Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>>[O:22]1[CH2:21][CH:20]1[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: Oc1ccccc1Cc1cccc2[nH]ccc12
Reactant: ClCC1CO1
Product: c1ccc(OCC2CO2)c(Cc2cccc3[nH]ccc23)c1

Procedure:
Using the procedure of Step A of Example 2, 10.0 g of the product of Step A and 3 times 17.56 m1 of epichlorhydrin were reacted to obtain 12.5 g of the desired product melting at 78° C. which was used as is for the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:26](OC(=O)C)(=O)[CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[C:26]2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ncnc3c2c(c1OC)N=C(C)N3c1cccc(Br)c1

Procedure:
A solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (120 mg, 0.32 mmol) (from Example 6, Step B, supra) in acetic anhydride (3 mL) was heated at 150° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was extracted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-2-methyl-3H-1,3,4,6-tetraaza-phenalene as a brown solid. (Yield 60 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K7) (246 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white amorphous substance (352 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH2:19]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH2:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: NCc1cccs1
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: N#CNC(=NCc1cccs1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 54.8 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 2-thiophenemethylamine (0.38 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.40 g, 1.7 mmol, yield: 54%) as colorless needles.
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: COc1ccc(CC(CC(=O)O)CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C(O)CC(CC(=O)O)Cc1ccc(O)cc1
Temperature: 165 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a stirred suspension of 57% sodium hydride-paraffin (1.4 g) in dry dimethylformamide (30 ml) is added dropwise a solution of ethanethiol (4.0 ml) in dry dimethylformamide (10 ml). After 15 minutes, a solution of 3-[(4-methoxyphenyl)methyl]glutaric acid (800 mg) in dry dimethylformamide (20 ml) is added. The resulting slurry is heated in a bath at 165° C. for 20 hours and evaporated in vacuo. The residue is acidified with 20% hydrochloric acid, extracted with ether and the extracts are discarded. The aqueous solution is saturated with salt and extracted with ethyl acetate. The extracts are combined, washed once with brine, dried, evaporated and the residue crystallized from a mixture of ethyl acetate-chloroform-hexane to give 600 mg of 3-[(4-hydroxyphenyl)methyl]glutaric acid, melting point 117°-119° C.
Reaction SMILES: Br[C:2]([CH:16]([CH3:18])[CH3:17])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:30]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:30]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(Br)=C(c1ccccc1)c1ccccc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Into a reactor were introduced 1.20 g (4.00 mmol) of the 2-bromo-1,1-diphenyl-3-methylbutene and 12 mL of THF under a nitrogen atmosphere. The contents were cooled to −70° C., and 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred at that temperature for 30 minutes. Thereafter, 1.1 mL (4.8 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred at that temperature for 3 hours and then heated to room temperature over 13 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and toluene to obtain 0.72 g (43%) of the target compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:1][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:15]([CH:16]([CH3:18])[CH3:17])=[O:19]
Reactant: CC(C)C(=O)Cl
Reactant: Oc1cc(O)c(O)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)C(=O)c1c(O)cc(O)c(O)c1O
Yield: 29.5 %

