[C:9]([C:7]#[N:8])[CH:25]=[CH:24][C:12]=2[CH2:13][CH2:14]1)=[O:4])([CH3:25])([CH3:10])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)Sc1c(C#N)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C)C(=O)Sc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
Add potassium carbonate (4.13 g, 30 mmol) to a stirred solution of 7-cyano-6-dimethylcarbamoylsulfanyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (740 mg, 2.0 mmol) in methanol (40 mL)/water (15 mL) and stir for 1.5 h. Add DCM (10 mL), di-text-butyl dicarbonate (480 mg, 2.2 mmol) and stir at ambient temperature for 3 days. Concentrate in vacuo and dilute with DCM, wash with water and extract with DCM. Combine the organic layers, wash with brine, dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc:heptane (0:1 to 1:1) to give the title compound as a colourless foam (370 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 3.69-3.48 (m, 4H), 3.26-3.02 (m, 10H), 1.45 (s, 9H).
Reaction SMILES: [C:1]1([C:7](=[CH:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@@H:14]1[C:25](=[O:26])[N:16]2[C@@H:17]([C:22]([OH:24])=[O:23])[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]12>>[C:1]1([C:7](=[CH:11][CH3:12])[C:8]([NH:13][CH:14]2[C:25](=[O:26])[N:16]3[CH:17]([C:22]([OH:24])=[O:23])[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]23)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=C(C(=O)O)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Product: CC=C(C(=O)NC1C(=O)N2C(C(=O)O)C(C)(C)S[C@H]12)c1ccccc1

Procedure:
In a similar manner to that of Example 17, 2-phenylbut-2-enoic acid (cis isomer) was converted into its acid chloride and coupled with (3S, 5R, 6R)-6-amino-2,2-dimethylpenam-3-carboxylic acid to give the title compound, λmax. (pH 6 phosphate buffer) 234, 345 nm (ε7,200; 4,260), νmax. (nujol) 1770 (β-lactam), τ (d6 -DMSO) values include 0.92 (d, NH), 3.83 (q, 6Hz vinylic proton), 4.3-4.5 (m, 5 and 6 H), 8.42 and 8.52 (gem dimethyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])(=[O:36])=[O:35])=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2C)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methylbenzenesulfonyl chloride (22 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 6-methoxy-1-methyl-8-[(2-methylphenyl)sulfonyl]-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (3.3 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (3.4 mg). MS m/z 387 [M+H]+.
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.[NH:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[NH2:27]>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:35])=[O:36])=[CH:30][CH:29]=2)[N:27]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-benzenesulfonamide according to the method described for example 43. MS: M=478.1 (M+H)+
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:8]([CH:12]([CH3:14])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.N([O-])=[O:24].[Na+]>S(=O)(=O)(O)O.O.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:6](=[O:22])[C:5]3[C:10](=[CH:11][C:2]([OH:24])=[CH:3][CH:4]=3)[N:9]=[C:8]2[CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=1
Reactant: O=N[O-]
Reactant: CC(C)c1nc2cc(N)ccc2c(=O)n1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a suspension of the compound of Example 1 (778 mg, 2.479 mmol) in concentrated sulphuric acid/water 972 μL/1.4 mL, cooled to ice bath temperature, is added a solution of sodium nitrite (188 mg) in water (680 μL). The mixture is stirred for 45 minutes at 0.0-5° C. (internal temperature) and then added to sulphuric acid/water 3/2 (5 mL), pre-heated to 150° C. After stirring for 15 minutes, the mixture is allowed to cool to room temperature, filtered and extracted with EtOAc (3×). The combined EtOAc extracts are washed with water, dried (Na2SO4) and evaporated to a yellow-orange solid. Purification by automated flash chromatography (gradient elution: EtOAc/hexane 0-25%) provides the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][C@H:50]([OH:52])[CH3:51])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1.COCCO>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:36][C:37]4[CH:38]=[CH:39][C:40]([N:43]5[CH2:44][CH2:45][N:46]([CH2:49][C@H:50]([OH:52])[CH3:51])[CH2:47][CH2:48]5)=[CH:41][CH:42]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc2)CC1
Yield: 60 %

Procedure:
N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (125.1 mg, 0.0003187 mol), N,N-Diisopropylethylamine (0.1665 mL, 0.0009561 mol) and (R)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (150 mg, 0.00064 mol) were dissolved in 2-Methoxyethanol (2.24 mL, 0.0284 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 107.72 mg of N-tert-Butyl-3-(2-{4-[4-((R)-2-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a lyophilized powder. (M+H)=564.2. 1H NMR (400 MHz, DMSO, d6) δ 9.38 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1H, J=7.92 Hz), 7.85 (d, 1H, J=8.12 Hz), 7.73 (m, 1H), 7.66 (d, 2H, J=9.00 Hz), 7.60 (s, 1H), 7.18 (d, 1H, J=4.76 Hz), 7.02 (d, 2H, J=9.01 Hz), 6.97 (d, 1H, J=4.76 Hz), 4.13 (m, 1H), 3.61 (m, 5H), 3.18 (m, 3H), 3.04 (m, 3H), 1.14 (d, 3H, J=6.16 Hz), 1.12 (s, 9H).
