Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[CH:14][C:13]=1[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([NH:8][C:9](=[O:10])[N:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[C:13]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:14]=1)[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN=C=O
Reactant: CCOC(=O)/C=C/c1ccc(-c2cc(NC)ccc2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)OCC)cc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
660 μL (4.0 mmol, 1.5 eq) of heptyl isocyanate are added to a solution of 805 mg (2.72 mmol, 1 eq) of ethyl (E)-3-(2′-methyl-5′-methylaminobiphenyl-4-yl)acrylate in 8 mL of a 7/1 dichloromethane/triethylamine mixture. The reaction medium is stirred at 50° C. for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residual oil is chromatographed on silica (7/3 heptane/ethyl acetate). 920 mg of ethyl (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylate are obtained in oil form. Yield=77%
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(-c3cnn(C)c3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)cn1
Temperature: 60 °C
Yield: 58.1 %

Procedure:
A 50 mL round-bottomed flask was charged N-(4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (23.8 mg, 0.0360 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 60° C. until LC-MS showed that the starting material had been consumed (overnight). The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (11.3 mg, 58%). LRMS (APCI pos): >99% purity, 254 nm, m/e 541 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 11.72 (s, 1H), 8.38 (d, 1H), 8.31 (d, 1H), 8.27 (d, 1H), 8.18 (s, 1H), 8.06 (dd, 1H), 7.96 (s, 1H), 7.69 (m, 2H), 7.60 (m, 2H), 7.42 (m, 2H), 6.31 (d, 1H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[S:18][CH2:19][C:20](O)=[O:21].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:20](=[O:21])[CH2:19][S:18][CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:3]=3[CH:4]=2)=[O:16])=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1C(SCC(=O)O)c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C1CSC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Yield: 4.4 %

Procedure:
A mixture of intermediate (19) (0.079 mol) and MgSO4 (35.5 g) in toluene (500 ml) was stirred and refluxed overnight in a Dean-Stark apparatus and then cooled. The precipitate was filtered off and the filtrate was evaporated till dryness. The residue (35 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 85/15; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile and DIPE. The precipitate was filtered off and dried, yielding 1.5 g (4.4%) of 7-(4-chlorobenzoyl)-5-(3-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (intermediate 20), mp. 222° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:13][C@H:12]1[CH3:32])=[O:10])([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29](=[O:30])[N:2]([CH3:3])[CH3:1])[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:13][C@H:12]1[CH3:32])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)O)cc32)CCN1C(=O)OC(C)(C)C
Reactant: CNC
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)N(C)C)cc32)CCN1C(=O)OC(C)(C)C

