Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.N1C=CC=CC=1.[CH3:53][N:54]([CH3:59])[S:55](Cl)(=[O:57])=[O:56]>O1CCCC1>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][S:55]([N:54]([CH3:59])[CH3:53])(=[O:57])=[O:56])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N(C)C)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(S)-2-(1-((5-(4-Amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with pyridine (19 μL, 0.23 mmol) and dimethylsulfamoyl chloride (23 mg, 0.16 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at 50° C. overnight. The title compound was obtained (76 mg, 74% yield, 57% purity) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[CH:7]=1.[C:21]([Si:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=1)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].C(N(CCCC)CCCC)CCC.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:25]([O:28][C:29]1[CH:34]=[C:33]([CH:11]2[CH:12]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:20])[CH2:9][N:10]2[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:32]=[CH:31][CH:30]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1C=CC(c2cc(Cl)ccc2F)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 65 °C

Procedure:
A deoxygenated mixture of tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (17-1, 1.100 g, 3.69 mmol, 1 equiv), tert-butyl(3-iodophenoxy)dimethylsilane (1.85 g, 5.54 mmol, 1.50 equiv), tributylamine (1.76 mL, 7.39 mmol, 2.00 equiv), triphenylarsine (0.453 g, 1.48 mmol, 0.400 equiv), and palladium acetate (0.166 g, 0.739 mmol, 0.200 equiv) in DMF (10 mL) was heated at 65° C. for 20 hours. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×85 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 50% ethyl acetate in hexanes) to provide tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (17-2) as an orange oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ 7.11-6.53 (m, 7H), 6.11 (s, 1M), 5.32 (m, 1H), 4.53 (m, 2H), 1.09 (s, 9H), 0.79 (s, 9H), 0.00 (s, 6H). LRMS m/z (M+H) 504.1 found, 504.2 required.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][O:36][CH2:37][CH2:38]Br.[OH-].[Na+]>CN(C=O)C>[CH3:35][O:36][CH2:37][CH2:38][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: COCCBr
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (500 mg, 1.2 mmol) in 12 mL of DMF was added Hunig's base (790 mg, 6.1 mmol) and 2-bromoethyl methyl ether (850 mg, 6.1 mmol). The solution was stirred at room temperature for 5 days. The solution was poured onto 2.5 N NaOH and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL) and brine (1×100 mL). The organic phase was dried over Na2SO4 and was filtered. The solvent was removed under reduced pressure to leave a solid. The solid was triturated and filtered to leave the title compound: 1HNMR (CDCl3) δ8.63 (d, J=4.23 Hz, 2 H), 7.28 (m, 4 H), 7.14 (d, J=4.43 Hz, 2 H), 3.57 (t, J=5.24 Hz, 2 H), 3.38 (s, 3 H), 3.14 (bd, J=10.1 Hz, 2 H), 2.79 (m, 1 H), 2.68 (t, J=5.04, 2 H), 2.08 (m, 4 H), 1.92 (m, 2 H). MS (M+H): 397 (base peak).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[CH:26][CH:27]=1)[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)C3CCCCN43)CC2)cc1
Temperature: 90 °C
Yield: 58.4 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (50 mg, 0.214 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (55.0 mg, 0.236 mmol), (cyanomethyl)trimethylphosphonium iodide (67.7 mg, 0.279 mmol) and N,N-diisopropylethylamine (187 μl, 1.072 mmol) were suspended in Propiononitrile (Volume: 644 μl) and heated in a closed vial at 90° C. for 1 h. It was cooled to ambient temperature, the resulting precipitate was filtered, washed with MeCN (5 mL) and dried in vacuum to afford N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (56 mg, 0.125 mmol, 58.2% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.43 (s, 1H), 8.12 (t, J=5.6 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 7.66 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.47-4.55 (m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32-3.40 (m, 2H), 3.18-3.28 (m, 6H), 2.61 (td, J=12.6, 2.5 Hz, 1H), 2.43-2.49 (m, 4H), 2.04 (d, J=13.1 Hz, 1H), 1.80-1.91 (m, 2H), 1.64 (d, J=12.6 Hz, 2H), 1.33-1.58 (m, 3H), 1.09 (d, J=14.4 Hz, 3H); [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([C:32]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=O>C(OCC)C.C(O)(C)(C)C.O>[Cl:41][C:38]1[CH:39]=[CH:40][C:32]([CH:30]=[CH:2][O:3][CH3:4])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: O
