Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[C:27]([O:29][CH3:30])=[O:28].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cccc2cc(O)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.55 mL, 3.4 mmol) was added to a solution of methyl 3-hydroxyquinoline-8-carboxylate (650 mg, 3.2 mmol) in pyridine (2.3 mL) and CH2Cl2 (13 mL) at 0° C. The reaction mixture was allowed to warm to room temperature. After 3 h, additional trifluoromethanesulfonic anhydride (0.55 mL, 3.4 mmol) was added and the reaction was stirred for an additional 18 h. Saturated aqueous NaHCO3 (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified on silica gel eluting with CH2Cl2 to afford 971 mg (91%) of methyl 3-(((trifluoromethyl)sulfonyl)oxy)quinoline-8-carboxylate.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=429.13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11](Br)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: CC(C)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cc1C#N

Procedure:
5-Bromo-2-hydroxybenzonitrile, isobutyl bromide, and potassium carbonate were heated at 80° C. in DMF in the presence of tetra-n-butylammonium bromide to obtain 5-bromo-2-isobutoxybenzonitrile. F: 254, 256.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH3:11][N:12]1[C:16]([OH:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][N:12]1[C:16]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]#[N:10])[N:3]=2)=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]1
Reactant: Cc1cc(Br)nc(C#N)c1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 74.4 %

Procedure:
7.6 g 2-bromo-6-cyano-4-methylpyridine, 9 g 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and 9.7 g potassium carbonate were mixed in 30 ml N,N-dimethylformamide and heated to reflux for 5 hours. After cooling, the reaction mixture was poured into 300 ml water and the aqueous layer extracted three times each with 100 ml ethyl acetate. The combined extracts were dried with anhydrous magnesium sulphate and the solvent removed in vacuo. Purification by silica gel column chromatography using hexane/ethyl acetate 7:3 afforded 8.1 g (50%) of the title compound as a pale brown solid of melting point 88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>>[CH2:15]([O:18][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH:16]=[CH2:17]
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Reactant: C=CCON
Agent: Cl
Product: C=CCON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 98.1 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to a similar manner to that of Preparation 5-2)(a) to give oil of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.5 g.).
Reaction SMILES: [Br:1][CH:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([Cl:18])[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2c(ncc3ccccc23)C=CC1Br
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccc(Br)cc2c2ccccc12
Temperature: 93 °C
Yield: 75.7 %

Procedure:
36.7 g (139 mmol) 2-bromophenanthridinone and 30.7 g (147 mmol) PCl5 were added to a 1 L multi-neck flask (equipped with stir arm, condenser, and base trap) along with 350 mL POCl3 and heated at 93° C. for 16 hours (note: evolution of HCl gas was predominant—destroyed by base trap). Afterwards, the mixture was assayed to determine complete consumption of 2-bromophenanthridinone. A dean stark trap was connected to the flask to remove the solvent by 1/2 volume. Subsequently, equal volumes of toluene were added and distilled off to remove majority of POCl3. After the third addition of toluene, the volume was reduced to 300 mL's and the remainder of the solvent removed via rotary evaporation. The solids were then recrystallized from toluene and dried to give 30.8 g (78.6% yield, 98% assay) 2-bromo-6-chlorophenanthridine as off white solids (GC-MS confirmed).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=O.[F:8][C:9]([F:19])([F:18])[C:10](=[O:17])[C:11]#CC(F)(F)F>O>[CH2:11]([C:3]([C:2]([F:7])([F:6])[F:1])=[O:5])[C:10]([C:9]([F:19])([F:18])[F:8])=[O:17]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(C#CC(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F

Procedure:
In view of the above circumstances, the present inventors have made extensive researches and resultantly found that: it is possible to form a 1,1,1,5,5,5-hexafluoroacetylacetone hydrate by reacting a 3,3,3-trifluoropropynyl metal with a trifluoroacetate and then bringing the resulting reaction mixture (A), in which at least 1,1,1,5,5,5-hexafluoro-3-pentyn-2-one or an equivalent thereof is contained, into contact with water in the presence of an acid; and it is possible to produce 1,1,1,5,5,5-hexafluoroacetylacetone by dehydration of the thus-formed hydrate.
Reaction SMILES: CN(C)C[CH2:4][CH2:5][C@:6]12[CH2:14][CH2:13][C@@H:12]3[C:15]4[CH:20]([CH2:21][CH2:22][C@H:11]3[C@@H:10]1[CH2:9][CH2:8][C@@H:7]2[OH:27])[CH:19]=[C:18]([O:23][CH3:24])[CH2:17][C:16]=4OC.CN(C)CCC[C@]12CC[C@@H]3C4C(OC)=CC(OC)=CC=4CC[C@H]3[C@@H]1CC[C@@H]2O.[Li].N>O1CCCC1>[CH2:5]([C@:6]12[CH2:14][CH2:13][C@@H:12]3[C:15]4[CH2:16][CH:17]=[C:18]([O:23][CH3:24])[CH2:19][C:20]=4[CH2:21][CH2:22][C@H:11]3[C@@H:10]1[CH2:9][CH2:8][C@@H:7]2[OH:27])[CH3:4]
Reactant: COC1=CC2CC[C@@H]3[C@H](CC[C@]4(CCCN(C)C)[C@@H](O)CC[C@@H]34)C2=C(OC)C1
Agent: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(CCCN(C)C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4

