Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][CH:22]=1>CN1C(=O)CCC1>[C:27]([C:25]1[N:26]=[C:21]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH:22]=[CH:23][CH:24]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: N#Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(C#N)n2)C1
Temperature: 140 °C

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (676 mg, 3.61 mmol) in NMP (4 mL) at 0° C. was added Cs2CO3 (1176 mg, 3.61 mmol) followed by 6-chloropicolinonitrile (500 mg, 3.61 mmol). The mixture was heated at 140° C. for 15 minutes in a microwave reactor to give the title compound. The crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]2[C:15]=1Br)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]2[C:15]=1[C:48]1[CH:47]=[CH:46][CH:45]=[C:44]([C:43]([F:54])([F:53])[F:42])[CH:49]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2cccc(C)n2c1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1nc2cccc(C)n2c1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 50.2 %

Procedure:
3-Bromo-5-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (compound o, 0.6 g, 0.002 mol), potassium carbonate (0.6 g, 0.004 mol), triphenylphosphine (0.06 g, 0.0002 mol), 3-(trifluoromethyl)phenylboronic acid (0.4 g, 0.002 mol) and bis(acetato) bis(triphenylphosphine)palladium (II) (0.08 g, 0.0001 mol) were mixed in a microwave vial. The mixture was purged with argon. Isopropyl alcohol (20 mL) and water (3 mL) was added. The mixture was heated (120° C.) by microwaved for 25 minutes. The solvent removed then water (10 mL) and ethyl acetate (10 mL) was added. The layers were separated and the organic layer dried (magnesium sulfate) then removed. The crude product was chromatographed using 50% ethyl acetate/hexanes to give 350 mg of 5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a white solid. Rf 0.42, 50% ethyl acetate/hexanes; MS m/z 349 (M+H).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]3([CH2:42][OH:43])[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37]3)[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]2([CH2:42][OH:43])[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37]2)[NH:13]1)=[O:11]
Reactant: CC1(C)OC[C@H](CCNC(=O)C2NC(CC3(CO)CC=CCC3)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)O1
Agent: Cl
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CC=CCC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 76.7 %

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 117d (0.2 g, 0.3 mmol) was reacted with aqueous HCl solution (1 N, 1 mL, 1 mol) in tetrahydrofuran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 75%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[O:7]1[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][NH:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.IC>CC(C)=O.ClCCl>[CH3:1][N:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]1=2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CNc2ccccc2O1
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C1CN(C)c2ccccc2O1
Temperature: 60 °C
Reaction time: 24 h
Yield: 65.5 %

Procedure:
In a sealable vessel, potassium carbonate (56 mg, 0.41 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (60 mg, 0.29 mmol) and iodomethane (22 □L, 0.35 mmol) in acetone (2 mL). The vessel was sealed and the reaction mixture was stirred at 60° C. for 24 h. The mixture was cooled to ambient temperature, diluted with dichloromethane (60 mL), and the organic layer was extracted with water (10 mL) and half-saturated brine (10 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the concentrate by flash column chromatography (5% to 10% EtOAc/hexane) afforded the title compound (43 mg, 0.19 mmol). MS m/z: 222 (M+1).
Reaction SMILES: [Cl:1]C1C=CC=CC=1O.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:1])[C:11]=1[OH:17]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1Cl
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
The chlorination was continued for 12 minutes until the ortho-chlorophenol and 2,4-dichlorophenol had almost completely disappeared (less than 0.2% in the mixture).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:31]([CH2:39][C:40](=O)[CH3:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[C:23]([CH2:22][NH:21][CH2:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][C@H:2]([NH:1][C:40]([CH3:41])=[CH:39][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 70 %

Procedure:
To 0.65 g (1.62 mmol) of methyl (S)-2-amino-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}propionate, 0.32 g (1.94 mmol) of benzoylacetone, 3 g of molecular sieve 4A are added to 15 ml of methanol. The reaction mixture is refluxed for 14 h and then filtered through Celite. After evaporation of the solvents, the residue is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 0.62 g of desired product is isolated with 70% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][S:12]2(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:23][CH:25]3[O:27][CH2:26]3)[S:12](=[O:19])(=[O:20])[CH2:13][CH2:14][CH2:15][S:16]2(=[O:17])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2S(=O)(=O)CCCS2(=O)=O)cc1OC
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2(CC3CO3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Temperature: 100 °C

Procedure:
9.6 of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (prepared as described in Example 2) are dissolved in 35 ml of dimethylformamide and, with stirring under argon, treated with 1.2 g of sodium hydride at room temperature. The suspension is stirred at 40° C for a further 0.5 hour, then cooled and treated with 2.8 g of epichlorohydrin. The mixture is then heated at 100° C for 16 hours. After cooling to room temperature, the suspension is poured on to water and the oily material extracted with chloroform. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/ethanol (98:2). The 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraoxide obtained is recrystallized from methylene chloride/ethanol and has a melting point of 175°-176° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:16])[C:14]#[CH:15]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH2:13][C:14]#[CH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: C#CCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: C#CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.8 %

