Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:9]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:2]1([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:16])[C:17]([O:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C#CC(C)(C)OC(=O)C(=O)c1ccccc1
Reactant: BrC1CCCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 18 h

Procedure:
A Grignard reagent, prepared from 3.38 g magnesium and 2.27 g cyclohexyl bromide in anhydrous THF in the usual way, was added dropwise under a nitrogen gas stream to a solution of 1,1-dimethyl-2-propynyl benzoylformate in anyhdrous THF under ice cooling, and stirring was continued for 18 hours under cooling with water. A solution of 7.5 g ammonium chloride in 30 ml water was then added under ice cooling. The separated organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 17.6 g of the objective compound as oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:28]=[C:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([C:38]#[N:39])=[CH:34][CH:35]=2)[NH:30]1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[ClH:3].[CH2:22]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:37]3[C:36]4[C:31](=[CH:32][C:33]([C:38]#[N:39])=[CH:34][CH:35]=4)[NH:30][C:29]=3[OH:28])=[N:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)[CH2:23][CH3:24]
Reactant: CCCN(CCC)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCN(CCC)CCN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4cc(C#N)ccc34)nc2)CC1
Product: Cl
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
To a suspension of sodium hydride (97%, 0.024 g, 1.0 mmol) in 1-methyl-2-pyrrolidinone (1.5 mL) was added (2-{4-[(6-chloropyridin-3-yl)sulfonyl]piperzin-1-yl}ethyl)dipropylamine (0.194 g, 0.5 mmol) at room temperature followed by addition of 2-oxoindoline-6-carbonitrile (0.095 g, 0.6 mmol). The formed mixture was stirred for 5 min under an N2 atmosphere and stirred for 1 h at 90° C. The cooled solution was poured into a cold saturated aqueous sodium hydrogen carbonate solution and the resulting precipitate was collected by filtration. The crude product was purified on a silica gel column using chloroform/methanol/triethylamine, (100:80:1), as the eluent to give 0.130 g (51% yield) of the title compound as the base. The base (0.127 g, 0.25 mmol) was dissolved in chloroform/methanol, (1:1), and treated with HCl in diethyl ether (1 M) at 0° C. The resulting orange crystals were collected by filtration and washed with diethyl ether to obtain 0.125 g (86% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 11.07 (s, 1H), 8.67 (s, 1H), 7.89 (s, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.0, 1.2 Hz, 1H), 7.28 (d, J=1.2 Hz, 1H), 4.04 (br s, 10H), 3.05 (br s, 6H), 1.69 (br s, 4H), 0.91 (t, J=7.2 Hz, 6H); MS (EI) m/z 511 (M++1).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([O:14]C)=O)[CH2:6]2>CO>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([NH2:1])=[O:14])[CH2:6]2
Reactant: COC(=O)C1Cc2cc(F)ccc2N1
Reactant: N
Solvent: CO
Product: NC(=O)C1Cc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 2M NH3 in methanol (0.6 mol), cooled in an ice bath under Ar, was added intermediate (16) (0.0574 mol) dissolved in methanol (150 ml). The mixture was allowed to warm to room temperature and stir under argon for 6 hours. The reaction was concentrated to 150 ml and filtered. The solid was rinsed with a small amount of cold methanol and allowed to dry, yielding 2.33 g of 5-fluoro-2,3-dihydro-1H-indole-2-carboxamide (intermediate 17, mp. 197–199° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=O)=[CH:3][CH:2]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:15][NH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: CCCCC(=O)c1ccncc1
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCCCC(=NNC(=O)OCC)c1ccncc1
Yield: 54 %

Procedure:
A mixture of 8.3 gm (0.055 mole) of n-butyl 4-pyridyl ketone, 6.1 gm (0.059 mole) of ethyl carbazate and 150 ml of absolute ethanol is refluxed 17 hr. A Tlc (3% MeOH/CH2Cl2 on Silica gel) shows 50% starting material remaining. p-Toluenesulfonic acid (0.3 gm) is added and the reaction mixture refluxed 17 hr more. Tlc shows no remaining starting materials. The reaction is concentrated in vacuo. The residue is slurried with water and the solid collected, washed with water and dried. Crystallization yields 7.41 gm of the title compound having a melting point of 102.1° C.
