Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH:41]([C:43]1[CH:57]=[CH:56][C:46]([O:47][C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=2)=[C:45]([CH3:58])[CH:44]=1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:41][C:43]1[CH:57]=[CH:56][C:46]([O:47][C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=2)=[C:45]([CH3:58])[CH:44]=1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC=Cc1ccc(Oc2ccc(C#N)cn2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Suspend (methoxymethyl)triphenylphosphonium chloride (1.14 g, 3.34 mmol)in THF (11 mL) under N2 and cool the mixture at 0° C., add slowly 0.5M KHMDS in toluene (6.7 mL, 3.34 mmol) and stir at 0° C. for 30 min. Cool the mixture at −78° C. and add a solution of aldehyde from step 1 above (663 mg, 2.78 mmol) in THF (2 mL). Wann the mixture slowly to room temperature, and stir for 1 h. Add water and extract the aqueous layer with Et2O. Dry the organic layer over MgSO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: gradient from EtOAc/hexane 10/90 to 20/80) to get the title compound (530 mg, 76%). Electrospray MS M+1 ion=267. 1H-NMR (CDCl3, 300 MHz, mixture of isomers): 8.47-8.45 (m, 2H), 7.92-7.86 (m, 2H), 7.50-7.45 (m, 1H), 7.15-6.93 (m, 8H), 6.14 (d, 1H, J=7.1 Hz), 5.79 (d, 1H, J=13.2 Hz), 5.20 (d, 1H, J=7.1 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:21][C:22](=[O:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:10][CH:11]=3)[N:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:44](O)[CH2:45][OH:46].C([O-])(O)=O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C1(C)C=CC=CC=1>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([F:32])=[C:25]([C:9]2[CH:8]=[C:7]3[C:5]4([CH2:4][O:3][C:2]([NH2:1])=[N:6]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:21][C:22]5([CH3:23])[O:46][CH2:45][CH2:44][O:24]5)[CH:18]=4)[O:13][C:12]3=[CH:11][CH:10]=2)[CH:30]=1
Reactant: OCCO
Reactant: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(-c3cc(Cl)ccc3F)ccc1O2
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC1(COc2cnc3c(c2)C2(COC(N)=N2)c2cc(-c4cc(Cl)ccc4F)ccc2O3)OCCO1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a vial charged with 1-(2′-amino-7-(5-chloro-2-fluorophenyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one (0.140 g, 0.308 mmol), p-toluenesulfonic acid (0.159 g, 0.925 mmol), and 4 Angstrom molecular seives was added 3 mL toluene. The resulting mixture was treated with ethylene glycol (0.022 mL, 0.401 mmol) and was heated to reflux. After stirring for 10 hours, copper(ii) sulfate (0.059 g, 0.617 mmol) was added followed by an additional portion of ethylene glycol (0.022 mL, 0.401 mmol). The reaction mixture was heated to reflux for an additional 4 hours before being allowed to cool to RT. The mixture was poured into saturated NaHCO3 (25 mL) solution and extracted with EtOAc (3×25 mL). The organics were washed with brine, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave 7-(5-chloro-2-fluorophenyl)-3-((2-methyl-1,3-dioxolan-2-yl)methoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine. MS m/z=498.0 [M+H].
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CS(C)=O>[Cl:3][C:4]1[N:5]=[N:6][C:7]([O:18][C:14]2[CH:13]=[C:12]([NH2:11])[CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1ccc(Cl)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccc(Cl)nn2)c1

