Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)/[CH:5]=[C:6]1\[CH2:7][CH2:8][C:9]2[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:13]\1=2.[OH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:30]=[CH:29][CH:28]=[C:4]([CH2:5][CH:6]3[C:13]4[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:10][C:9]=4[CH2:8][CH2:7]3)[CH:3]=2)=[CH:34][CH:33]=1.[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:30]=[CH:29][CH:28]=[C:4](/[CH:5]=[C:6]3\[CH2:7][CH2:8][C:9]4[N:10]([S:18]([C:21]5[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=5)(=[O:19])=[O:20])[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:13]\3=4)[CH:3]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(Br)c1
Reactant: OB(O)c1ccc(O)cc1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(O)cc2)c1
Product: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(-c2ccc(O)cc2)c1

Procedure:
The title compound was synthesized in three steps. First, (E)-methyl 4-(3-bromobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.301 g, 0.62 mmol) was coupled with 4-hydroxyphenylboronic acid (0.129 g, 0.94 mmol) according to General Procedure 9.1 to give (E)-methyl 4-((4′-hydroxybiphenyl-3-yl)methylene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, then tosyl deprotection according to General Procedure 10.1 to give (E)-methyl 4-((4′-hydroxybiphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Hydrogenation of (E)-methyl 4-((4′-hydroxybiphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate according to General Procedure 6 (with 5% Pd/C), provided the title compound, which was used without purification in the next step. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.08-2.18 (m, 1H), 2.49-2.60 (m, 1H), 2.60-2.68 (m, 2H), 2.84 (d, J=7.27 Hz, 2H), 3.33 (d, J=6.93 Hz, 1H), 3.70-3.73 (m, 3H), 6.37 (d, J=1.81 Hz, 1H), 6.89-6.95 (m, 2H), 7.15 (d, J=7.66 Hz, 1H), 7.30-7.36 (m, 1H), 7.40-7.45 (m, 2H), 7.46-7.51 (m, 2H), 10.47 (br. s, 1H). LCMS ESI− 346.2 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=O)[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[CH3:14]>C(O)C>[CH3:8][C:9]1[CH:10]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[CH3:14]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: Nc1ccccc1
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=Nc2ccccc2)C(C)=C1C
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Under a nitrogen atmosphere, aniline (31.5 mmol) was added dropwise to a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (30.0 mmol) in ethanol (90.0 mL) and the mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-phenylamine (9.00 g, yield 100%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH:17][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH3:12]
Reactant: CCOC(=O)CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzenesulfonyl chloride (500 mg, 2.83 mmol) in pyridine (10 mL) is added 3-amino-propionic acid ethyl ester (672 mg, 8.49 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using a gradient of 10-50% heptane/EtOAc to afford 3-benzenesulfonylaminopropionic acid ethyl ester. MS 258.3 (M+1); 1H-NMR (400 MHz, CDCl3); δ ppm 1.24 (t, 3H), 2.53 (t, 2H), 3.21 (q, 2H), 5.22 (m, 1H), 7.51-7.61 (m, 3H), 7.87 (d, J=7.20Hz, 2H).
Reaction SMILES: [Na].C(Cl)C[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([O:37]CCOCCOO)[CH2:21]CCCCCCCCCCCCCCC>C(O)COCCO>[CH2:13]([CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH2:21][CH2:20][OH:37])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCOCCOCCOO
Reactant: CCCCCCCCCCCCCCCCCCl
Agent: [Na]
Solvent: OCCOCCO
Product: CCCCCCCCC(CCO)CCCCCC
Temperature: 140 °C
Reaction time: 17 h