Reaction SMILES: [OH:1][CH2:2][C:3]#[CH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 112 g. (2.0 mol.) of 3-hydroxy-1-propyne and 260 g. (3.0 mol.), of dihydropyran in 1.20 1. of methylene chloride cooled to 0° C. in an ice bath, is added a solution of 20 mg. of para-toluenesulfonic acid in 100 ml. of methylene chloride, dropwise. The reaction mixture is stirred at 0° C. for one-half hour, and at ambient temperature for 1 hour. It is then poured into 200 ml. of a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueous phase extracted with 100 ml. of methylene chloride, the combined organic phases washed with 100 ml. of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm.) at 45° C., to give 300 g. of crude product, which is purified by fractional distillation, b,p, 71°-73° C. (14 mm.) to yield 250 g. (89%) of a liquid.
Reaction SMILES: NC1N=C(N)C(C2C=CC([N+:15]([O-:17])=[O:16])=CC=2C2C=CC=C(Cl)C=2Cl)=CN=1.[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]([C:34]2[CH:39]=[C:38]([N+]([O-])=O)[CH:37]=[C:36]([Cl:43])[C:35]=2[Cl:44])=[C:29]([CH3:45])[N:28]=1>>[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]([C:34]2[CH:39]=[CH:38][C:37]([N+:15]([O-:17])=[O:16])=[C:36]([Cl:43])[C:35]=2[Cl:44])=[C:29]([CH3:45])[N:28]=1
Reactant: Nc1ncc(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)c(N)n1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([C:17]#[N:18])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:25][NH:24][C:17]([C:13]1[C:14]2[CH:15]=[CH:16][C:7]([NH:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[O:2][CH3:1])=[N:8][C:9]=2[CH:10]=[CH:11][CH:12]=1)=[NH:18]
Reactant: NO
Reactant: COc1ccccc1CNc1ccc2c(C#N)cccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1CNc1ccc2c(C(=N)NO)cccc2n1
Yield: 90 %

Procedure:
A stirred suspension of 2-(2-methoxy-benzylamino)-quinoline-5-carbonitrile (example 136, step B) (289 mg, 1.0 mmol), hydroxylamine hydrochloride (257 mg, 3.7 mmol) and sodium carbonate (212 mg, 2.0 mmol) in EtOH (4 ml) and water (4 ml) was heated under reflux conditions for 17 h, water (5 ml) was added, the precipitate was collected by filtration, washed with water and heptane and dried to yield the crude product as solid which was further purified by crystallization (diethyl ether/MeOH) to yield N-hydroxy-2-(2-methoxy-benzylamino)-quinoline-5-carboxamidine as off-white solid (290 mg, 90%).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH3:6][N:7]([C:9]([N:12]([CH3:14])[CH3:13])(Cl)[Cl:10])[CH3:8]>O>[S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[CH3:6][N:7]([C+:9]([N:12]([CH3:14])[CH3:13])[Cl:10])[CH3:8]
Reactant: O=S(=O)(O)O
Reactant: CN(C)C(Cl)(Cl)N(C)C
Solvent: O
Product: CN(C)[C+](Cl)N(C)C
Product: O=S(=O)([O-])O
Temperature: 25 °C

Procedure:
3.24 g (33 mmol) of sulfuric acid are added with stirring and ice-cooling to a solution of 5.65 g (33.0 mmol) of bis(dimethylamino)dichloromethane in 30 ml of water. The reaction mixture is warmed to room temperature. All volatile compounds are removed under reduced pressure (7.0 Pa), giving 7.68 g of highly viscous bis(dimethylamino)chlorocarbenium hydrogensulfate, corresponding to a virtually quantitative yield.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:43](=[O:44])[N:14]2[C:15]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:16]([CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH3:26])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:43](=[O:44])[N:14]2[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH3:26])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: Cc1ncsc1C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Benzhydryl 7-(phenoxyacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (0.725 g) was dissolved in anisole (2 ml), to which trifluoroacetic acid (7 ml) was added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was concentrated under reduced pressure to give a syrup, whcih was then solidified by addition of isopropyl ether thereto. The solid obtained was pulverized and was mixed with isopropyl ether for the washing purpose, and the mixture was filtered to recover the solid which was then dried under reduced presssure. 7-(Phenoxyacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (0.512 g) was thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:23]1([S:33](Cl)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([S:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: NCCCCSc1cccc2nccn12