Procedure:
A concentrated aqueous solution of 44 g of sodium hydroxide was added to a stirred solution of 149 g of 3,6-dichloropyridazine and 114.5 g of meta-aminophenol in 500 ml of dimethyl sulfoxide, at room temperature. The stirred mixture was heated, refluxed (150°-155° C.) for two hours, cooled, and filtered. The filter cake was recrystallized from aqueous methanol to give 3-(6-chloro-3-pyridazinyloxy)benzeneamine (1A), as an off-white solid, mp: 76°-77° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:16]([CH:18]=O)=O.C(Cl)Cl>O>[N:9]1[C:8]2[C:4](=[CH:5][S:6][CH:7]=2)[N:3]=[CH:16][CH:18]=1
Reactant: Nc1cscc1N
Reactant: O=CC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1cnc2cscc2n1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
3,4-diaminothiophene dihydrochloride (12, 1.03 g, 5.52 mmol) was added into 5% aqueous Na2CO3(60 mL). An glyoxal aqueous solution (0.36 g, 6.1 mmol) prepared by diluting 40% glyoxal solution (0.885 g) with water (15 mL) was added to the reactant for 5 minutes. The reaction mixture was stirred at room temperature for at least 3 hours, and extracted with ether and/or ethylacetate several times. A collected organic layer was washed with water and dried with anhydrous sodium sulfate, followed by concentration in a rotary evaporator, thereby obtaining a light brown oil. An assay sample was prepared by dissolving the oil into a small amount of CH2Cl2 and purified with column chromatography using hexane as an eluent, thereby obtaining 13 (0.57 g, 76%) as a light brown oil. 1H NMR (CDCl3, 400 MHz, d/ppm): 8.51 (s, 2H, N═CHCH═N), 8.03 (s, 2H, 2×CH—S). 13C NMR (CDCl3, 100 MHz, d/ppm): 144.41, 142.80, 118.00. C6H4N2S (136.17): Theoretical value C, 52.92; H, 2.96; N, 20.57; S, 23.55; Experimental value C, 53.07; H, 3.11; N, 20.50; S, 23.63.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O.[OH-].[Li+].Cl>ClCCl.CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 81A (5.31, 22.96 mmol) and imidazole (7.82 g, 115 mmol) in dichloromethane (106 mL) and DMF (21.3 mL) was added tert-butyldimethylsilyl chloride (7.61 g, 50.5 mmol) and the mixture stirred at room temperature overnight. The mixture then had water (425 mL) added and the solution was extracted with EtOAc and the organic extract concentrated to a residue that was dissolved in 25% EtOAc and 75% hexanes then extracted with brine and the organic extract concentrated to a solid. The resultant solid was dissolved in methanol (65 mL) and water (85 mL) then lithium hydroxide monohydrate (1.93 g, 46 mmol) added and the solution stirred at room temperature for 2 h. Afterwards water (106 mL) and a solution of 1N aqueous hydrochloric acid was added until a pH of 2 was reached. The mixture was then extracted with a mixture of 25% EtOAc and 75% hexanes, the organic extract dried, filtered and concentrated to a colorless solid. MS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[SH:12].[C:13](#N)[CH2:14][C:15]#[N:16].Cl>C(O)C>[C:15]([CH2:14][C:13]1[S:12][C:3]2[CH:4]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1)#[N:16]
Reactant: N#CCC#N
Reactant: Nc1ccc(S(N)(=O)=O)cc1S
Agent: Cl
Solvent: CCO
Product: N#CCc1nc2ccc(S(N)(=O)=O)cc2s1
Yield: 22.8 %

Procedure:
A suspension of 4-amino-3-mercaptobenzenesulfonamide (74 g, 208 mmol) and malononitrile (25 g, 375 mmol) in 650 mL of ethanol with 1.3 mL of conc. HCl was refluxed under argon overnight. The dark brown solids were isolated by filtration and were washed with ethanol and ether to yield approximately 30 g of the crude product. The volume of the filtrate was reduced by evaporation and the solids that precipitated were isolated by filtration to yield an additional 12 g of product. The crude material was purified by flash column chromatography eluting with CH2Cl2:MeOH:ammonia (60:20:1 mL) to yield a total of 22.2 g (35% for three steps) of the title compound as an orange powder.
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>>[CH3:14][CH:13]([CH3:15])[CH2:12][N:16]1[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2]1
Reactant: CC(C)CN
Reactant: O=C(Cl)c1ccccc1SCl
Product: CC(C)Cn1sc2ccccc2c1=O

Procedure:
This was prepared by the process described in Example 17 except using 2-chlorosulphenylbenzoyl chloride (4.14 parts, 0.02M) and isobutylamine (7.95 parts, 0.08M). The product (4 parts, 97% theory) was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23](O)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O1CCCC1.CO>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[N:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:12]=[C:13]([CH2:23][OH:24])[CH:14]=2)=[CH:21][CH:20]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Yield: 71.5 %