Procedure:
To a round bottom flask is added 42.4 (0.4 mol) of diethylene glycol under a nitrogen atmosphere. To this reaction mass is added 2.3 g (0.1 mole) of sodium over 1 hour. The reaction mass is heated to 130° C. whereby all of the sodium has reacted. Then 27.4 g (0.1 mol) of C17H35Cl is added over 1 hour and then kept for 17 hours at these conditions. Reaction temperature is then increased to 140° C. and kept for 17 hours at these conditions for 24 hours. The reaction mass upon cooling consists of 2 layers. GC shows the bottom layer to be mostly diethylene glycol. The reaction mass is filtered and the bottom diethylene glycol layer separated. The top organic layer is diluted with diethyl ether, water washed and dried over anhydrous MgSO4. After filtering, the organic layer is fractionally distilled to give a fraction at from 200°-220° C. and 2.25-2.5 mm containing the desired product, C17H35O(CH2CH2O)2OH, in two isomeric forms, one of which is the desired isomer of this invention, namely C8H17 (C6H13)CHCH2CH2 (OCH2CH2)2OH.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].I[N:25]1C(=O)[CH2:28][CH2:27][C:26]1=O.C(N)CC>C(O)(=O)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[N:10]3[CH:9]=[N:8][C:7]([C:5]4[O:6][C:2]([CH2:3][NH:25][CH2:26][CH2:27][CH3:28])=[CH:1][N:4]=4)=[C:11]3[CH2:12][N:13]([CH3:23])[C:14](=[O:22])[C:15]=2[CH:20]=1
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: O=C1CCC(=O)N1I
Solvent: CCCN
Solvent: CC(=O)O
Product: CCCNCc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 90 h
Yield: 9.9 %

Procedure:
A solution of 10 g (0.032 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 10.8 g (0.048 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 90 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark residue was dissolved in 200 ml of THF, treated with 23 ml (0.278 mol) of propylamine and stirred at room temperature for 5 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the orange crystalline product was chromatographed twice; firstly over basic Alox (grade III) with ethyl acetate/methanol 4:1 as the eluent, then over silica gel with dichloromethane/methanol 9:1 as the eluent. There were obtained 1.17 g (10%) of 8-fluoro-5-methyl-3-(5-propylaminomethyl-oxazol-2-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 134°-136°.
Reaction SMILES: I[C:2]1[C:3]([CH3:19])=[C:4]([CH:8]=[C:9]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O.C(O)C>[CH3:19][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][C:9]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:10][C:2]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: Cc1c(I)cc(S(=O)(=O)N2CCCC2)cc1C(=O)O
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)O)c2C)cc1
Temperature: 25 °C

Procedure:
To a mixture of 3-iodo-2-methyl-5-(pyrrolidin-1-ylsulfonyl)benzoic acid (1.00 g, 2.53 mmol), p-tolylboronic acid (0.378 g, 2.78 mmol), toluene (10 mL), ethanol (3 mL), cesium carbonate (0.907 g, 2.78 mmol), and water (1 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.126 mmol). The mixture was heated to reflux for 6 h, and then cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel column (0-50% EtOAc/hexane) to yield a yellow solid.
Reaction SMILES: O.[NH2:2]N.Cl.[N+:5]([C:8]1[CH:9]=[C:10]([C:14](=[NH:16])[NH2:15])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].[C:17]([NH:20][CH:21]([CH3:29])[C:22](=O)[C:23](OCC)=[O:24])(=[O:19])[CH3:18]>C(O)C>[N+:5]([C:8]1[CH:9]=[C:10]([C:14]2[NH:15][C:23](=[O:24])[C:22]([CH:21]([NH:20][C:17](=[O:19])[CH3:18])[CH3:29])=[N:2][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: NN
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)NC(C)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.89 g (2.81 ml, 57.73 mmol) of hydrazine hydrate are added dropwise to 9.70 g (48.11 mmol) of 3-nitrobenzenecarboximidamide hydrochloride from example 2A in 200 ml of ethanol. The mixture is stirred for one hour at 20° C. After this time, 13.51 g (72.17 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate from example 4A are added in ethanol, and the reaction mixture is stirred for 4 h at a bath temperature of 70–80° C., subsequently for 12 h at 20° C. The mixture is concentrated and the residue is purified by flash chromatography (eluent: ethyl acetate, subsequently dichloromethane/methanol 30:1).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][NH:11][C:12](=O)[C:6]=2[CH:5]=1.O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:12]1[C:6]2[CH:5]=[C:4]([Cl:3])[CH:17]=[CH:16][C:7]=2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Agent: N#N
Solvent: Cc1ccccc1
Product: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 87.1 %

