Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:18])([F:17])[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[C:9](F)[CH:8]=1.[F:19][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][CH:25]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:19][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][C:25]=1[C:11]([C:10]1[CH:14]=[CH:15][C:7]([C:6]([F:18])([F:17])[F:5])=[CH:8][CH:9]=1)=[O:12]
Reactant: COc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
1.4 l of nitrobenzene were cooled in an ice bath and treated in succession at a maximum temperature of 6° C. with 492.6 g (3.656 mol) of aluminum chloride and 700 g (3.355 mol) of 4-trifluoromethyl-2-fluoro-benzoyl chloride in 350 ml of nitrobenzene. The mixture was stirred (15 min) and 427.5 g (3.388 mol) of 3-fluoroanisole were added slowly so that the temperature did not rise above 6° C. The solution was left to warm to room temperature, stirred 2 h at this temperature, poured on to ice-water (2.5 l) and extracted with methylene chloride. The organic phase was washed with water and concentrated. After crystallization from THF (1.2l)/hexane (4.2l), 237 g (24%) of (2-Fluoro-4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methanone were obtained, MS: 298 (M).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)[NH2:2].[Cl:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([NH:2][NH:1][C:3]2[N:8]=[N:7][C:6]([N:9]([CH3:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=2)=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: CN(c1ccccc1)c1ccc(NN)nn1
Reactant: O=C(O)c1cccc(Cl)n1
Agent: Cl
Solvent: ClCCl
Product: CN(c1ccccc1)c1ccc(NNC(=O)c2cccc(Cl)n2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 6-hydrazino-N-methyl-N-phenylpyridazine-3-amine (1.14 g) in methylene chloride (10 ml), 6-chloropicolic acid (0.83 g) and WSCD hydrochloride (1.22 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (eluent: chloroform) to obtain 6-chloro-N′-{6-[methyl(phenyl)amino]pyridazin-3-yl}pyridine-2-carbohydrazide (0.57 g). This compound (0.56 g) was stirred at 150° C. overnight in xylene (20 ml), and the reaction solution was concentrated to obtain 3-(chloropyridin-2-yl)-N-methyl-N-phenyl-1,2,4-triazolo[4,3-b]pyridazine-6-amine (0.54 g) as colorless solids.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[CH2:15][C:16](OCC)=[O:17]>>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]1[S:12][CH2:15][C:16](=[O:17])[N:13]=1)([CH2:4]3)[CH2:2]2
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Reactant: CCOC(=O)CBr
Product: O=C1CSC(NC23CC4CC(CC2C4)C3)=N1

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and ethyl bromoacetate according to Method D1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.CC[N:18]([CH:22]([CH3:24])[CH3:23])C(C)C.C1(N)CC1>C(Cl)Cl.CCOC(C)=O>[CH:22]1([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Reaction time: 3 h

Procedure:
To 3-iodo-4-methylbenzoic acid (3.5 g, 13 mmol) was added thionyl chloride (10 mL) before heating the mixture to reflux for 1.5 h. The reaction mixture was concentrated in vacuo, and dissolved in DCM (50 mL) and Hünigs base (4.6 mL, 27 mmol). After the addition of cyclopropylamine (1.87 mL, 27 mmol) at −78° C., the reaction mixture was stirred at ambient Temp. for about 3 h. The mixture was diluted with 100 mL DCM, washed with 20 mL saturated, aqueous NaHCO3 and 20 mL 3 N HCl, and dried over anhydrous Na2SO4. The solid obtained was suspended in EtOAc and filtered to give the title compound. MS (ES+): 302 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([O:23][CH2:24][CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([O:23][CH2:24][CH2:25][NH:26][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCOCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1Cl
Yield: 82.9 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 2-benzyloxyethyl amine(1.04 g, 6.88 mmol) and triethylamine(1.92mL, 13.76 mmol) were reacted to form the desired product (2.31 g, 83%). 1H NMR (MeOD-d4): δ 7.69 (d, 1H), 7.53 (d, 1H), 7.25 (m, 3H), 7.14 (d, 2H), 4.26 (s, 2H), 3.45 (t, 2H), 3.36 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][CH3:31])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:28][O:29][CH2:30][CH3:31])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 4-fluoro-N2-phenylbenzene-1,2-diamine (562 mg, 2.8 mmol) in DCM (18 mL) at 0° C. were added (S)-2-tertbutoxycarbonylamino-3-ethoxypropionic acid (720 mg, 3.1 mmol), HOAt (0.420 g, 3.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.59 g, 3.1 mmol) and the resulting mixture stirred at 0° C. for 1 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-2-ethoxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (770 mg, 66%). LCMS (Method B): RT 3.87 min [M+H]+ 418.3
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[ClH:18].N1C=CC=CC=1.Cl[C:26]1[CH:33]=[C:30]([O:31][CH3:32])[C:29]([NH2:34])=[CH:28][CH:27]=1>C(OCCO)C>[Cl:18][C:27]1[CH:26]=[CH:33][C:30]([O:31][CH3:32])=[C:29]([NH:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:28]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1cc(Cl)ccc1N
Reactant: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(Cl)cc1Nc1c(C#N)cnc2cc(OC)c(OC)cc12
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 189.1 mg (1.2 mmol) of 5-chloro-o-anisidine to give 240.5 mg (65.0%) of the product as a cream solid, m.p. 200-202° C., mass (electrospray, m/e): M+H 369.9, 371.8.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.CC(C)N=C=NC(C)C.C1C=C2N=NN(O)C2=CC=1.O>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AM using 5-({cyclopropyl[(4-methoxy-2,6 dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (126 mg, 0.33 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (59 mg, 0.30 mmol), DIC (79 μL, 0.5 mmol) and HOBt monohydrate (76 mg, 0.5 mmol) in DCM (2.5 mL). The crude product was purified by FCC eluting with 95:5 DCM:7N NH3 in MeOH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pd].O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C