Procedure:
Starting with dimethylamine and 1-[2-((R)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid, the title compound was prepared by using similar methods to those described in General Procedure 1. MS: [M+H]+=431.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([O:7]CCCCC)=[O:6].O.[OH-].[Li+]>C1COCC1.O.Cl>[CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([OH:7])=[O:6]
Reactant: CCCCCOC(=O)[C@H](CC(C)C)OCCCCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCO[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 9 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.[Br:17][C:18]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([I:25])[N:19]=1.O>CN(C)C=O>[Br:17][C:18]1[C:23]([O:24][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:22][CH:21]=[C:20]([I:25])[N:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(I)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(I)nc2Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Potassium carbonate (12 g) and 4-methoxybenzyl chloride (8.8 mL) were added to a solution of 2-bromo-6-iodopyridin-3-ol (12 g) in N,N-dimethylformamide (130 mL), and the mixture was stirred at room temperature for six hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:1→0:100) to give 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (18 g, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][O:14][C:15]2[C:25]3[O:24][CH2:23][CH2:22][NH:21][C:20](=O)[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([CH2:13][O:14][C:15]2[C:25]3[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NCCOc2c(OCc3ccccc3)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(COc2cccc3c2OCCNC3)cc1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
1M Lithium aluminum hydride (60 ml, 60.0 mmol) in THF was added to a stirred solution of 9-[(phenylmethyl)oxy]-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Preparation 59) (7.4 g, 27.5 mmol) in THF (150 ml) under argon and heated at 60° C. for 2 hours then cooled and quenched by careful addition of 100 ml of 2M sodium hydroxide with ice bath cooling and the resulting suspension filtered, the solids washed with water and EtOAc and the organic dried (magnesium sulphate) and evaporated to give 7.01 g of white solid. MS (ES): C16H17NO2 requires 255; found 256 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc2scnc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2scnc2c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a suspension of benzothiazole-5-carboxylic acid (1 eq.) in MeOH at 0° C. was added dropwise thionyl chloride (2 eq.). The reaction was stirred at 60° C. for 15 h. The solvents were concentrated under reduced pressure to afford benzothiazole-5-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]1COCC1.[CH3:6][C:7]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][N:8]=1.C[Mg]Br.Cl>C(OCC)(=O)C>[CH3:6][C:7]1[C:11]([CH:12]([OH:13])[CH3:1])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][N:8]=1
Reactant: C1CCOC1
Reactant: Cc1noc(-c2ccccc2)c1C=O
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccccc2)c1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To the THF solution of the above Compound 25 was slowly added 1.4 eq of methylmagnesium bromide at room temperature. The reaction mixture was stirred at r.t. for 1 h. To the reaction mixture was added ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the crude product, obtained in 96% yield, was used directly for the next step without purification.
Reaction SMILES: ClC1N2[C:8](=[O:11])NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45](NCC)(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][CH2:8][O:11][CH2:45][CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=2)=[CH:33][CH:32]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CCOCC3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.306 min, [M+H]30 =470.
Reaction SMILES: [F:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([Cl:17])=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]2[N:6]=[C:4]([C:3]3[CH:19]=[CH:20][N:21]=[CH:22][C:2]=3[F:1])[O:18][C:8]=2[CH:9]=1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a mixture of 2.08 g of 3-fluoro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 13 ml of tetrahydrofuran and 1.79 g of triphenylphosphine, 2.98 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.74 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 90”).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][NH:8][C:9](=O)[CH3:10].N1C(C)=CC=CC=1C.[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:7][N:8]1[C:9]([CH3:10])=[N:29][N:28]=[C:20]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: CNC(C)=O
Reactant: NNC(=O)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1nnc(-c2ccncc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
860 μl (10 mmol) oxalyl chloride was slowly added to a solution of 731 mg (10 mmol) N-methyl-acetamide and 2.33 ml (20 mmol) 2,6-lutidine in 20 ml CH2Cl2 at 0° C. After 15 min 1.37 g (10 mmol) isonicotinic acid hydrazide was added in one portion. The resulting mixture was stirred at room temperature for 1 h and the neutralized with NaHCO3(sat). The phases were separated and the water phase was extracted with CH2Cl2. The combined organic phases were dried and concentrated. The residue was dissolve in 20 ml acetic acid and heated at 120° C. for 2 h. After cooling the solvent was removed. Flashchromatography (CH2Cl2/MeOH 10:1) afforded 765 mg (44%) of a grey/white solid. 1H NMR (CDCl3), d (ppm): 2.52 (s, 3 H) 3.66 (s, 3 H) 7.58 (d, 2 H) 8.76 (d, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22].O1CCCC1>>[CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]([OH:9])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)CC(C)C
Yield: 83 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (805 mg) and 1N isobutylmagnesium bromide-tetrahydrofuran solution (6.0 mL) to give the title compound (819 mg, 83%) as an oil.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([C:13]([F:16])([F:15])[F:14])[N:12]=[N:11]2)[CH:5]=1)=O.Cl.[OH-].[Na+]>CO>[F:16][C:13]([F:14])([F:15])[C:10]1([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:3])[N:11]=[N:12]1
Reactant: O=CNc1cccc(C2(C(F)(F)F)N=N2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc(C2(C(F)(F)F)N=N2)c1
Temperature: 0 °C