Procedure:
In DMF, 700 mg (3.4 mol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and then an aqueous solution of 413 mg (7.5 mmol) of 2-propynylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for 1 hour and allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 620 mg (yield: 76.5%) of the title compound.
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([C:26]([NH:28][NH2:29])=[O:27])[O:23][C:24]=1[CH3:25]>C(Cl)(Cl)Cl>[NH2:16][C:5](=[N:29][NH:28][C:26]([C:22]1[O:23][C:24]([CH3:25])=[C:20]([CH3:19])[CH:21]=1)=[O:27])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C(=O)NN)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)NN=C(N)CS(=O)(=O)c2ccccc2)oc1C
Yield: 85 %

Procedure:
A suspension of 1.18 g (0.004 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 15 ml chloroform was treated with 6 ml 1N aqueous sodium hydoxide. The mixture was extracted with dichloromethane. The extracts were combined and dried with magnesium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 0.68 g (0.004 mol) 4,5-dimethyl-furan-2-carboxylic acid hydrazide in 10 ml chloroform for 24 hours at reflux temperature. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 19/1 gave 1.14 g (76%) 4,5-dimethyl-furan-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide as white crystals with mp. 197-199° C., MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:46][CH2:47][C@@H:48]([C:50]1[CH:51]=[CH:52][C:53]([OH:61])=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:55]=1)[OH:49].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[OH:61][C:53]1[CH:52]=[CH:51][C:50]([C@@H:48]([OH:49])[CH2:47][NH:46][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([S:24]([N:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)(=[O:26])=[O:25])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)=[CH:7][CH:6]=2)=[CH:55][C:54]=1[NH:56][S:57]([CH3:60])(=[O:59])=[O:58]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(Cc1ccc(NC2CCN(c3ccc(S(=O)(=O)N4CCCCC4)cc3)CC2)cc1)OC
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: CO
Solvent: CC#N
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(c4ccc(S(=O)(=O)N5CCCCC5)cc4)CC3)cc2)ccc1O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 16 %

Procedure:
N-[4-(2,2-Dimethoxyethyl)phenyl]-1-[4-(1-piperidinylsulfonyl)phenyl]-4-piperidinamine (0.395 g, 0.81 mmol) was added to a pre-prepared mixture of sodium iodide (0.303 g, 2.02 mmol) and trichloro(methyl)silane (0.191 mL, 1.62 mmol) in anhydrous acetonitrile. The reaction was stirred at ambient temperature for 3 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and the solvent partially removed in vacuo. The aldehyde solution was used directly and treated with methanol, acetic acid (0.06 mL, 1.01 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.20 g, 0.812 mmol) followed by sodium cyanoborohydride (0.056 g, 0.81 mmol). The reaction was stirred at ambient temperature for 4 hours. The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 10:1 chloroform-containing 1% ammonium hydroxide) to yield the title compound (0.130 mmol, 0.19 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[CH2:6][CH2:7][C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28].O>CN(C=O)C>[CH3:3][O:4][C:5](=[O:25])[CH2:6][CH2:7][C:8]1[N:12]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: COC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
47 mg of sodium hydride were added portionwise to a solution of 300 mg of 3-(4,5-diphenyl-1H-imidazol-2-yl)-propionic acid methyl ester in 2 mL of anh. DMF at 0° C. The mixture was stirred for 1 h at 0° C. then 179 mg of SEM-Cl were added dropwise at 0° C. The reaction mixture was allowed to warm up to rt, stirred for 1 h then poured into water and extracted with Et2O. The organic phase was washed with water/brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 88/12 to 0/100 as eluant to yield 308 mg of 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid methyl ester as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][NH2:13].Br[C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[N:20]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:21][C:19]1[N:20]=[C:15]([NH:13][CH2:12][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]=[CH:8][CH:7]=[CH:6]3)[C:16]([NH2:22])=[N:17][CH:18]=1
Reactant: NCc1cc2cccnc2cc1F
Reactant: Nc1ncc(Br)nc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1cc2cccnc2cc1F
Temperature: 120 °C
Yield: 77.5 %