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCCSc1cccc2nccn12)c1cccc2ccccc12
Yield: 53.3 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (300 mg, 1.36 mmoles) and triethylamine (0.29 ml, 2.08 mmoles) in methylene chloride (15 ml) was added 1-naphthalenesulfonyl chloride (307 mg, 1.35 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 296 mg of the desired product (53.0%, colorless solid).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH2:26])[C:9]1=[O:27])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44](O)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26][C:44](=[O:45])[C@@H:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:9]1=[O:27])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)CN2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
Under argon atmosphere, 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (4.75 g) obtained from Step 2 of Example 95 was dissolved in anhydrous N,N-dimethylformamide (40 ml), N-tert-butoxycarbonyl-L-phenylalanine (3.80 g), 1-hydroxybenzotriazole (1.93 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.74 g) and triethylamine (3.65 ml) were added under ice-cooling, the mixture was stirred for 5 minutes at same temperature, and subsequently the resultant mixture was allowed to come to room temperature, stirred for 2 hours. Ice-water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 8.06 g of the titled compound (Yield: 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[C@H:10]([O:15][C:16](=[O:18])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.C(Cl)(Cl)Cl.CC(O)=O.O=[Pt]=O>[C:16]([OH:18])(=[O:15])[CH3:17].[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[C@H:10]([O:15][C:16](=[O:18])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
79.3 A suspension of (3S,4S)-3-acetoxy-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (89 mg) in 10 ml of AcOEt and 0.2 ml of chloroform, 0.2 ml of AcOH and 4 mg of PtO2 was hydrogenated at 22° C. and atmospheric pressure for 16 h. The suspension was filtered and the filtrate evaporated to give (3S,4R)-3-acetoxy-4-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester acetate. Colorless semisolid. MS 259.3 ([M+H]+)
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=O.[OH:13][C:14]1[C:15]([CH3:34])=[C:16]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)[CH:17]=[CH:18][CH:19]=1.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:3][O:13][C:14]1[C:15]([CH3:34])=[C:16]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]4)[CH2:30]2)[CH2:24]3)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (0.20 ml) was added to a solution of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.20 g, Example 26), methanol (0.10 ml) and triphenylphosphine (0.41 g) in toluene (10 ml) and tetrahydrofuran (5 ml). After 2 hours stirring at room temperature further triphenylphosphine (0.20 g) and diethyl azodicarboxylate (0.10 ml) were added and the solution stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel to chromatography eluting with dichloromethane:ethyl acetate (19:1) to give the title compound as a colourless solid (0.20 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH:5]1[CH:11]([OH:12])[CH2:10][CH:9]2[CH:6]1[CH2:7][CH2:8]2.C1C[O:16]CC1>CC(C)=O>[CH3:1][N:2]([CH3:3])[CH:9]1[CH:10]2[CH:11]([OH:12])[CH2:5][CH:6]1[C:7](=[O:16])[CH2:8]2
Reactant: OC1CC2CCC2C1Br
Reactant: C1CCOC1
Reactant: CNC
Solvent: CC(C)=O
Product: CN(C)C1C2CC(O)C1CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of dimethylamine (2.0 M, 24 ml, 48 mmol) in THF was added to a solution of 2-bromo-bicyclo[3.2.0]heptan-3-ol (4.00 g, 19.5 mmol) in acetone (40 ml) at 0° C. and the mixture allowed to warm to ambient temperature over 1 h and stirred at ambient temperature overnight. The orange solution was filtered and the filtrate was evaporated to dryness. Purification was achieved by column chromatography on silica gel using 5% MeOH in DCM to yield 3.01 g (91%) of the product as a tan powder. LC-MS (Method 2): Rt 0.37 min, m/z 170.09 [MH]+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:17]2[C@@H:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19][CH2:18]2)=[O:9])[CH:3]=1