Procedure:
1.3 g (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethyl acetate (40 ml) at ambient temperature. 0.3 g of 10% Palladium on Carbon (Engelhard 4505) and water (0.3 ml) is added to the mixture. The mixture is then pressurised under a hydrogen atmosphere to 4 bar. The mixture is stirred at ambient temperature and 4 bar hydrogen pressure for 4 days. The mixture is then filtered to remove the catalyst and concentrated under reduced pressure. The residue is then purified by column chromatography (ethyl acetate/hexane, 70:30) to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 67:33 (3-a, R1=Boc:3-b, R1=Boc) as determined by hplc.
Reaction SMILES: O.C1(C2N=C(C=CC3C=C([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4C(O)=O)C=CC=3)SC=2)CCC1.Cl.C(N=C=NCCCN(C)C)C.C(N)C=C>C(Cl)Cl>[C:22]1([CH2:21][C:20]([NH2:19])=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:23]=1
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(C=Cc2nc(C3CCC3)cs2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C=CCN
Solvent: ClCCl
Solvent: O
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.1 g (0.13 mmol) of (E)-5-t2-[4-(2-chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethyl]-2-[2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]-benzoic acid monohydrate, 0.03 g (0.16 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.02 mL (4 mmol) of allylamine and 15 mL of dry CH2Cl2 was stirred at room temperature under nitrogen for 18 hours and concentrated to dryness. The residue was purified by thick layer chromatography using ethyl acetate/CH3OH (5:1) as the eluent. The product was isolated and partitioned between CH2Cl2 and dilute NH4OH. The organic phases were concentrated and the residue triturated with hot ethyl acetate and filtered. The filtrates were concentrated and the solid triturated with diethyl ether and filtered to give 60 mg (57%) of (E)-4-[2 -[4-(2-Chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4 ]-diazepin-2-yl]ethyl]-N-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]-phenyl]-2-[2-propenylamino)carbonyl]benzeneacetamide as a tan powder: mp 127-132° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[O:12]2)=[C:4]([NH:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[N:3]=1.[N:30]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CS(C)=[O:41]>>[CH:18]([OH:22])=[O:41].[CH2:26]([CH:25]([NH:24][C:4]1[N:3]=[C:2]([NH:38][CH2:37][CH2:36][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[O:12]1)[CH2:28][CH3:29])[CH3:27]
Reactant: CS(C)=O
Reactant: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Reactant: NCCN1CCCCC1
Product: CCC(CC)Nc1nc(NCCN2CCCCC2)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Product: O=CO

