Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH2:29][CH3:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([NH:74][CH2:75][C:76](O)=[O:77])(OC(C)(C)C)=O>CN(C=O)C.C(OCC)(=O)C.O.C1COCC1>[NH2:74][CH2:75][C:76]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH2:29][CH3:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1)=[O:77]
Reactant: CCNc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNc1cc(N[C@H]2CC[C@H](NC(=O)CN)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension containing 6-((trans)-4-aminocyclohexylamino)-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.025 g, 0.061 mmol), diisopropylethylamine (0.053 mL, 0.303 mmol), and BOP (0.080 g, 0.182 mmol) in DMF at room temperature was added BOC-glycine (0.021 g, 0.121 mmol). The resulting suspension was stirred 30 min at ambient temperature. The dark brown solution was diluted with ethyl acetate and water. The layers were separated and the aqueous phase extracted three times with 5 mL ethyl acetate. The organic extracts were combined, washed with water and 10% aq. lithium chloride five times before drying over anhydrous sodium sulfate. Filtration and concentration under reduced pressure revealed a white solid which was suspended in CH2Cl2 (0.5 mL) at room temperature. TFA (0.5 mL) was added, resulting in a homogeneous solution. After 30 min at room temperature, the crude material was diluted with 1 mL of THF and purified via preparative HPLC using a YMC ODS C-18 30×250 mm column with 10-100% B (Solvent A: 10% aq MeOH with 0.1% TFA; Solvent B: 90% aq. MeOH with 0.1% TFA) and a linear gradient over 30 min at 25 mL/min, monitoring at 220 nm (Rt=27.545 min) The appropriate fractions were concentrated and lyophilized overnight, furnishing 6-((trans)-4-(2-aminoacetamido)cyclohexylamino)-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (19 mg, 0.027 mmol, 44.9% yield) as a white foam. MS: [M+H]=470.0. HPLC: Rt=3.121 min. (Waters sunfire 4.6×50 mm C18.5 um 4 min/1 min hold time 0-100% (A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10% water-0.1% TFA).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Br:15])[CH:5]=[CH:4][C:3]=1[OH:16].[CH:17]([O-])([O-])OCC>>[Br:15][C:6]1[CH:5]=[CH:4][C:3]2[O:16][CH:17]=[N:1][C:2]=2[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1c(O)ccc(Br)c1Oc1ccccc1
Product: Brc1ccc2ocnc2c1Oc1ccccc1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 2-amino-4-bromo-3-phenoxyphenol (0.075 g, 0.268 mmol) in ethyl orthoformate (0.405 mL, 2.43 mmol) was heated at 100° C. for 2.5 h. after which time the reaction mixture was cooled to RT and concentrated in vacuo to a crude residue. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (75.1 mg, 97%) as a white solid. LCMS calculated for C13H9BrNO2 (M+H)+: m/z=290.0, 292.0. found: 289.9, 291.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([O:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[CH:74]1([NH:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([Cl:85])[C:80]=2[Cl:86])[CH2:76][CH2:75]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([O:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:77]([CH:74]2[CH2:75][CH2:76]2)[CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([Cl:85])[C:80]=2[Cl:86])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cccc(CNC2CC2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(OCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(c3cnc(OCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A sol. of compound D4 (1.39 mmol, 0.87 g) in CH2Cl2 (11.2 mL) was treated with DMAP (0.35 mmol, 42 mg), HOBt (1.67 mmol, 0.23 g), EDC.HCl (3.47 mmol, 0.66 g), and DIPEA (5.55 mmol, 0.95 mL). After 30 min at rt, cyclopropyl-(2,3-dichlorobenzyl)-amine (prepared by reductive amination from 2,3-dichlorobenzaldeyhde and cyclopropylamine; 4.16 mmol, 0.90 g) was added and the mixture was stirred for 4 days at rt. The reaction was then diluted with CH2Cl2 (40 mL), washed with aq. 1M HCl (2×50 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.48 g, 42%). LC-MS: tR=1.29 min; ES+: 823.50.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:9])[CH2:16][CH2:15]2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Clc1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.50 g (8.48 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 50 mL dichloromethane were cooled with a bath of ice/ethanol and combined with 1.20 g (7.81 mmol) 5-chloro-2,3-dihydro-1H-indole. 7.90 mL (7.90 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 2 h while being cooled and for 1 h at RT. Then 50 mL of an aqueous saturated sodium hydrogen carbonate solution were added. After 10 min stirring the organic phase was separated off and extracted with water (1×30 mL) and with 1 M hydrochloric acid (1×50 mL). The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][C@H:6]([C:13]([OH:15])=[O:14])[CH2:5]2.B([O-])([O-])[O-].[Na+].[Na+].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>O>[C:23]([N:7]1[C@H:6]([C:13]([OH:15])=[O:14])[CH2:5][C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=2)[CH2:8]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1C(=O)c1ccccc1
