Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:43](=[O:45])[CH3:44])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 98.1 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dichloromethane (13 parts) at 0° C. are added pyridine (6 equivalents) and acetic anhydride (6 equivalents). After 14 hours at 0° to 5° C., the mixture is diluted with ice-water. The organic layer is taken, washed with hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The reaction is crystallized from a mixture of dichloromethane and hexane to give 3-acetoxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3a). Yield: 98.1%. mp. 187°-188° C. (decomposition).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.Cl>C1COCC1.[Zn+2].[Br-].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:3]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCBr
Reactant: N#Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCCc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Magnesium (4.2 g, 173 mmol) was activated by washing with dilute HCl, water and acetone and was then dried in vacuo. ZnBr2 (37 g, 165 mmol) was sublimed under reduced pressure (approx. 5-20 mmHg) by gentle heating in a glovebox. The glovebox was used as it was extremely humid in the lab. Mg and ZnBr2 were mixed in a dry 3-necked flask under N2 and dry THF (30 mL) was added. 4-Bromo-1-butene (25.1 g, 186 mmol) dissolved in dry THF (175 mL) was added dropwise to the Mg/ZnBr2 slurry and, during the addition, the reaction mixture turned greyish and then black. Some heat was also evolved (>40° C.). After complete addition, the mixture was heated to 50° C. overnight. 4-Bromobenzonitrile (30.5 g, 167 mmol) was co-evaporated with toluene twice and was then dissolved in dry THF (250 ml) together with Pd(PPh3)4 (5 g, 4.3 mmol, 2.5 mole). The slurry was added to the Grignard reagent and the reaction mixture was stirred at room temperature overnight. HCl (500 mL, 3 M) was added dropwise to the reaction mixture, and the resulting solution was extracted with ether (1000+3×500 mL), the combined ether solutions were washed with NaHCO3 (satd. 3×250 mL), dried, filtered and evaporated. The crude product (29.7 g) was subjected to Dry-Flash chromatography (diameter 12 cm, height 5 cm, heptane:EtOAc (99:1 to 90:10)) to give 21.2 g of the sub-title compound contaminated with 4-bromobenzonitrile (about 20%). This material was used in the next step.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:14]=[C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][N:10]=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[CH2:19]([N:15]([CH2:16][CH2:17][CH3:18])[C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)c1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CCCN(CCC)c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To 0.235 g (0.66 mmol) of N2-diphenylmethylene-N4,N4-dipropylpyridine-2,4-diamine in 9 mL of methanol was added 0.13 g (1.6 mmol) of sodium acetate followed by 0.082 g (1.2 mmol) of hydroxylamine hydrochloride. The resulting clear golden reaction mixture was stirred at room temperature for 45 min and concentrated in vacuo. The crude solids were slurried in dichloromethane, filtered and the filtrate was concentrated. The resulting oil was purified by flash chromatography eluting with a 13% to 20% methanol/dichloromethane gradient containing 2% triethylamine to give 0.106 g (83%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C(O)(=O)C>[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: OC1CCNC1
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)CCN1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Acetic acid (31 μL), pyrrolidin-3-ol (3.47 g, 39.8 mnol) and 3,3-dimethyl-butyraldehyde (3.99 g, 39.8 mmol) were dissolved in THF (100 mL) and stirred at room temperature for 40 min. The solution was then cooled to 0° C. on an ice bath. To the cold solution sodium triacetoxyborohydride (10.98 g, 51.8 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was basified with a 5.0 M solution of NaOH and extracted with CH2Cl2 (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford 1-(3,3-dimethyl-butyl)-pyrrolidin-3-ol in (6.34 g, 92.5%), which was used without purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]([C:8]1([CH3:32])[CH2:14][C:13]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:12]=2[C:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH3:31])[CH:23]=2)=[N:10][NH:9]1)#[N:7]>>[C:6]([C:8]1([CH3:32])[CH2:14][C:13]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:12]=2[C:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH3:31])[CH:23]=2)=[N:10][N:9]1[C:1](=[O:4])[CH2:2][CH3:3])#[N:7]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C2=NNC(C)(C#N)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Product: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1(C)C#N)OCO3