Product: COC=Cc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a cooled (0° C.) slurry of methoxymethyltriphenylphosphonium chloride (39 g) in a mixture of diethyl ether (200 ml) and tert-butanol (50 ml) was added potassium tert-butoxide (12.8 g) portionwise. The resulting mixture was stirred at 0° C. for 1 hour, then a solution of 2-formyl-5-chlorobenzoic acid (prepared as described in J. Org. Chem. 1996, 61, 3402)(10 g) in diethyl ether (50 ml) was added dropwise over 15 minutes. The resulting mixture was stirred for 1 hour at 0° C., then warmed to ambient and stirred for an additional 90 minutes. The mixture was diluted with water (200 ml) and the organic phase removed. The aqueous phase was acidified to pH1 with 1M HCl and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by flash chromatography (50% ethyl acetate/hexane) to afford the sub-title compound as a yellow solid (9.13 g, 80%): 1H NMR (400 MHz, CDCl3) δ 3.70-3.81 (3H, s), 6.20(0.3H, d), 6.30 (0.3H, d), 6.80(0.7H, d), 7.01 (0.7H, d), 7.30-8.15 (3H, m).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1Cl)([CH3:4])([CH3:3])[CH3:2].[C:25]([O-])([O-])=O.[Cs+].[Cs+].CB1OB(C)OB(C)O1.O>COCCOCCOC>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)C)cc2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1=Cc2cc(C)c(C(C)(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 38.2 %

Procedure:
The ethyl 7-tert-butyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 8, Step 2 (1 g, 2.75 mmole) was dissolved in diglyme (20 mL). Cs2CO3 (1.5 g, 3.07 mmole), trimethylboroxaine (0.75 mL, 5.36 mmole), and [(t-Bu3P)PdBr]2 (20 mg) were added to above solution. The mixture was heated to 115° C. for 15 hrs under nitrogen. LCMS indicated that there was 50% conversion. The reaction was cooled down and the water was added to quench the reaction. The product was extracted with EtOAc and washed with water. The crude mixture was purified by RPHPLC to give the desired product 360 mg as an oil (38% yield), which had suitable purity to use without further purification.
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](SC)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[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:38][C:35]4[CH:34]=[CH:33][C:32]([N:31]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:37][CH:36]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)c1
Temperature: 250 °C
Yield: 19.7 %

Procedure:
The title compound was prepared in the following manner from N-tert-Butyl-3-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.1 g, 0.3 mmol), 4-(4-morpholino)aniline (90 mg, 0.5 mmol), N,N-Diisopropylethylamine (0.124 mL, 0.712 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 250° C. for 30 minutes. An LCMS showed product and left over amine. The reaction was concentrated and redissolved in 3 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate and extracted with DCM, dried filtered and concentrated to give N-tert-Butyl-3-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo-[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a yellow solid (30 mg, 20%). MP 225-226 C. LCMS (E/I+) 507 (M+H). NMR 1H (DMSO-d6)-9.40 (bs, 1H), 8.96 (bs, 1H), 8.52 (bs, 1H), 7.77 (d, 1H, J=7.40 Hz), 7.50-7.45 (m, 2H), 7.22-7.05 (m, 4H), 6.93 (s, 2H), 6.54 (d, 1H, J=7.91 Hz), 4.45-4.40 (m, 1H), 3.18-3.25 (m, 2H), 3.04-3.11 (m, 2H), 1.98-2.06 (m, 2H), 1.74-1.84 (m, 2H).