Reactant: C1CCC2NCCCC2C1
Reactant: O=C(O)c1csc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
5-Bromothiophene-3-carboxylic acid (0.5 g, 2.4 mmol) was dissolved in acetonitrile (10 mL) and triethylamine (7.1 mmol). Decahydroquinoline (3:2 mixture of cis- and trans-isomers; 4.8 mmol) and HATU (2.4 mmol) were added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in DCM and washed with water. After drying with anhydrous magnesium sulphate, the solution was filtered and evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white crystalline solid (0.39 g). LCMS m/z 330.11 [M+H]+ RT=4.07 min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[CH:8]=[CH:9]/[O:10][CH2:11][CH3:12])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][C:24]=3[C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[CH:17][CH:16]=1>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[N:3]=[C:4]([C:31]2[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:23]3[O:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)=[C:25]([C:26]([NH:28][CH3:29])=[O:27])[C:24]=3[CH:30]=2)[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[O:10][CH2:11][CH3:12]
Reactant: CCO/C=C/c1ccc(Cl)nc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a degassed solution of (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (500 mg, 2.29 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (1.15 g, 2.29 mmol) in 1,4-dioxane (8 mL) and water (200 μL) was added CS2CO3 (1.49 g, 4.59 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (120 mg, 0.18 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-30% EtOAc/DCM) to provide (E)-5-(6-chloro-5-(2-ethoxyvinyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, yield: 16%). MS (M+H)+: 558.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([CH:13]([CH2:24][CH2:23][S:22][C:19]([F:21])([F:20])[F:18])[C:14]#[N:15])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Compound II-5 was prepared from (3-trifluoromethyl-phenylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[N:10]=[C:9]([C:12](=[O:20])[NH:13][O:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH:8]=[C:7]([C:21]([O:23]C)=[O:22])[C:6]=2[C:5]2[NH:25][C:26]([C:28]([O:30]C)=[O:29])=[CH:27][C:4]=2[C:3]21OCC[O:32]2.Cl.C(Cl)Cl.CO.[Li+].[OH-]>C1COCC1>[O:32]=[C:3]1[C:2](=[O:1])[C:11]2[N:10]=[C:9]([C:12](=[O:20])[NH:13][O:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH:8]=[C:7]([C:21]([OH:23])=[O:22])[C:6]=2[C:5]2[NH:25][C:26]([C:28]([OH:30])=[O:29])=[CH:27][C:4]1=2
Reactant: C=CCCCONC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C1(OCCO1)c1cc(C(=O)OC)[nH]c1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCCCONC(=O)c1cc(C(=O)O)c2c(n1)C(=O)C(=O)c1cc(C(=O)O)[nH]c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A solution of the product from EXAMPLE 3 (4, 32 mg, 64 μMol) in THF (6 mL) was treated with 1N HCl (0.6 mL) was kept at 45-47° C. for 24 hours. The reaction mixture was cooled to room temperature. TLC (DCM-MeOH 95:5) shows no 4 (Rf=0.75) and one major product (Rf=0.4). The solution was concentrated on a rotary evaporator to remove THF. The resulting mixture was partitioned between EtOAc (25 mL) and saturated aqueous NaCl (25 mL). The organic layer was separated and allowed to stand for 15 minutes. The organic solution was decanted from some aqueous droplets. It was then evaporated at reduced pressure to give an orange solid. The solid was dissolved in 0.25 M LiOH (1 mL, 0.25 mMol). The resulting black solution was stirred at room temperature for 24 hours. The reaction mixture was then acidified by dropwise addition of concentrated HCl (3 drops from a Pasteur pipet) to give a slurry of an orange solid. The slurry was cooled on an ice bath for 10 minutes then the solid was collected by filtration, rinsing with ice-cold water (2×2 mL) and Et2O (2×2 mL). The solid was then dried under vacuum for 6 hours to afford 5 (13.5 mg, 51%). MS (AP− taken from a MeOH solution) 444 (M+MeOH−1), 412 (m−1). NMR (DMSO-d6, δ), 13.55 (br, 1H, CO2H), 12.65 (br, 1H, CO2H), 12.02 (br, 1H, CONH), 11.83 (br, 1H, NH), 8.24 (s, 1H, H-8), 7.20 (s, 1H, H-3), 5.87 (m, 1H, vinyl-H), 5.05 (dd, 1H, vinyl-H), 4.99 (dd, 1H, vinyl-H), 4.03 (t, 2H, OCH2), 2.18 (q, 2H, allyl-CH2), 1.75 (m, 2H, CH2).