Procedure:
A mixture of C-(7-fluoro-quinolin-6-yl)-methylamine (1.69 g, 9.63 mmol), 3,5-dibromopyrazin-2-amine (2.43 g, 9.63 mmol) and DIPEA (2.96 g, 22.90 mmol) was heated with microwave irradiation at 120° C. for 10 h. The reaction mixture was diluted with DCM and water. The organic layer was separated and washed with saturated NH4Cl solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM:MeOH) to give the title compound as a yellow solid (2.60 g, 69%). LCMS (method E): [MH]+=348/350, tR=5.21 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].Br[C:13]1[C:21]([N+]([O-])=O)=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:8]([C:6]1[CH:7]=[C:2]2[C:3]([S:11][C:19]3[CH:20]=[CH:21][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:18]=3[NH:1]2)=[CH:4][CH:5]=1)[CH2:9][CH3:10]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: CCCc1ccc(S)c(N)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1)Nc1c(cccc1C(=O)O)S2

Procedure:
A mixture of 11.7 g. (0.07 mol.) of 2-amino-4-propylbenzenethiol, 17.4 g. (0.07 mol.) of 2-bromo-3-nitrobenzoic acid, 38.7 g. (0.28 mol.) of anhydrous potassium carbonate and 6 g. (0.03 mol.) of sodium hydrosulfite in 125 ml. of dimethylformamide is stirred and heated for two hours at 125°-130°. The reaction mixture is cooled and stirred into 1000 ml. of dilute acetic acid. The solid that separates is collected, washed with water and dried to give 8-propylphenothiazine-1-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl>C(O)C.[Fe]>[Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2sncc2c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(Br)c2sncc2c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 7-bromo-5-nitro-benzo[d]isothiazole (1.0 g, 3.9 mmol) and iron powder (1.0 g, 19 mmol) in ethanol (40 mL) was heated to reflux with vigorous stirring. An aqueous 0.1 N hydrochloric acid (10 mL, 1 mmol) solution was added and the reaction continued until TLC showed no starting material. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated and aqueous sodium carbonate was added to the residue until it became basic. This mixture was filtered through Celite, washing with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to give 500 mg (56%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.8 (s, 1H), 7.2 (s, 1H), 7.1 (s, 1H), 3.82 (br. s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[C:5]2=[CH:4][N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=3)=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Nc1ccc(F)cc1
Reactant: Fc1cccc(F)c1-c1n[nH]c2nc(Cl)ncc12
Product: Fc1ccc(Nc2ncc3c(-c4c(F)cccc4F)n[nH]c3n2)cc1
Yield: 59 %

Procedure:
The compound was prepared from 6-chloro-3-(2,6-difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 12) and 4-fluoroaniline (Aldrich) in an analogous manner as described in Example 32 (160° C.). Filtration and washing with 2-propanol after the reaction gave the title product (59%). MS (M+H)+, 342.1
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of (5S)-5-(azidomethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.31 g, INTERMEDIATE 8) and triphenylphosphine (3.58 g) was heated to 65° C. for 6 h in 444 ml of tetrahydrofuran and 56 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (5 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (5 column volumes), to provide the title compound (1.70 g, 82%). Mass spectrum (ESI) 228.1 (M+1).
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[O:6]([C:13]1[N:14]=[CH:15][C:16]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]3[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[O:22][N:21]=2)=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a tetrahydrofuran (2 mL) solution of (2-phenoxy-pyridin-5-yl)-acetohydroximoyl chloride (100 mg, 0.381 mmol) described in Manufacturing Example 40-1-4 and 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (714, 0.51 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 50° C. Water was added to the reaction mixture at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (27 mg, 31%).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:41]=[CH:40][O:39][CH:38]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[O:39]1[CH:40]=[CH:41][C:37]([C:33]2[C:30]3[C:31]([CH3:32])=[C:27]([C:25]([NH:24][C:21]4[CH:22]=[CH:23][C:18]([C:15]5[CH:16]=[CH:17][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:42])=[O:2])(=[O:10])=[O:11])=[CH:13][CH:14]=5)=[CH:19][CH:20]=4)=[O:26])[O:28][C:29]=3[CH:36]=[CH:35][CH:34]=2)=[CH:38]1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccoc5)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(-c3ccoc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
To 240 mg of (S)-2-{4′-[(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester was added 2 mL of THF and 4 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified to pH2 and the resulting suspension was filtered. The solid product was dried under vacuum to give 171 mg of (S)-2-{4′-[(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid was obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=13.1, 6.8 Hz, 6 H) 2.4 (s, 3 H) 3.5 (m, 1 H) 6.8 (dd, J=1.9, 0.9 Hz, 1 H) 7.2 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=7.6 Hz, 1 H) 7.7 (dd, J=8.5, 0.9 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.8 (m, 4 H) 7.9 (m, 2 H) 7.9 (dd, J=1.5, 0.8 Hz, 1 H) 8.0 (m, 3 H) 10.6 (s, 1 H) 12.6 (s, 1 H).