Temperature: 25 °C
Reaction time: 192 h
Yield: 77 %

Procedure:
To 55 ml of propionyl chloride 7.06 g (19.4 millimoles) of (±)-8-cyano-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are added at 15° C. The reaction mixture is stirred at 25° C. for 8 days and evaporated in vacuo. To the residue 200 ml of water are added. The mixture is stirred under cooling with icecold water for an hour. The precipitated crystals are filtered and washed with icecold water. The crude product obtained is recrystallized from 100 ml of acetonitrile. The crystals are filtered, washed with acetonitrile and ether and dried. Thus 6.30 g of the desired compound are obtained, yield 77%, mp.: 191–193° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:41]=[CH:42][CH:43]=1)[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][C:21]=2[O:39][CH3:40])[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:40][O:39][C:21]1[CH:22]=[C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:10]=[C:9]([CH2:8][CH2:7][C:6]2[CH:5]=[C:4]([CH:43]=[CH:42][CH:41]=2)[C:1]([NH2:2])=[O:3])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
A mixture of tert-butyl 4-(4-((4-(3-carbamoylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I36) (0.070 g, 0.12 mmol) and TFA (0.200 mL, 2.61 mmol) in THF (3 mL) was stirred 16 hours at room temperature. The mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was then purified using a SCX cartridge (MeOH, 0.5% NH3/MeOH). The methanolic ammonia eluent was concentrated then dissolved in hot acetonitrile which was allowed to cool to room temperature. The cooled acetonitrile solution was filtered and the filtrate was concentrated, taken up in hot acetonitrile (2 mL) and water (1 mL) then freeze dried to give the title compound (5) (49.4 mg, 85%) as a white solid. A portion of this material was further purified by mass directed auto preparative HPLC to give the title compound (5) (4.5 mg) as a while solid; 1H NMR (400 MHz, d6-DMSO) δ 8.90 (m, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.71 (m, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.34 (m, 2H), 6.94 (dd, J=7.3, 1.6 Hz, 1H), 6.82 (ddd, J=7.9, 3.4, 1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 2H), 3.05 (m, 4H), 2.89 (m, 1H), 2.68 (m, 2H), 2.20 (m, 1H), 1.78 (m, 2H), 1.64 (m, 2H). LCMS Method C: rt 4.89 min; m/z 500.1[M+H]+.
Reaction SMILES: [K].[C:2]1([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]3)=[C:13]([O:25]CC3C=CC=CC=3)[CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[C:2]1([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]3)=[C:13]([OH:25])[CH:12]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2ccc(S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Agent: [K]
Solvent: ClCCl
Product: O=C1CN(c2ccc(S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-benzenesulfonyl-2-benzyloxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium in CH2Cl2 (5 mL), cooled in an ice/salt bath, is added dropwise BBr3 (4.8 mL, 1M in CH2Cl2). The mixture is stirred for 30 min then is quenched with water, basified with potassium carbonate, and separated. The aqueous layer is washed with ether, then lyophilized, and purified by preparative HPLC to afford the title compound as an amorphous solid: mp=126-180° C.; 1H NMR (DMSO-d6) δ 10.89 (br s, 1H), 7.93 (d, J=7.0 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 2H), 4.56 (s, 2H); (M−1)−=367.
Reaction SMILES: C1CO[C:3]2([CH:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:17][CH3:18])[CH2:4]2)[O:2]1.Cl>CC(C)=O>[CH3:18][O:17][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:12]([CH2:13][C:14]([OH:16])=[O:15])[C:3](=[O:2])[CH2:4]2
Reactant: COc1cccc2c1CC(CC(=O)O)C1(C2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cccc2c1CC(CC(=O)O)C(=O)C2
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A solution of 8.0 g (28.7 mmol) of 2,2-ethylenedioxy-5-methoxy-1,2,3,4-tetrahydronaphthalen-3-ylacetic acid, 80 ml of 3N aqueous hydrochloric acid, and 80 ml of acetone was degassed and heated to 60° C. under nitrogen then stirred under nitrogen at 60° C. for 4 hours. The reaction was cooled to room temperature, approximately 50% of the solvent was removed by rotary evaporation, diluted with 100 ml of brine, and extracted with three 100 ml portions of ethyl acetate. The organic layers were combined and washed with two 100 ml portions of brine, dried over anhydrous sodium sulfate, filtered, and concentrated via rotary evaporation to give an orange solid. The orange solid was triturated with 10 ml of ether and filtered to give 4.9 g (73%) of the title compound (f), m.p. 129°-131° C.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=2[F:30])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO.C(OCC)(=O)C>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=1[F:30])=[O:11]