Yield: 82.1 %

Procedure:
(3S)-6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [J. Org. Chem., 26, 3533 (1961)] (33.9 g) and sodium borate.10H2O (62 g) are suspended in water (500 ml). Benzoyl chloride (27.5 g) and a solution of sodium hydroxide (13 g) in water (100 ml) are added dropwise to the suspension at 0° C. under stirring. The mixture is stirred at room temperature for 4 hours. The mixture is washed with ethyl acetate, and acidified with conc. HCl, and extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The crystals are collected by filtration, washed with benzene and then recrystallized from water, whereby (3S)-2-benzoyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (41.7 g) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=3)([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1C
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1C
Temperature: 70 °C

Procedure:
A mixture of rac-6-chloro-3-(3,4-dimethyl-phenyl)-1,3-dihydro-indol-2-one (0.18 g, 0.66 mmol) (from Example 52b supra), 3-chlorobenzyl bromide (0.16 g, 0.77 mmol) (Aldrich), potassium iodide (0.13 g, 0.78 mmol) and potassium carbonate (0.197 g, 1.42 mmol) in acetone (5 mL) was heated at 70° C. for 4 hours. After cooling, mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3,4-dimethyl-phenyl)-1,3-dihydro-indol-2-one as yellow solid. (Yield 0.08 g, 30.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH:15]=[C:14]2[C:18]2[CH:23]=[CH:22][C:21]([C@H:24]([O:30]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].C1COCC1.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH:15]=[C:14]2[C:18]2[CH:19]=[CH:20][C:21]([C@H:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC[C@@H](O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A mixture of 45 (40 mg, 0.069 mmol), K2CO3 (10 mg, 0.072 mmol) in methanol (0.5 mL) was stirred at room temperature. After 1 h, the diester had not dissolved and so 0.2 mL THF was added. The reaction was stirred further for 1.5 h and then 10 mL 1 M HCl was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography using a Combiflash unit by Teledyne Isco (12 g silica gel, 0%→20% ethyl acetate/hexanes) gave the title compound (22 mg, 0.051 mmol, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O>C1(C)C=CC=CC=1.CCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: N#Cc1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cc(C#N)ccn2)cc1
Temperature: 50 °C

Procedure:
A solution composed of 2-bromo-4-pyridinecarbonitrile (5.00 g, 36.1 mmol), 4-[(tert-butyldimethylsilyl)oxy]aniline (8.06 g, 36.1 mmol), sodium tert-butylate (4.50 g, 46.9 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.458 g, 1.08 mmol) in toluene (50 mL) is purged with nitrogen. Tris(dibenzylideneacetone)-dipalladium(0) (0.99 g, 1.08 mmol) is then added to the reaction mixture, and then the batch is heated at 50° C. for 1.5 hours. The mixture is then allowed to cool to ambient temperature. Water is added and the reaction mixture is extracted with ethyl acetate (3×20 mL). The combined organic phases are washed with brine, and then concentrated under reduced pressure. The crude product is absorbed onto silica gel and purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product obtained is dissolved in the warm state in heptane and precipitates, with stirring, at ambient temperature, and then at 0° C. After filtration, the expected compound is obtained in the form of a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl>C1COCC1.O1CCOCC1>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Clc1ncnc2sc3c(c12)CCNC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate (3500 mg, 10.7 mmol) in THF (100 mL) was added 4 N HCl in 1,4-dioxane (4 N, 6 mL). The reaction mixture was stirred at room temperature for 24 h. The white precipitate was collected and dried under reduced pressure and gave 2000 mg (82%) of the desired product. LCMS RT=0.21 min, [M+1]+=226.