Procedure:
N-formyl m-[3-(trifluoromethyl)diazirine-3-yl]aniline (120 mg) is dissolved in 3 ml of methanol. Concentrated HCl (1 ml) is added. The mixture is reacted for 10 min at ambient temperature. The reaction mixture is cooled to 0° C. in an ice bath and neutralised with NaOH (3 ml, 6N). The aqueous phase is extracted with ethyl ether (5 times 4 ml). The combined organic phase is washed with deionised water (5 ml) and dried over MgSO4. The solvent is evaporated under reduced pressure to give a yellow oil m-[3-(trifluoromethyl)-diazirine-3-yl]aniline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH:15]=1)#[N:12]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Solvent: c1ccncc1
Product: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (1.5 g, 3.96 mmol) in pyridine (4 mL) was added cyclopropanecarbonyl chloride (467 μL, 5.15 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→60/40), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (1.26 g, 63%) as a colorless powder.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[CH:33][C:34]([C:37](=[O:39])[CH3:38])=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccc(C(C)=O)cc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)c1ccc(-c2cc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)ccn2)cc1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.25 mL, 2.37 mmol) was dropwise added to a solution of the methoxy compound (0.1 g, 0.24 mmol) prepared in Example 37 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (21 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)c(F)c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A stirred mixture of 3,4-difluoroaniline (12.9 g, 0.1 mol) in concentrated hydrochloric acid (60 mL) was chilled to −10° C. with an ice/methanol bath. A solution of sodium nitrite (6.9 g, 0.1 mol) in water (30 mL) was added at a rate which maintained the temperature of the reaction mixture below 10° C. After stirring for 2 hours, the reaction mixture was cooled to 0° C. and a solution of tin(II) chloride (56.88 g, 0.3 mol) in concentrated hydrochloric acid (50 mL) was added dropwise with vigorous stirring. Additional concentrated hydrochloric acid (150 mL) was added to the reaction mixture and stirring was continued for 2 hours. The reaction mixture was filtered to collect the precipitated hydrochloride salt of the title compound. This precipitate was dissolved in water (75 mL) and the resulting solution was basified with 50% aqueous sodium hydroxide and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to provide the title intermediate as a brown oil (8.11 g, 57.4%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:46]([N:42]1[CH2:43][CH2:44][C@@H:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCN(C(=O)c2ccccc2)C1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 40% yield. LCMS for C30H28ClN6O2 (M+H)+: m/z=539.2.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C>ClCl.O>[C:13]([NH:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(N)CC2)cc1
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
To a stirred suspension of Compound 7 (1.25 g, 7.66 mmol) in CH2 Cl2 (40 ml) was added acetic anhydride (860 mg, 8.42 mmol) and triethylamine (2.32 g, 22.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 22 h. The mixture was diluted with H2O (50 ml) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with 10% HCl aq., sat. NaHCO3 aq. and brine, dried (MgSO4) and concentrated in vacuo to give crude product (1.58 g, quant.), which was recrystallized from hexane-ethyl acetate to give Compound 8 (1.26 g, 80%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@@H:5]([OH:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:33](I)[CH3:34]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([O:31][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](O)Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1
Reactant: CCI
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)OCC

Procedure:
A solution of (2S)-2-hydroxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid ethyl ester, AgO2 (1.5 eq) and ethyl iodide (excess) in dichloromethane was stirred over 10 days. The crude mixture was filtered through celite and concentrated to dryness. The compound was purified by chromatography to give the title product. 1H-NMR (CDCl3, 200.15 MHz): δ 7.34–7.26 (m, 2H), 7.18–6.82 (m, 11H), 4.18–4.17 (m, 6H), 4.01–3.94 (m, 1H), 3.68–3.53 (m, 1H), 3.43–3.28 (m, 1H), 2.96 (d, 2H, J=6.5), 2.25 (qn, 2H, J=6.2), 1.20 (dt, 6H, J=12.6, 7.3).