Procedure:
In a 1 L 2 neck RBF equipped with mechanical stir, condenser and N2 inlet, 7-chloro-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (42.5 g, 0.189 mol) was suspended into 400 ml, of toluene. To this was added N,N-dimethylanaline (45.5 g. 0.375 mol) followed by the addition of POCl3 (29 g, 0.189 mol) and the reaction mixture stirred for 3 min (RT). Reaction flask was placed in a 90° C. oil bath and the reaction mixture stirred/heated for 7 h and then at RT for 9 h. Reaction was quenched by adding 500 mL of ice water and stirred for 15 min. Organic layer was separated and quickly washed with cold 0.5 M HCl (300 mL), cold water (300 mL), and then cold saturated NaHCO3 (300 mL). Organic layer was dried (MgSO4), filtered and concentrated on a rotary evaporator to give 40 g of yellow solid. Yield 87.5%. 1H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 3.8-3.9 (s, 1H, br), 4.3-4.4 (s, 1H, br), 7.4 (d, 1H), 7.7-7.8 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH:27]=[O:28])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:32])(=O)=O>CC(O)=O.C(Cl)Cl>[Cl:32][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH:27]=[O:28])[N:14]2[S:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=Cc1cc2c(Cl)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3.22 g, 8.22 mmol) in 1:1 AcOH—CH2Cl2 (140 mL) was added sulfuryl chloride (1.24 g, 9.19 mmol) dropwise and the resulting mixture was stirred at rt for 15 h. Additional sulfuryl chloride (0.084 g, 0.62 mmol) was added and stirring was continued for 1 h. The mixture was partially concentrated to ˜½ volume under a stream of N2 and the resulting light yellow crystals were collected by filtration and washed sequentially with cold AcOH and hexanes, to afford the title compound (2.58 g, 74% yield): 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.58-7.54 (m, 2H), 7.46-7.30 (m, 7H), 7.22 (d, J=9 Hz, 1H), 5.19 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:18]#N)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(=[O:40])C.[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:40])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Temperature: -15 °C