Reactant: CSc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncn23)c(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)cc3ccncn23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution of 7-(2-fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (246 mg, 0.56 mmol) in methanol (1 mL) was added a solution of hydrochloric acid in dioxane (1 mL, 4M, 4 mmol). The reaction was stirred at room temperature for 1 hour then diluted with ethyl acetate (5 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% DCM in methanol) to yield a light brown solid. The solid was triturated with acetonitrile (3 mL) to yield the title compound as a beige solid (100 mg, 45%). 1H NMR (DMSO-d6): 11.38 (1H, s), 8.64 (1H, t, J=1.05 Hz), 7.86 (1H, s), 7.41-7.39 (2H, m), 7.15 (1H, dd, J=12.09, 2.09 Hz), 6.82-6.79 (1H, m), 6.73 (1H, s), 6.06 (1H, t, J=8.82 Hz), 4.82 (1H, s), 4.53 (1H, s), 3.80 (1H, dd, J=9.68, 3.51 Hz), 3.67-3.57 (2H, m), 3.31-3.24 (2H, m). (SMe coincident with solvent). LCMS (Method A): RT=7.14 min, M+H+=407.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](Cl)(Cl)Cl.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH:2]1[N:1]=[CH:9][N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=12
Reactant: NCc1ccccn1
Reactant: ClC(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccn2cncc2c1
Yield: 16.5 %

Procedure:
To a flask were added 2.0 g of 2-(aminomethyl)pyridine, 0.12 g of tetrabutylammonium bromide, 5.7 g of chloroform, and 30 ml 1,2-dimethoxyethane. While stirring under nitrogen, 40 ml of 40% aqueous Sodium hydroxide was added and the mixture was heated to 50 C for 4.5 hours. After cooling to 22 C, the mixture was extracted twice with ethyl acetate, and the ethyl acetate layer was dried over sodium sulfate. After filtration and solvent removal, the product was purified by silica gel chromatography using straight ethyl acetate to 5% acetonitrile in ethyl acetate resulting in a brown oil which crystallized on standing. The product was sublimed to give 0.36 g of a yellow solid.
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:14]([OH:17])(=[O:16])[CH:15]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Yield: 79.6 %

Procedure:
A mixture of 129 g of 1,1,1,3-tetrachloro-3-phenylpropane, 74 g of glacial acetic acid, and 31 g of monohydrate of p-toluenesulphonic acid is heated while stirring to the boiling point 115° to 120° C. for 13 h with gradual addition of 18 g of water. The precipitated crystals are filtered off, washed with water, to give 59 g of cinnamic acid. Then, the filtrate, is condensed, crystals are filtered off and washed with water to give another 11 g of cinnamic acid with the total yield of 94.5% (melting point 131° to 133° C., min. 98% purity).
Reaction SMILES: [CH2:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1)[CH3:2]>Br>[CH2:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CN(C)CCO1
Agent: Br
Product: CCC1(c2cccc(O)c2)CN(C)CCO1

Procedure:
2-Ethyl-2-(3-methoxyphenyl)-4-methylmorpholine (4.0 g, 0.015 mol) was refluxed for 2.5 hour with aqueous 48% hydrobromic acid (50 ml). The residue on evaporation was dissolved in 2 M sodium hydroxide (50 ml) and the non-phenolic material (about 1.0 g) extracted with ether. The aqueous layer was neutralised with solid ammonium chloride and the phenol extracted with ether/chloroform. The residue on removal of the solvents (1.3 g) was dissolved in isopropyl alcohol and treated with 40% aqueous HBr. The residue on evaporation crystallised from isopropyl alcohol as the hydrobromide hemi-isopropanolate of the title compound (1.24 g, m.p. 99°-104° C.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH2:8][C:9]=1[NH:10]2.[H-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:25])[CH2:8][C:9]=1[NH:10]2