Procedure:
In a vessel fitted with a calcium chloride tube, 1.00 g (7.04 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved in 20 ml of nitrobenzene and stirred. Into the stirred mixture, 2.82 g (21.1 mmol, 3.00 equivalents) of granular aluminum chloride was added piecemeal and stirred. One hour thereafter, a nitrobenzene (5.0 ml) solution of 0.750 g (7.04 mmol, 1.00 equivalent) of isobutyryl chloride was added dropwise. Ten hours thereafter, the reaction solution was poured into 100 ml of cold 2 M hydrochloric acid solution, stirred for 30 minutes, and then extracted from ether. The ether layer was washed with water, distilled to remove ether, combined with a large volume of water, and distilled water under reduced pressure to remove nitrobenzene by steam distillation. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain 1.38 g of crude product. By purifying the crude product by column chromatography (SiO2, 20 g of Wako Gel C-300, hexane:ether=1:1), 441 mg (yield 65.9%) of the product (8) was obtained in the form of yellow powder crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:28]3[CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCN1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCCCC1
Reaction time: 10 h
Yield: 88.8 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 250 ml of toluene, 4.05 ml (0.0305 mol) of 2-piperidinoethylamine and 0.13 g of p-toluenesulphonic acid monohydrate were added thereto and the mixture was boiled for 4 hours on a water separator. After concentration the residue was hydrogenated with 1.3 g of Raney-nickel in 500 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with CH2Cl2 /MeOH 49:1. There were obtained 4.45 g (89%) of oily rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-piperidinoethyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[F:27])[NH:20][CH:19]=2)=[O:17])[CH:11]([C:29]([O:31]CC)=[O:30])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[F:27])[NH:20][CH:19]=2)=[O:17])[CH:11]([C:29]([OH:31])=[O:30])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2cccc(F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1C(=O)O)c1c[nH]c2cccc(F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a stirred solution of N-(benzoyl)-3-ethoxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (100 mg, 0.02 mmol) in methanol (1 ml) and water (1 ml), was added potassium carbonate (9 mg, 0.06 mmol). After stirring for 8 hours at room temperature, the product was concentrated in vacuo to give a residue which was purified by preparative HPLC to yield 2 mg of N-(benzoyl)-3-hydroxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 101).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:57][C@@H:58]([CH2:63][NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C:59]([O:61][CH3:62])=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C>[C:68]([O:67][C:65]([NH:64][CH2:63][C@H:58]([NH:57][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)[C:59]([O:61][CH3:62])=[O:60])=[O:66])([CH3:71])([CH3:70])[CH3:69]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (23.82 mg) and (S)-methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride (18.90 mg) and iPr2NEt (0.052 ml). After stirring at rt for 4 h, the mixture was purified by preparative HPLC to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate.
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:4]#[N:5].N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[F:1][CH2:2][C:3]([N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])([CH2:6][CH2:7][CH2:8][CH2:9][O:10][S:29]([CH3:28])(=[O:31])=[O:30])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-6-hydroxyhexanenitrile (9.0 g, 31 mmol) and pyridine (60 ml) in dry dichloromethane (150 ml) is cooled in an ice bath, and methanesulfonyl chloride (3.6 g, 31 mmol), diluted with a small amount of dichloromethane, is added slowly with efficient stirring. Stirring is continued at room temperature overnight. The reaction mixture is washed with 2N HCl and dried. Evaporation of solvent gives 2-fluoromethyl-2-phthalimido-6-methanesulfonyloxyhexanenitrile as a yellow oil (10.84 g).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10](=O)[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=O.[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([OH:30])C=CC=2)CCCCC1.NN>>[N:6]1([CH2:7][C:8]2[CH:15]=[C:14]([CH:13]=[CH:12][CH:9]=2)[O:30][CH2:26]/[CH:25]=[CH:24]/[CH2:23][NH2:17])[CH2:10][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: NN
Product: NC/C=C/COc1cccc(CN2CCCCC2)c1

Procedure:
In the same manner as in Example 1, the N-[4-chloro(trans) 2-butenyl]phthalimide was reacted with 3-(1-piperidinomethyl)phenol, followed by hydrolysis with hydrazine to obtain 1.56 g of 4-[3-(1-piperidinomethyl)phenoxy]-(trans) 2-butenylamine. To a solution of 1 g of this amine compound in 30 ml of chloroform was added 0.9 g of the 3-chloro-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide, followed by the same treatment as in Example 1 to obtain 1.57 g of white crystalline 3-[N-[4-[3-(1-piperidinomethyl)phenoxy]-(trans) 2-butenyl]amino]-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide (compound 23, yield 90% ). M.p. 116°~120° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[C:20]([C:19]1[CH:22]=[C:23]([CH3:24])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)#[N:21]
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)nc2)CC1
Yield: 51.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (105 mg) described in Preparation Example 131 and 5,5-dimethyloxazolidin-2-one (47 mg) described in Preparation Example 43, the title compound (59 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[N:3]=1.ClC1N=C(O[CH:33]2[CH2:50][CH:49]3[N:35]([C:36](=[O:56])[N:37]([CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH:43][CH:44]4[C:46]([C:52]([OH:54])=[O:53])([NH:47][C:48]3=[O:51])[CH2:45]4)[CH2:34]2)C2C(C=1)=CC(OC)=CC=2>>[N:14]1([C:4]2[N:3]=[C:2]([O:1][CH:33]3[CH2:50][CH:49]4[N:35]([C:36](=[O:56])[N:37]([CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH:43][CH:44]5[C:46]([C:52]([OH:54])=[O:53])([NH:47][C:48]4=[O:51])[CH2:45]5)[CH2:34]3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: COc1ccc2c(O)nc(-n3cccn3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title product 67 was prepared from 1-hydroxy-6-methoxy-3-(pyrazol-1-yl)isoquinoline following the same procedures described for the preparation of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, Example 10): m/z=575 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[P:3]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([N:5]([CH3:7])[CH3:6])=[O:4].[I:21]I>C1COCC1>[CH3:20][N:2]([CH3:1])[P:3]([O:8][C:9]1[C:10]([I:21])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([N:5]([CH3:6])[CH3:7])=[O:4]
Reactant: CCOC(=O)c1cccc(OP(=O)(N(C)C)N(C)C)c1
Reactant: II
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OP(=O)(N(C)C)N(C)C)c1I
Temperature: 0 °C
Yield: 77.9 %