Reaction SMILES: [Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[C:3]=1[Br:14].[NH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[NH2:16].Cl>CCO.CC(O)C>[Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=[N:16][NH:15][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])[C:4]=2[C:3]=1[Br:14]
Reactant: O=C1NCCC(=O)c2c1[nH]c(Br)c2Br
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: O=C(O)c1ccccc1NN=C1CCNC(=O)c2[nH]c(Br)c(Br)c21

Procedure:
To a solution of 2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (32.2 mg, 0.10 mmol) in EtOH (5 mL) is added 2-hydrazinobenzoic acid (22.6 mg, 0.12 mmol) and HCl in i-PrOH (6N, 0.3 mL). The mixture is refluxed for 2 hours and then concentrated under reduced pressure. The residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give 2-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoic acid; 1H NMR (DMSO-d6) δ 2.80-2.86 (m, 2H), 3.30-3.34 (m, 2H), 6.82 (t, 1H, J=8.0 Hz), 7.51 (d, 1H, J=7.2 Hz), 7.83-7.88 (m, 2H), 8.13 (t, 1H, J=6.0 Hz), 11.03 (s, 1H), 12.95 (s, 1H), 13.13 (s, 1H); m/z [M++1] 456.9.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:22](Cl)(=[O:24])=[O:23].[CH3:26][NH:27][CH3:28].CO>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:22](=[O:24])(=[O:23])[N:27]([CH3:28])[CH3:26]
Reactant: Cn1c(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)csc1=Nc1ccccc1
Reactant: CNC
Agent: Br
Solvent: CO
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3)n2C)ccc1Cl

Procedure:
4.8 g (0.01 mole) of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-phenylimino-4-thiazoline hydrobromide are added in portions to a mixture of 5 ml (about 0.05 mole) of 40% strength aqueous dimethylamine solution and 50 ml of methanol (or ethanol), with external cooling and stirring, at a rate such that the temperature as far as possible does not rise above 35° C. The reaction mixture is stirred for 14 hours at room temperature, the solvent is distilled off under a waterpump vacuum and the residue is crystallized under 50 ml of water, stirring with a magnetic stirrer. Colorless crystals; melting point 178°-181° C.
Reaction SMILES: [N+:1]([O-])(O)=[O:2].[N+:5]([C:8]1([N+:24]([O-:26])=[O:25])[CH2:15][NH:14][CH2:13][C:12]([N+:19]([O-:21])=[O:20])([N+:16]([O-:18])=[O:17])[CH2:11][N:10]([N:22]=[O:23])[CH2:9]1)([O-:7])=[O:6]>>[N+:24]([C:8]1([N+:5]([O-:7])=[O:6])[CH2:15][N:14]([N:1]=[O:2])[CH2:13][C:12]([N+:19]([O-:21])=[O:20])([N+:16]([O-:18])=[O:17])[CH2:11][N:10]([N:22]=[O:23])[CH2:9]1)([O-:26])=[O:25]
Reactant: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CNCC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: O=[N+]([O-])O
Product: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CN(N=O)CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
To 7.0 ml 60 percent nitric acid at 40°-45° C. was added 0.2 g 3,3,7,7-tetranitro-1-nitrosoperhydro-1,5-diazocine (I). The mixture was heated at 40°-45° C. for five minutes and was then poured into ice. The solid was filtered off, washed with water and dried in a vacuum desiccator to give 0.109 g solid 3,3,7,7-Tetranitro-1,5-dinitrosoperhydro-1,5-diazocine. The solid was recrystallized from nitromethane to remove a small amount of starting material; mp: 190° C., onset of decomposition; 228°-229° C. melts; 1H NMR (acetone-d6): δ 4.81 (s), 5.26 (s), 5.73 (s), 6.16 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19]CC.[NH3:23].C(O)C.O>C(Cl)Cl>[NH2:23][C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: N
Reactant: CCCOc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Reaction time: 16 h

Procedure:
10 g (32.45 mmol) of the intermediate product 2a were suspended in 100 ml methylene chloride. After the addition of 100 ml 2-molar ethanol ammonia solution, the reaction mixture was stirred for 16 h. After this, everything was poured on to icy water and the organic phase was separated. The aqueous phase was cooled, wherein a white crystallizate formed, which was isolated. 5.7 g of the product were obtained.