Reaction SMILES: [C:1](/[CH:4]=[CH:5]\[C:6]1[CH:7]=[C:8]([CH2:20][C:21]([OH:23])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:3])=[O:2].[C:24](N1C=CN=C1)(N1C=CN=C1)=O.[CH3:36][NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CO>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:36][N:37]([CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:21](=[O:23])[CH2:20][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6](/[CH:5]=[CH:4]/[C:1]([O:3][CH3:24])=[O:2])[CH:7]=1
Reactant: O=C(O)/C=C\c1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)/C=C/c1cc(CC(=O)N(C)CCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg (1.61 mmoles) of cis-3-carboxyvinyl-4-benzyloxyphenylacetic acid in 30 ml of CH2Cl2 is added 522 mg (3.22 mmoles) of 1,1'-carbonyldiimidazole (CDI). After 30 minutes, 234 ml (1.61 mmoles) of N-methyl-N-phenethylamine is added. After 18 hours a catalytic amount of 4-dimethylaminopyridine and 5 ml of methanol are added. After stirring for 21/2 hours, the reaction mixture is concentrated down in vacuo, taken up in ethyl acetate, washed with 1N NaOH, 1N HCl, H2O (2 times), brine (2 times), dried with MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography to yield trans-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbomethoxyvinyl)phenyl]acetamide. NMR confirms this structure which is used directly in the next step.
Reaction SMILES: C(Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][CH:12]2[CH2:15][N:14]([CH:16](C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13]2)=[CH:8][CH:7]=1.[CH2:31]([NH2:34])[CH:32]=[CH2:33].Cl>C(Cl)Cl.[Cl-].[Na+].O.O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][CH:12]2[CH2:13][N:14]([C:16]([NH:34][CH2:31][CH:32]=[CH2:33])=[O:2])[CH2:15]2)=[CH:29][CH:30]=1
Reactant: Clc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: C=CCN
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(OCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
Phosgene solution (1.75-M in toluene, 24 mmol) was added at 0° C. to a solution of compound (1) (20 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at room temperature for 90 min, concentrated in vacuo, then redissolved in CH2Cl2 (40 mL) and treated with allylamine (42 mmol) at 0° C. The reaction was stirred for 4 h at room temperature, then water (40 mL) was added and the layers were separated. The aqueous layer was extracted with further CH2Cl2 (2×40 mL). The organic layers were washed with dilute HCl (20 mmol) and brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated using diethyl ether to give the product (2) as a crystalline solid (3.5 g, 60%), m.p. 110-111° C. Found: C, 59.84; H, 6.11; N, 9.98. C14H17ClN2O2 requires: C, 59.89; H, 9.6.10; N, 9.97%.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:20][CH:21]=[CH2:22]>CC(N(C)C)=O>[CH2:22]([O:1][CH2:2][C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a solution of e tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (479 mg, 2.089 mmol) in DMA (3 mL) was added 60 wt % sodium hydride (125 mg, 3.13 mmol). Reaction immediately turned yellow. Stirred for 5 min and added 3-bromoprop-1-ene (1263 mg, 10.44 mmol). After 3 h, partitioned between EtOAc and sat.aq.NH4Cl. The organic phase was washed with water (3×), brine and dried (MgSO4), filtered, and concentrated to give 471 mg (75%) of tert-butyl 4-((allyloxy)methyl)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.91 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.29 (dq, J=17.1, 1.7 Hz, 1H), 5.19 (dq, J=10.4, 1.5 Hz, 1H), 3.98 (dt, J=5.3, 1.5 Hz, 2H), 3.62 (br. s., 2H), 3.23-3.14 (m, 4H), 1.56-1.49 (m, 2H), 1.48 (s, 9H), 1.37-1.28 (m, 2H), 1.02 (s, 3H). LCMS (M+1)=270.25.