Procedure:
A dry and nitrogen-flushed 25-ml Schlenk flask, equipped with a magnetic stirring bar and a septum, was charged ethyl 3-{[bis(dimethylamino)phosphoryl]oxy}benzoate 44 (300 mg, 1.00 mmol) in dry THF (3 ml). After cooling to 0° C., a freshly prepared (TMP)Mg(Bt).2LiCl solution (4.33 ml, 0.3 M in THF, 1.3 mmol) was added dropwise and the reaction mixture was stirred at the same temperature. The completion of the metalation (10 min) was checked by GC-analysis of reaction aliquots quenched with a solution of I2 in dry THF. Iodine (508 mg, 2.0 mmol) dissolved in dry THF (2 ml) was then added at 0° C. and the resulting mixture warmed to room temperature. After stirring for 1 hour, the reaction mixture was quenched with sat. aq. Na2S2O3, extracted with ether (3×20 ml) and dried over Na2SO4. After filtration, the solvent was removed in vacuo. Purification by flash-chromatography using ethyl acetate as eluent furnished ethyl 3-{[bis(dimethylamino)phosphoryl]oxy}-2-iodobenzoate 44a (332 mg, 78%) as a yellow oil.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:16][C:17]=1[C:23]([F:26])([F:25])[F:24])#[N:20]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Product: N#Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-amino-2-trifluoromethyl-benzonitrile.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O1CCCC1.O>[OH:16][N:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of methyl 4-formyl-2-methylbenzoate (1.3 g) in tetrahydrofuran (50 mL) was added dropwise to a solution of hydroxylamine hydrochloride (1.0 g), sodium acetate (1.2 g) in tetrahydrofuran (50 mL) and water (50 mL) under ice cooling, and after finishing the dropwise addition, the mixture was stirred for one hour at room temperature. The reaction mixture was diluted with water and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of methyl 4-[(hydroxyimino)methyl]-2-methylbenzoate (1.3 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[S:13][CH:14]=1.CCCCCC>C(OCC)(=O)C>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[S:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (3.80 g, 9.96 mmol) in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 14 hours. Hexane was poured to the reaction mixture, and crystals were collected by filtration to give 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine hydrochloride. The hydrochloride was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.06 g, (73.7%) of the desired product as a solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd]Cl.CN(C=O)C>[CH2:15]([C:14]1[N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=[C:8]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1ccccc1C#Cc1ccccc1
Reactant: NNc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(Cc2c3ccccc3nn2-c2ccccc2)cc1
Temperature: 130 °C
Yield: 80.9 %

Procedure:
Following the general procedure outlined above, a reaction tube was charged with 4.4 mg PdCl2 (5 mol %), 14.5 mg tBu3PHBF4 (10 mol %), 228.1 mg Cs2CO3 (1.4 equiv.) and 2.5 mL DMF. After stirring for 30 min at RT under a flow of argon, 1-chloro-2-phenylethynyl-benzene (106.3 mg, 1.0 equiv.) and phenylhydrazine (75.7 mg, 1.4 equiv.) were added and the reaction was heated to 130° C. for 3 hours. After cooling to RT, the reaction mixture was quenched with brine (30 mL) and extracted with EtOAc (2×30 mL) and the organic phase was dried by eluting through a Varian Chem Elut 12198007 cartridge. Removal of the solvents afforded the crude indazole as a dark-brown oil that purified by FC on silica using CH2Cl2/EtOAc to afford 115.0 mg (81%) of 3-benzyl-2-phenyl-2H-indazole colorless oil that solidified upon standing. 1H-NMR (DMSO-d6) δ 4.47 (s, 2H), 6.98 (d, 2H, J=7.1 Hz), 7.03 (dd, 1H, J=7.9, 7.0 Hz), 7.13-7.24 (m, 3H), 7.30 (dd, 1H, J=8.1, 7.0 Hz), 7.52-7.58 (m, 5H), 7.60 (d, 1H, J=8.6 Hz), 7.65 (d, 1H, J=8.6 Hz); 13C-NMR (DMSO-d6) δ 30.4, 117.1, 120.5, 121.0, 121.2, 125.9 (2C), 126.3, 126.4, 128.1 (2C), 128.4 (2C), 128.9, 129.2 (2C), 134.5, 137.9, 139.5, 147.9; HRMS (FAB): Calculated for C20H17N2 (M+H+) 285.1391, found 285.1385.