Procedure:
To prepare 13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1(10),3-dien-17β-ol react 13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1,3,5(10)-trien 17β-ol in tetrahydrofuran with lithium in liquid ammonia according to the manipulative procedure described above.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.[CH3:24][C:25]([CH3:40])([C:29]([NH:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:26](O)=[O:27]>>[CH:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:26](=[O:27])[C:25]([CH3:24])([CH3:40])[C:29]([NH:31][CH2:32][C:33]([F:38])([F:39])[C:34]([F:35])([F:36])[F:37])=[O:30])[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]1=2)([CH3:15])[CH3:14]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CC(C)OCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CC(C)OCCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-Amino-5-(2-isopropoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (78%). White solid. MS: m/e=556(M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[N:21]\[S@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: O=C(CCCCl)c1cc(F)ccc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C(\CCCCl)c1cc(F)ccc1F
Temperature: 27.5 °C
Yield: 86.4 %

Procedure:
Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 162) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (114 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].Cl.[Cl:38][CH2:39][CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>CN(C=O)C>[Cl:38][CH2:39][CH2:40][CH2:41][NH:42][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:36])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: NCCCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCCl)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (206 mg, 0.4 mmol) in DMF (4 mL) was added (3-chloropropyl)amine hydrochloride (78 mg, 0.6 mmol) and triethylamine (112 uL, 0.8 mmol). The mixture was heated with microwave at 60° C. for 2 hrs. The mixture was separated by flash chromatography to afford the title compound (100 mg, 47%).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([O:26][CH3:27])[C:15]([CH3:25])=[C:16]([O:23][CH3:24])[C:17]=3[CH2:21][CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:31])(=O)=O>>[Cl:31][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([O:26][CH3:27])[C:15]([CH3:25])=[C:16]([O:23][CH3:24])[C:17]=2[CH2:21][CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Product: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 22 %

Procedure:
By the method of Example 21 phenylthiomethylation of 4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.65 g) with chloromethyl phenyl sulfide (0.24 mL) gave 2-phenylthiomethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, reaction of which with sulfuryl chloride gave 2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, 0.16 g, 22% yield.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10]([CH:17]([Cl:22])[C:18]([F:21])([F:20])[F:19])([C:13]([F:16])([F:15])[F:14])[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[H][H]>[NH2:1][C:4]1[C:12]2[O:11][C:10]([CH:17]([Cl:22])[C:18]([F:21])([F:19])[F:20])([C:13]([F:14])([F:15])[F:16])[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Solvent: C1CCOC1
Product: Nc1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
84 g of 4-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2 -trifluoromethyl-1,3-benzodioxole from Example 7 were dissolved in 500 ml of tetrahydrofuran and hydrogenated with 15-20 bar of hydrogen over 5 g of palladium-oncharcoal (5% strength) at room temperature for 5 hours. The mixture was then filtered, the filtrate was concentrated and the residue was distilled in vacuo. The yield was 31 g (40% of theory), and the boiling point was 70° C. under 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -68.6 and -81.5 ppm. 1H-NMR: 4.69 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]([CH2:23][CH2:24][O:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=3)[CH3:22])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)[CH3:22])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(OCCN(C)C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N(C)CCOc3ccc(C(=O)O)cc3)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Methyl 4-(2-((2-(2-methylphenylamino)-6-benzoxazolyl)-N-methylacetamido)ethoxy)benzoate (206.9 mg, 0.44 mmol) was dissolved in THF (5 ml). To the resulting solution was added 0.25N NaOH (5 ml), and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added NaOH (500 mg), followed by heating under reflux for 3 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with a chloroform-methanol mixture (5:1, v/v). The solution was washed with 1N HCl, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-methanol (20:1, v/v) eluate fractions, the title compound (101 mg, 51%) was obtained as a pale red solid.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:25]=[CH:26][CH:27]=2)[CH2:11][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1(S(Cl)(=O)=O)C=CC=CC=1>C(N(CC)CC)C>[CH3:33][O:31][C:30](=[O:32])[CH2:29][CH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:11][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)[CH:23]=1
Reactant: O=C(O)CCc1cccc(CN(Cc2cc3ccccc3o2)S(=O)(=O)c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2cc3ccccc3o2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(benzofuran-2-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.52-7.42 (m, 3H), 7.26-7.09 (m, 8H), 6.39 (d, 1H), 4.46 (s, 2H), 4.39 (s, 2H), 3.68 (s, 3H), 2.88 (t, 2H), 2.57 (t, 2H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:22](=[O:23])[CH2:21][Cl:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: NCCCCOc1cc(CN2CCCCC2)ccn1
Product: O=C(CCl)NCCCCOc1cc(CN2CCCCC2)ccn1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 67(a), but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and 2-chloroacetyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 59°-63° C., in an 80% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Br:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=3)[CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(Br)c2)nc1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C