Procedure:
4-[4-(Aminosulfonyl)phenyl-5-(4 chlorophenyl)-1H-pyrazole-3-carboxylic acid from Step 2 (3.8 g, 10 mmol) and tetrahydrofuran (100 mL) were stirred at room temperature during dropwise addition of 1.0 M borane-tetrahydrofuran complex (30 mL, 30 mmol). The mixture was held at reflux for 16 hours. The mixture was cooled and methanol was added dropwise until gas evolution ceased. Ethyl acetate (100 mL) was added and the mixture was washed with 1N hydrochloric acid, brine, sat. aq. sodium bicarbonate solution, and water, dried over magnesium sulfate, filtered and concentrated. The resultant alcohol was recrystallized from ethanol:water to yield a white solid (2.6 g, 71%): mp 192–194° C. 1H NMR (DMSO-d6/300 MHz) δ 7.81 (d, J=8, 7 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (brs, 2H), 7.40 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0 Hz, 1H), 4.50 (d, J=8.0 Hz, 2H). Anal. Calc'd for C16H14N3SO2Cl: C, 52.82; C, 52.91; H, 3.88; H, 3.88; N, 11.55; N, 11.50.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)[N:10]3[N:17]=[CH:18][C:19]([CH:20]=O)=[C:9]3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:22]1[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].N1CCCCC1>C(O)C>[CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)[N:10]3[N:17]=[CH:18][C:19](/[CH:20]=[C:28]4/[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22]/4)=[C:9]3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(NC3CCCC3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(NC4CCCC4)nc23)N1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
5-(Cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.0 eq, 20 mg, 0.070 mmol) was mixed in a vial with hydantoin (2.8 eq, 20 mg, 0.20 mmol) in Ethanol (0.3 ml). Piperidine (2.9 eq, 20 ul, 0.202 mmol) was added and the mixture was stirred at 90° C. for 3 hours. The mixture was cooled down, the precipitate was filtered, washed with ethanol and dried. (Z)-5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (25 mg, 100%). LCMS (ES): >95% pure, m/z 368 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C(N(CC)CC)C>[C:15]1([CH:4]2[CH:3]([CH2:2][O:1][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[C:9](=[O:10])[NH:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[S:5]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)C1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2C(=O)Nc3ccccc3SC2c2ccccc2)cc1
Yield: 91.3 %

Procedure:
5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 1 was dissolved in 20 ml of triethylamine. 3.8 g of p-toluenesulfonyl chloride was added to the solution while stirring and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the precipitated crystals were separated by filtration and recrystallized from a mixture of dichloromethane-n-hexane to obtain 8 g of 2,3-dihydro-2-phenyl-3-[(p-toluenesulfonyloxy)methyl]-1,5-benzothiazepin-4(5H)-one as colorless prisms having a melting point of 215° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4]
Reactant: ClCc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[C:16](=O)[NH:15][CH2:14][CH2:13][N:12]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNCC1Cc1ccc2c(c1)OCO2
Yield: 66.3 %

Procedure:
Dissolving 2.00 g of 2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine as synthesized in the above step in 50 ml of tetrahydrofuran, 1.00 g of lithium aluminium hydride was added to the solution which then was heated under reflux for 16 hours. To the solution 10% aqueous potassium hydroxide solution was added, the insoluble matter was filtered off, extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (methanol:chloroform=1:19) to provide 1.27 g (66%) of 2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2Br)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:26]([N:28]([CH2:45][CH3:46])[CH2:29]/[CH:30]=[CH:31]\[Sn](CCCC)(CCCC)CCCC)[CH3:27].[F-].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:31]=[CH:30]\[CH2:29][N:28]([CH2:45][CH3:46])[CH2:26][CH3:27])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2Br)ccc(Br)c1OC
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Yield: 62.6 %