Reaction SMILES: [I:1]I.N1CCOCC1.[C:9]1(/[CH:15]=[C:16](\[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26])/[CH2:17][OH:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[I:1][C:26]#[C:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]#[C:19]/[C:16](=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH2:17][OH:18]
Reactant: II
Reactant: C#CCCCCC#C/C(=C\c1ccccc1)CO
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: OC/C(C#CCCCCC#CI)=C/c1ccccc1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To a solution of iodine (1.479 g, 5.83 mmol) in toluene (80 mL) was added morpholine (1.354 g, 15.54 mmol) followed by heating at 60° C. for 30 minutes. To the resultant mixture was added a solution of Compound 3 (462.3 mg, 1.94 mmol) in toluene (10 mL) and the mixture was heated at the same temperature for 6 hours. The reaction mixture was then allowed to cool down to room temperature and purified, without aqueous work up, by flash column chromatography (silica gel, 100 percent hexane and then 17 percent EtOAc in hexane) to give 630.3 mg (89 percent) of Compound 4: yellow oil; Rf=0.17 (17 percent EtOAc in hexane); IR (neat) 3362 (br), 2942, 2860, 2210, 1446, 1072 cm−1; 1H NMR (300 MHz, CDCl3) δ7.83-7.79 (m, 2H), 7.37-7.24 (m, 3H), 6.71 (s, 1H), 4.26 (d, J=1.20 Hz, 2H), 2.51-2.39 (m, 4H), 1.95 (br s, 1H), 1.76-1.62 (m, 4H); 13C NMR (75 MHz, CDCl3) δ136.7, 133.5, 129.1, 128.9, 128.8, 122.5, 98.7, 94.7, 79.4, 68.2, 28.3, 28.1, 21.0, 20.1, −5.9; MS (+CI) m/z (relative intensity) 365 (M+H+, 10), 220 (100); HRMS (+EI) calcd for C17H17IO 364.0324 (M+), found 364.0299.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:40])([F:39])[CH2:37]I>CN(C)C=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([NH:4][C:5]([S:28][CH2:37][C:36]([F:40])([F:39])[F:35])=[N:6]3)=[C:2]([NH2:1])[N:10]=2)=[N:12]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2nc(SCC(F)(F)F)[nH]c12
Temperature: 70 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
150 mg (0.382 mmol) of the compound from example 28 were dissolved in 2 ml of dimethylformamide, and 58 mg (0.420 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 38 μl (0.382 mmol) of trifluoroethyl iodide were added and the mixture was stirred at RT for 16 h. The mixture was concentrated, and the residue was adsorbed on silica gel and purified by means of chromatography on silica gel (eluent: dichloromethane/methanol=20:1). 49 mg of the title compound were obtained (25% of theory).
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:26]=[CH:25][C:7]2[O:8][CH2:9][CH2:10][C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:12](OS(C(F)(F)F)(=O)=O)[C:6]=2[CH:5]=1>C(OCC)C.[Cu]I>[Br:3][C:4]1[CH:26]=[CH:25][C:7]2[O:8][CH2:9][CH2:10][C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:12]([CH3:1])[C:6]=2[CH:5]=1
Reactant: [Li]C
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2OCC1
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C1=C(C)c2cc(Br)ccc2OCC1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
A solution of 0.4 M (Me)2CuLi was prepared via dropwise addition of methyl lithium in hexanes (1.6 M, 72 mmol, 45 mL) to a suspension of CuI (6.86 g, 36 mmol) in anhydrous diethyl ether (45 mL) in a ice-salt bath. After stirring for 20 min, a homogeneous solution resulted. The solution of dimethyl cuprate was slowly added to a solution of methyl 7-bromo-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-4-carboxylate from step H4 (5.1 g, 11.8 mmol) in diethyl ether (40 mL) at −78° C. The mixture was stirred from −78° C. to −40° C. over 2 h. The reaction was quenched with 30 mL of water and the mixture was extracted with diethyl ether (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3.41 g, 11.5 mmol, 97% yield). The crude mixture was used in the next step without purification. 1H NMR (500 MHz, chloroform-d) δ 7.45 (d, J=2.4 Hz, 1H), 7.40 (dd, J=8.5, 2.4 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 4.53 (t, J=6.1 Hz, 2H), 3.84 (s, 3H), 2.54-2.49 (m, 2H), 2.45-2.42 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:12]#[N:13].[K+]>CN(C)C=O.O.[Na+].[Cl-]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[CH2:10][CH3:11]
Reactant: [C-]#N
Reactant: CCc1ncc(CCl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ncc(CC#N)cc1Cl
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A solution of 3-chloro-5-chloromethyl-2-ethyl-pyridine (4.03 g, 21 mmol) in dimethylformamide (26 mL, 0.8 M) is cooled to 0° C. and treated with a solution of potassium cyanide (1.48 g, 22.7 mmol) in water (10 mL). After 4 h, the solution is diluted with 50% aq NaCl and extracted with ethyl acetate. The organic extracts are washed with sat'd aq lithium chloride and purified by MPLC (30-90% ethyl acetate in heptane) to give 5-chloro-6-ethyl-pyridin-3-yl-acetonitrile as a light brown oil (3.42 g, 90%): Rf 0.29 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.38 (br s, 1 H), 7.67 (br s, 1 H), 3.74 (s, 2 H), 2.97 (q, J=7.5 Hz, 2 H), 1.30 (t, J=7.5 Hz, 3 H) ESI-LCMS m/z calcd for C9H9ClN2: 180.0; found 181.0 (M+1)+.