Procedure:
2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine (2.5 g; 6.3 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.1 g; 4.9 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane→ethyl acetate:heptane 2:9). Yield 1.4 g (53%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.80 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O.C(O)C.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>[Cl:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: ClCCCOc1ccc(Br)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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCCOc1ccc(-c2ccncc2)cc1
Yield: 53.3 %

Procedure:
To a mixture of 1-bromo-4-(3-chloropropoxy)benzene (1.25 g) and tetrakistriphenylphosphinepalladium (58 mg) in toluene (12 mL) and potassium carbonate (2.07 g) in water (6 mL) is added pyridine-4-boronic acid (380 mg) dissolved in ethanol. The mixture is heated for five hours at a temperature close to 80° C. Solvents are removed under reduced pressure and the residue dissolved in ethyl acetate. The organic phase is washed with a 10% aqueous solution of potassium hydroxide, then with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 95/5) to give 408 mg of 4-(4-(3-chloropropoxy)phenyl]pyridine as an ochre oil used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.C([O-])(=O)C.[K+]>CS(C)=O>[O:12]1[CH2:13][CH2:14][CH:9]([O:8][C:4]2[CH:3]=[C:2]([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1ccnc(OC2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OB(O)c1ccnc(OC2CCOCC2)c1
Temperature: 100 °C

Procedure:
To 4-Bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.2 g, 0.77 mmol) in DMSO (5 ml) (degassed by bubbling N2 through) was added 4,4,5,5,4′,4′,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.39 g, 1.55 mmol) and potassium acetate (0.27 g, 2.31 mmol). PdCl2ddpf (0.028, 0.04 mmol) was added, the reaction mixture again degassed and then heated at 100° C. for 5 h. The compound was passed through a C18 reverse phase chromatography column to afford the desired product, used crude. MS: [MH]+ 224.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)C=CC=CC=1.[C:29]1(=[O:41])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31][NH:30]1.N1C=CC=C(/C=C\C2C3C(=CC=CC=3)C(=O)NN=2)C=1>>[CH3:16][C:13]1[N:12]=[CH:11][C:10](/[CH:9]=[CH:39]\[C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29](=[O:41])[NH:30][N:31]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=Cc1n[nH]c(=O)c2ccccc12
Agent: O=c1[nH]nc(/C=C\c2cccnc2)c2ccccc12
Agent: [Cl-]
Product: Cc1ccc(/C=C\c2n[nH]c(=O)c3ccccc23)cn1

Procedure:
Prepared by Wittig reaction of triphenyl-(6-methylpyridin-3-yl-methyl)phosphonium chloride and phthalazin-1(2H)-one-4-carbaldehyde as described in expl. 4d): HPLC5-40 tR=11.7/12.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)[CH:10]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[Cl:23][C:18]1[N:17]=[C:16]([NH:15][C:11]2[CH:10]=[C:9]([S:8][CH2:7][CH2:6][NH:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[CH:14]=[CH:13][CH:12]=2)[C:21]([Cl:22])=[CH:20][N:19]=1
Reactant: CS(=O)(=O)OCCSc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCCSc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 10.6 %

Procedure:
A solution of 2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethyl methanesulfonate (0.17 g, 0.43 mmol) in N,N-dimethylformamide (2 mL) was treated with potassium carbonate (0.15 g, 1.1 mmol) followed by tert-butyl (3-aminophenyl)carbamate (0.17 g, 0.81 mmol) and stirred at 20° C. for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (23 mg, 10% for 2 steps). LCMS for C23H26Cl2N5O2S (M+H)+: m/z=505.9, 508.0.