Procedure:
To a solution of 2-(2-chlorophenyl)-7-fluoroquinoline-3-carbonitrile (1.000 g, 3.537 mmol) in toluene (3.537 mL, 3.537 mmol) at −78° C. was added with stirring, DIBAL-H, 1 M sol. in Toluene (3.891 mL, 3.891 mmol) and the mixture was allowed to warm to −15° C. with stirring over 13 h. The mixture was cooled in ice water bath, quenched by addition of 1 N aq. HCl (14.15 mL, 14.15 mmol), and stirred for 2 h. To the mixture was added potassium acetate (3 g, 30.56 mmol, 8.6 eqv) and the mixture extracted with ethyl acetate (50 mL×2). The combined organic layers were washed saturated NaHCO3 (50 mL×1), brine (50 mL x), filtered, and concentrated at reduced pressure to give a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 2-(2-chlorophenyl)-7-fluoro-quinoline-3-carbaldehyde as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (1 H, s), 9.11 (1 H, s), 8.44 (1 H, dd, J=9.1, 6.4 Hz), 7.92 (1 H, dd, J=10.3, 2.6 Hz), 7.72-7.78 (1 H, m), 7.50-7.66 (4 H, m); LC-MS (ESI) m/z 286.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(O)cc2)s1
Temperature: 120 °C
Yield: 56.5 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 4-hydroxythiophenol (1.3 g) and potassium carbonate (2 g) in N,N-dimethylformamide (30 ml) was heated at 120° C. for 2.5 hours with stirring. The reaction mixture was poured into ice water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-hydroxyphenylthio)thiazole (1.5 g, yield: 56.6%). mp: 265°-267° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]Br>C1(C)C=CC=CC=1.O>[Br:38][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrBr
Reactant: NCCCCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a suspension n of phthalic anhydride (2.96 g, 20 mmol) in toluene (20 mL) was added 5-amino-1-pentanol (2.2 mL, 20 mmol) and the resulting mixture was heated to reflux for 14 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (20 mL). This solution was cooled to 0° C. and triphenylphosphine (4.7 g, 18 mmol) and bromine were added. After warming to room temperature, the solution was stirred overnight and then poured into water (20 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL) and the combined organic phases were dried over sodium sulfate and evaporated to dryness. Silica gel chromatography using hexane/ethyl acetate (4:1) as the eluent gave the title compound as a syrup (4.13 g, 70% for 2 steps).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([CH2:18][CH:19]=[CH2:20])=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:2]1[O:4][CH2:3]1.C(OO)(=[O:29])C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Na+]>[CH2:1]([O:5][C:6]1[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][C:9]([CH2:18][CH:19]2[O:29][CH2:20]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:2]1[O:4][CH2:3]1
Reactant: CC(=O)OO
Reactant: C=CCc1cc(-c2ccccc2)c(OCC2CO2)c(-c2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(CC3CO3)cc(-c3ccccc3)c2OCC2CO2)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A 100 ml sulfurating flask equipped with stirrer, cooler, thermometer and drip funnel is charged with 13.7 g (0.04 mole) of 4-allyl-2,6-diphenylphenyl glycidyl ether in 20 ml of toluene and 0.7 g of sodium acetate. Over 2 hours, 9.13 g (0.048 mole) of 40% peracetic acid are added at a temperature in the range from 30° to 50° C. When the dropwise addition is complete, the reaction mixture is stirred for a further 7 hours. When the reaction is complete, the reaction mixture is diluted with 700 ml of toluene, the resultant aqueous phase is separated and the organic phase is washed with two 150 ml portions of NaHCO3 (5%) and then washed with 150 ml of water. The organic phase is dried over Na2SO4 and made peroxide-free with Na2SO3 and filtered. The filtrate is concentrated, affording 12.46 g (86.5%) of a yellow resin with an epoxide content of 4.99 eq/kg (89.5%) and a viscosity of 6850 mPas/40° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[CH:22]([N:25](C(C)C)CC)(C)[CH3:23].C(N)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:22]([NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[N:11][C:12]=2[CH:18]=1)=[O:20])[CH3:23]
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 80 °C

Procedure:
A stirred solution of [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid [130 mg, Example 247(a)], hydroxybenzatriazole (189 mg) and diisopropyl ethylamine (732 μL) in dimethylformamide (3 mL) was treated with ethylamine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (267 mg). The reaction mixture was heated at 80° C. overnight and then partitioned between ethyl acetate and 5% citric acid. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, then with brine, then dried over magnesium sulfate and then evaporated. The residual oil was subjected to preparative HPLC to give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, ethylamide as a white solid. LC-MS (METHOD B): RT=2.37 minutes; 306.27 (M+H)+. (b) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, methylamide
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=2)[N:3]=1.[S:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=3)[N:3]=[C:2]([N:37]3[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[S:34][CH2:35][CH2:36]3)[N:11]=2)[CH2:17][O:16][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1ccc2nc(Cl)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of (2-chloro-6-methylquinazolin-4-yl)-[3-(dibenzylamino)oxetan-3-ylmethyl]-amine (2 g, 4.4 mmol, prepared in analogy to N-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine in Example 55-1), 2,3,4,5-tetrahydro-1,4-benzothiazepine (720 mg, 4.4 mmol), triethylamine (1.2 mL, 8.6 mmol) in N,N-dimethylformamide (20 mL) was heated with stirring in a 30 mL of microwave process vial for 2 hours at 150° C. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 1.7 g of the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=O)=[CH:4][C:3]=1[S:16]([CH3:19])(=[O:18])=[O:17].C(O)(C(F)(F)F)=O.[NH2:27][C:28]1[N:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:40]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:4]=3)=[N:33][CH:32]=2)[CH2:39][CH2:38]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CC(C)(C)OC(=O)Cc1cnc(Cl)c(S(C)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(S(C)(=O)=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetate 197-5 (40 mg, 0.13 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetic acid 197-6, was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (35 mg, 0.16 mmol) and DIEA (114 uL, 0.65 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (75 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetamide 197-7. MS m/z 452.1 (M+1).