Reaction SMILES: COC1C=CC([N:9]2[C@H:12]([CH:13]=[C:14]([CH3:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:21])=CC=1>C(#N)C.O>[C:18]([O:17][C@H:11]1[C@@H:12]([CH:13]=[C:14]([CH3:16])[CH3:15])[NH:9][C:10]1=[O:21])(=[O:20])[CH3:19]
Reactant: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2C=C(C)C)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@@H]1C(=O)N[C@@H]1C=C(C)C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
A solution of the (±)-cis-N-(4-methoxyphenyl)-3-acetyloxy-4-isobutenylazetidin-2-one (4.88 g, 16.2 mmol) was dissolved in acetonitrile (50 mL) and cooled to 0°-5° C. in an ice bath. To this was added a cold solution of ceric ammonium nitrate (26.6 g, 48.6 mmol, 50 mL) in one portion. The deep red reaction was allowed to stir for 10 min and during that time the color gradually lightened to orange. The cold solution was transferred to a separatory funnel, diluted with water, and extracted with ethyl acetate. The organic fraction was washed with several portions of 10% aqueous sodium sulfite, followed by saturated aqueous sodium bicarbonate. The organic fraction was dried (MgSO4) and concentrated to give the desired product (2.71 g, 91%) as a yellow-orange solid that was used directly in the next step; 1H NMR (300 MHz, CDCl3): δ 6.11 (bs, 1H), 5.73 (dd, 1H, J=2.2, 4.7 Hz), 5.12-5.08 (m, 1H), 4.63 (dd, 1H, 4.7, 9.1 Hz), 2.09 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:13])[NH:6]2.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([NH:24][NH2:25])(=[O:23])=[O:22])=[CH:17][CH:16]=1>CO>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([NH:24][N:25]=[C:4]2[C:3]3[C:7](=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]2=[O:13])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: COc1ccc(Cl)c2c1NC(=O)C2=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CO
Product: COc1ccc(Cl)c2c1NC(=O)C2=NNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
25.0 g (0.118 mole) of 4-chloro-7-methoxyisatin is taken up in 500 ml CH3OH at 60° and treated portionwise with 23.8 g of 97% p-toluenesulfonylhydrazine (≅ 23.1 g or 1.05 equivalents). The mixture is kept at ~60° for 15 minutes and then stirred at room temperature for 20 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15]N1C(=O)CCC1=O.[OH-].[Na+].C(OC(=O)C)C>C(#N)C>[Cl:15][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:7]=1[NH2:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 97.1 %

Procedure:
4-Nitro-2-trifluoromethylaniline (15 g) and N-chlorosuccinimide (10.7 g) dissolved in acetonitril (100 ml) was heated to 150° C. for 15 minutes in a sealed microwave process vial. The reaction mixture was cooled to ambient temperature and poured into 5% sodium hydroxide (500 ml) and ethylacetate (400 ml). After seperation the organic phase was dried (MgSO4), filtered and concentrated in vacuo, followed by purification by flash chromatography to furnish 17.0 g (97% yield) of the title compound as a yellow solid. LC-MS (m/z) 240 (MH+); tR=4.76, (UV, ELSD) 97%, 96%. 1H NMR (500 MHz, DMSO-d6): 7.15 (s, 2H), 8.15 (d, 1H), 8.40 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15].[O:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]1>>[O:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]([C:2]2[N:3]=[C:4]([NH:15][CH2:14][CH2:13][CH2:12][NH2:16])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:19][CH2:18]1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: NCCCN
Reactant: c1ccc2c(c1)CNCCO2
Product: NCCCNc1nc(N2CCOc3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamine, followed by reaction with 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine. MS obsd. (ESI+) [(M+H)+] 356, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (d, J=5.3 Hz, 1H), 7.43 (d, J=7.1 Hz, 1H), 7.12-7.18 (m, 1H), 7.08 (d, J=5.6 Hz, 1H), 6.93-7.04 (m, 2H), 4.93 (s, 2H), 4.20-4.26 (m, 2H), 4.14-4.19 (m, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 1.96 (m, 2H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=[C:22]3[C:21]2=[O:31])=[C:16]([CH3:32])[CH:15]=1.[Cl:33][C:34]1[S:38][C:37]([CH2:39][NH2:40])=[CH:36][CH:35]=1>C(Cl)Cl.C(N(CC)C(C)C)C.CC(N(C)C)=O>[Cl:33][C:34]1[S:38][C:37]([CH2:39][NH:40][C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:24](=[O:25])[C:23]4[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:22]=4[C:21]3=[O:31])=[C:16]([CH3:32])[CH:15]=2)=[O:4])=[CH:36][CH:35]=1
Reactant: NCc1ccc(Cl)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: CCN(CC)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCc2ccc(Cl)s2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