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CNC(=O)CCCBr)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CN1CCCC1=O)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step 5 A solution of 5-bromo-2-((4-bromobutanamido)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (80 mg, 0.170 mmol) in DMF (1 mL) was treated with NaH (60% in mineral oil, pre-washed with hexane, 34 mg, 0.849 mmol). The mixture was stirred at rt for 30 min, the was diluted with water and extracted three times with DCM. The combined organic phases were dried and concentrated, and the residue was purified by column chromatography (eluting with 5% aqueous ammonium hydroxide-methanol-DCM) to provide 5-bromo-2-((2-oxopyrrolidin-1-yl)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a light yellow solid, used without further purification (40 mg, 60%). Mass spectrum m/z 390, 392 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CCCCCC>[CH2:18]([N:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])=[CH:15][CH:14]=1)[C:34]([NH:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[F:25])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCc1ccc(CNCCCCCCC)cc1
Solvent: CCCCCC
Product: CCCCCCCN(Cc1ccc(CN(CCCCCCC)C(=O)Nc2ccc(F)cc2F)cc1)C(=O)Nc1ccc(F)cc1F
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 1.5 g N,N'-diheptyl-p-xylylenediamine in 20 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 1.4 g 2,4-difluorophenyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, and the solid which separated out was collected by filtration and recrystallized from methanol, giving 2.3 g of 1,4-bis[[1-heptyl-3-(2,4-difluorophenyl)ureido]methyl]benzene.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([F:14])[CH:5]=1.Cl.[N:16]1([C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[S:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([F:14])[CH:5]=3)[CH2:20][CH2:21]2)=[N:23]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)Nc1ccc(CCBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1F
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
N-[4-(2-Bromo-ethyl)-2-fluoro-phenyl]-acetamide (0.2609 g, 1.00 mmol), 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.3887 g, 1.52 mmol), potassium carbonate (0.2109 g, 1.53 mmol), potassium iodide (0.1662 g, 1.00 mmol) and acetonitrile (5.0 mL) were added to a Smith microwave reaction tube containing a magnetic stir bar and then crimped shut. The reaction was run on a Smith Personal Chemistry microwave at 140° C. for 0.5 h. After removing the crimped septum, the contents were transferred to a separatory funnel with water (10 mL) and extracted with methylene chloride (2×40 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give an oily residue. Purification by MPLC on a 40M silica gel cartridge using a linear gradient over 1 h of 0–3% methanol in methylene chloride provided 0.1230 g (0.309 mmol) of the product as an off-white solid after drying in vacuo. Several fractions containing product and a by-product (0.1487 g total) were discarded. Yield: 31%; MS (APCI): 399.2 [M+H]+; Anal. Calcd. For C21H23FN4OS.0.25 H2O: C, 62.59; H, 5.88; N, 13.90. Found: C, 62.72; H, 5.53; N, 13.53.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:21][C:22]([C:24]1[N:25]([NH:29][CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1)=O)C=C.ClCCl.[O-]CC.[Na+].Cl>CN(C)C=O.C(O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][N:29]1[C:13](=[O:14])[C:12]([C:7]2[NH:6][C:5]3[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=3[S:9](=[O:11])(=[O:10])[N:8]=2)=[C:22]([OH:21])[C:24]2=[CH:28][CH:27]=[CH:26][N:25]12
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: C=CCOC(=O)c1cccn1NCCC(C)(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (Example 4b, 0.3 g, 0.819 mmol) was dissolved in N,N-dimethylformamide (4.1 mL). 1-(3,3-Dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 4c, 0.205 g, 0.819 mmol) was added followed by a 1.0 M solution of N,N-dicyclohexylcarbodiimide in dichloromethane (0.860 mL, 0.86 mmol). The mixture was stirred at 25° C. for 2 h. N,N-Dicyclohexylurea precipitation was visible at this point. The mixture was diluted with dichloromethane (5 mL) and filtered under reduced pressure. The filtrate was washed with 1.0 M aqueous hydrochloric acid solution (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4.1 mL). A 21% solution of sodium ethoxide in ethanol (0.673 mL) was added and the mixture was stirred at 80° C. for 4 h. Additional sodium ethoxide in ethanol (0.673 mL) was added and the mixture was stirred at 80° C. for 4 h. Upon cooling to 25° C., the pH was adjusted to approximately 6 by the addition of 3.0 M aqueous hydrochloric acid solution. Immediate precipitation was observed. Methanol (3 mL) was added and the mixture was shaken vigorously. The solid was collected by vacuum filtration, rinsed with methanol (3×2 mL) and dried in vacuo for 16 h to afford the desired product, 1-(3,3-dimethyl-butyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (0.268 g, 0.67 mmol, 82% yield) as a white powder. LC-MS (ESI) calcd for C20H21IN4O4S. found 540.03. found 366.95 [M+H+].