Procedure:
Intermediate 11 (0.069 g, 0.163 mmol) and 2-piperidinoethylamine (0.116 ml, 0.815 mmol) were dissolved in DMSO (0.03 ml) and heated at 80° C. for 40 h in a sealed vial (Reacti vial™) a further portion of 2-piperidinoethylamine (0.058 ml, 0.407 mmol) was added after the first 20 h. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a brown solid (0.031 g). LC/MS system B Rt=2.25 min, m/z=516 MH+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6])=[N+]=[N-].[BH4-].[Na+].C(O)(C)C>CO>[NH2:1][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropyl alcohol (100 mL) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[OH:25][C@@H:26]([CH2:39][NH2:40])[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[OH:25][C@H:26]([CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH2:39][NH:40][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:23][CH:24]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-sulfonyl)-benzyl]-thiazolidine-2,4-dione and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one according to the reductive amination procedure of Intermediate 21 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6): δ 1.20-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.30-4.00 (m, 12H), 4.65 (dd, J=8.0, 3.5 Hz, 1H), 6.56 (d, J=3.2 Hz, 1H), 6.59 (d, J=3.8 Hz, 1H), 6.85 (t, J=3.5 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 10.70 (s, 1H), 10.79 (brs, 1H); MS (ES) m/z: 576.0 (M++H); HRMS Calcd. for C25H30N507S2 (M++H): 576.1587. Found: 576.1596.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6](=[O:19])[C:5]12[C:23](=[O:24])[N:22]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:21](=[O:34])[NH:20]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6](=[O:19])[C:5]12[C:23](=[O:24])[N:22]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:21](=[O:34])[NH:20]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(NC(=O)N(Cc3cc(Cl)ccc3F)C2=O)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)C2(NC(=O)N(Cc3cc(Cl)ccc3F)C2=O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
An ice-cold solution of tert-butyl [5′-chloro-1-(5-chloro-2-fluorobenzyl)-2,2′,5-trioxospiro[imidazolidine-4,3′-indol]-1′(2′H)-yl]acetate (168.00 mg; 0.33 mmol) in DCM (4.00 ml) was treated with trifluoroacetic acid (1.00 ml). After stirring for 4 hours the reaction the solvents were evaporated. Toluene was added twice and evaporated to give the titla compound as a beige solid in 67.5% yield (96.1% purity by HPLC). MS (ESI+): 452.1; MS (ESI−): 454.4
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:17]1[CH:22]=[CH:21][C:20](N)=[CH:19][CH:18]=1)=[CH:11][C:10]2=[O:24].[CH2:25]=O.[OH-].[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N:2]([CH3:1])[CH3:25])=[CH:19][CH:18]=1)=[CH:11][C:10]2=[O:24]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: COc1ccc2oc(-c3ccc(N)cc3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2oc(-c3ccc(N(C)C)cc3)cc(=O)c2c1

Procedure:
Sodium cyanoborohydride (891 mg, 14.1 mmol) was slowly added to an acetic acid solution (30 ml) that contained compound 24 (630 mg, 2.36 mmol) and paraformaldehyde (707 mg, 23.6 mmol), while stirring. The obtained mixture was stirred at room temperature for 3 hours. After completion of the reaction, 50 ml of a 1 N sodium hydroxide aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with 50 ml (25 ml×2) of chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain a product of interest, 6-methoxy-4′-dimethylaminoflavone (compound 25) in the form of a yellow crystal. Yield: 450 mg (yield constant: 64.6%) 1H NMR (300 MHz, CDCl3) δ8.31 (s, 1H), 7.69-7.75 (m, 3H), 7.39 (d, J=8.7 Hz, 1H), 6.62-6.66 (m, 3H), 4.18 (s, 1H). 2.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (400 mg, 0.83 mmol) produced in Example C52(v) in pyridine (4.0 mL) was added cyclopropanecarbonyl chloride (112 μL, 1.24 mmol), and the mixture was stirred at room temperature for 6 hr. Cyclopropanecarbonyl chloride (112 μL, 1.24 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (190 mg, 44%) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].F[C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[N:21]1[C:26]2[CH:27]=[CH:28][O:29][C:25]=2[C:24](=[O:30])[C:23]([C:31]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:34]=[CH:33][CH:32]=2)=[N:22]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:36]1([N:35]2[C:31]([C:23]3[C:24](=[O:30])[C:25]4[O:29][CH:28]=[CH:27][C:26]=4[N:21]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH:20]=[CH:19][CH:18]=[N:17]5)=[CH:15][C:10]=4[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:22]=3)=[CH:32][CH:33]=[N:34]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCC(F)(F)F
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2F)c2ccoc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2OCC(F)(F)F)c2ccoc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (48 mg) in DMF (1 mL) was added 60% NaH (19.2 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (70 mg) was added. The reaction mixture was stirred at 100° C. for 6 hr, and saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)(=[O:18])=[O:19])=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1-n1ccnc1
Temperature: 150 °C
Yield: 77 %

Procedure:
2,4-Difluoro-1-(2-{4-[(2-fluorophenyl)sulfonyl]phenyl}ethyl)benzene (Example 124, 100 mg, 0.26 mmol), potassium carbonate (126 mg, 0.39 mmol) and imidazole (26 mg, 0.39 mmol) were combined in dimethylsulfoxide (1.3 mL) and heated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% ethanol/ethyl acetate to yield the title compound as a white solid (85 mg, 77%). δH (400 MHz, d6 DMSO): 8.31–8.29 (1H, m), 7.87–7.79 (2H, m), 7.41–7.39 (2H, m), 7.31–7.23 (5H, m), 7.16–7.12 (1H, m), 6.99–6.95 (1H, m), 6.88 (1H, t, J=1.1 Hz), 6.85 (1H, t, J=1.3 Hz), 2.92–2.84 (4H, m). m/z (ES+) 425 [MH+].