To a solution of triphosgene (22 mg, 0.074 mmol) in CH2Cl2 (1 mL) was added a suspension of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (57 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) and diethylisopropylamine (70 μL) dropwise over 10 min. The reaction mixture was stirred for 10 min, then a solution (5-chloro-2-thienyl)methylamine from step B (47 mg, 0.32 mmol) in CH2Cl2 (1 mL) and DMA (35 μL) was added. The mixture was stirred at room temp for 17 hr, acidified and HPLC purified to give {[(5-chloro(2-thienyl))methyl]amino}-N-[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]carboxamide (18 mg, 20%). ES-MS (M+H)+=460, 462 (Cl). 1H-NMR (DMSO-d6): δ 2.02 (s, 3H), 4.34-4.36 (d, 2H), 6.77-6.80 (t, 1H), 6.82-6.93 (2d, 2H), 7.14-7.16 (d, 1H), 7.29-7.32 (dd, 1H), 7.41 (d, 1H), 7.93 (ABq, 2H), 8.02 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[O:18]C(C(=O)NCCC3C=CC=CC=3)=C[CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(C(C)C)CC)(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46].[O:49]1CCOC[CH2:50]1>C(Cl)Cl>[CH3:50][O:49][C:44]([C:45]1[O:18][C:17]([S:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:33])[CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:21][CH:46]=1)=[O:47]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)o2)CC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
[1-(5-Phenethylcarbamoyl-furan-2-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.15 g, 0.3 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.3 ml, 1.6 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 50% EtOAc, 50% heptane) to give the title compound (0.01 g, 2% yield) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:8]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)N(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a mixture, under nitrogen, of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionate (1.5 g, 3.53 mmol) in dry ethanol (5 ml) was added ammonium formate (1.12 g , 17.69 mmol) followed by the addition of 10% palladium on carbon (0.50 g). The mixture was stirred overnight at room temperature and then heated at 80° C. for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness in vacuo to give a semisolid. Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9].[N:16]([O-])=O.[Na+].[S:20](=[O:22])=[O:21]>Cl.C(O)(=O)C.O>[CH2:12]([N:11]([CH2:14][CH3:15])[S:8]([C:3]1[C:2]([S:20]([NH2:16])(=[O:22])=[O:21])=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:10])=[O:9])[CH3:13]
Reactant: O=S=O
Reactant: CCN(CC)S(=O)(=O)c1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)S(=O)(=O)c1ccccc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 114 g of o-amino-N,N-diethylbenzenesulfonamide in a mixture of 400 ml of concentrated hydrochloric acid and 100 ml of glacial acetic acid was added a solution of 50 g of sodium nitrite in 130 ml of water at -5° to 0°. The solution was stirred at 0° for 15 minutes then poured into a mixture of 14 g of cuprous chloride and 100 ml of liquid sulfur dioxide in 550 ml of glacial acetic acid at 0°-5°. This mixture was stirred at 0° for 15 minutes then at room temperature for 3 hours before pouring into three liters of ice water. The crude suflonyl chloride was filtered off and washed with water. It was then dissolved in 1 l of ethyl ether, washed with water and dried over magnesium sulfate. To this ether solution was added 20 ml of liquid anhydrous ammonia at 5°-15°. After stirring overnight at room temperature the solid was filtered off, washed with water, ethanol and then 1-chlorobutane, Oven drying at 60° gave 91.8 g N,N-diethyl-1,2-benzenedisulfonamide, m.p. 156°-9°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14]CC)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:5]2[N:6]([C:8]([C:12]([OH:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Br)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
1.5 g of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 21A; 3.5 mmol, 1 equivalent) were dissolved in 72 ml of THF/methanol 5:1, 17.6 ml of 1N aqueous lithium hydroxide solution (17.6 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 6 h. Using 6 N aqueous hydrochloric acid, the mixture was then adjusted to pH 4 and concentrated. Water was added to the solid formed and the solid was triturated, filtered off, washed with water and dried under reduced pressure. This gave 1.24 g of the title compound (88% of theory).