Procedure:
A mixture of methyl 3-bromo-6-(2-bromo-4-fluorobenzenesulfonylmethyl)-2-methoxybenzoate (Intermediate 70, 5.85 g), N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 5.00 g) and cesium fluoride (3.29 g) in THF (100 mL) was de-gassed and purged with nitrogen for 5 minutes. Palladium tetrakis-(triphenylphosphine) (0.720 g) was added and the reaction mixture was heated at reflux overnight. The mixture was cooled, diluted with ethyl acetate, filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 3-bromo-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-2-methoxybenzoate (3.9 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33](O)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([N:46]2[CH2:47][CH2:48][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44][CH2:45]2)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2-carboxy-4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 10)(30.0 mg, 0.06 mmol) is suspended in N,N-dimethylformamide (0.5 mL) and triethylamine (20.0 μL, 0.14 mmol) is added. The mixture is stirred at room temperature for 5 min and O-(7-azabonzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (24.6 mg, 0.065 mmol) is added and the mixture is stirred for 15 min. A solution of tert-butyl 1-piperazinecaboxylate (17.2 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL) and triethylamine (20.0 μL, 0.14 mmol) is added and the reaction mixture stirred at room temperature for 2 h. The crude product is purified by reversed phase HPLC. ESI mass spectrum [M-tBu+H]+=600; Retention time HPLC: 1.21 min (HPLC method Z018_S08).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[NH:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>O>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[NH:7])[NH:10]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(=O)N1
Solvent: O
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21

Procedure:
11.4 parts of 2-oxo-4-iminothiazolidine are stirred with 15 parts of 1,3-diiminoisoindoline in 300 parts of water for 40 hours at about 25° C., whilst passing a slight stream of nitrogen over the mixture. The product is then filtered off and washed with water, giving 22 parts of 1-imino-3-(2'-oxo-4'-iminothiazolidinylidene)-isoindoline (Formula II, Z=>O), the spectroscopic properties of which correspond to those of the product obtained as described in Example 11.
Reaction SMILES: [N:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[C:6]2[N:11]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:5]=12)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:10][C:9]1[C:4]([NH2:1])=[C:5]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[CH:12][N:11]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:6]2=[N:7][CH:8]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(N=[N+]=[N-])c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(N)c12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
4-Azido-5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (115 mg, 0.24 mmol), triphenylphosphine (64 mg, 0.24 mmol), and water (44 μL, 2.4 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction was stirred at 23° C. for 1 h. Water (100 μL, 5.5 mmol) was added and the mixture was stirred an additional 14 h. The reaction mixture was directly loaded onto silica gel and purified using flash silica gel chromatography using a gradient of (ethyl acetate and methanol 9:1) in hexanes to afford 5-Bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamine (MS: m/z 448.1/450.1 (M+H+).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:31][CH3:32])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)[CH3:21].C(#N)C.N>C(OCC)(=O)C.C1CCCCC1.CO.ClCCl>[CH2:31]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:32]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCC1CCCCN1
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 37 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-(diethylamino)ethyl]piperidine in a yield of 37% of theory. Colourless crystals, m.p. 100° C. (D.) (from acetonitrile), Rf 0.25 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/,ethyl acetate/cyclohexane/methanol/conc. ammonia 57/25/8/8/1, v/v/v/v/v)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:13]#[N:14])([O:9][CH2:10][CH2:11][OH:12])[CH2:7][Cl:8])(=[O:3])[CH3:2].[NH2:15][OH:16]>C(O)C>[C:1]([O:4][CH2:5][C:6]([CH2:7][Cl:8])([O:9][CH2:10][CH2:11][OH:12])[C:13]([NH:15][OH:16])=[NH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C#N)(CCl)OCCO
Reactant: NO
Solvent: CCO
Product: CC(=O)OCC(CCl)(OCCO)C(=N)NO
Temperature: 65 °C

Procedure:
A solution of 3-chloro-2-cyano-2-(2-hydroxyethoxy)propyl acetate (9.40 g, 42.4 mmol) in ethanol (150 mL) was treated with 50% aqueous hydroxylamine solution (2.94 g, 44.5 mmol, Aldrich) and the reaction was heated (65° C.) for 1.5 hrs. The solution was cooled to room temperature and the product was used as-is in the subsequent reaction: LC/MS m/z 255.20 (M+H).