Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][CH:25]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:38])([F:26])[F:39])[CH:29]=2)[CH:3]=1)#[N:22]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1c(Oc2cccc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.285 mmol) produced in Example 3(vi), [3-(trifluoromethyl)phenyl]acetic acid (138 mg, 0.684 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (260 mg, 0.684 mmol) and pyridine (2 mL) was stirred at 85° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/2) to give the title compound (87 mg, 57%) as a white powder.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>N1C=CC=CC=1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: c1ccncc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
To a suspension of 5.084 g of 4-carbamoyl-imidazolium-5-olate in 104 ml of dry pyridine was added 11.41 g of p-bromobenzoyl chloride at room temperature. After addition was over, the mixture was stirred at 40°-45° C. for 2.5 hours. The separated crystals were filtered off, washed with chloroform and diisopropyl ether, dried under vacuum to give 10.535 g of 5-carbamoyl-1H-imidazol-4-yl p-bromobenzoate, m.p. 232°-233° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][OH:15]>C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:14]=[O:15])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Clc1ccc(I)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
In a dry 50 ml flask 2.47 g (10.3 mmole) 2-chloro-5-iodo-pyridine was dissolved in 20 ml of dry diethyl ether. The flask was placed under N2-atmosphere, cooled to −78° C. and 5.1 ml of a 2M solution (10.3 mmole) butyl lithium (BuLi) was added. The reaction mixture was stirred for one hour at −78° C. before adding 1 g (4.1 mmole) of the nitrile compound of example 7. Stirring was continued for 30 minutes at −78° C. and the reaction mixture was then allowed to slowly warm up to room temperature. After 16 hours at room temperature methanol was added in order to neutralise the excess BuLi, and the volatile components were evaporated. The reaction mixture was redissolved in 25 ml of a 1:1 mixture of methanol and 0.5M HCl. 0.5 g of silica gel was added and the mixture was stirred for 15 hours at room temperature. The pH was adjusted to approximately 8 by adding a concentrated NaHCO3 solution. The resulting reaction product was extracted three times by means of dichloromethane and the combined organic phases were dried over MgSO4. After filtration of the solids and evaporation of the volatile components, purification was performed by means of column chromatography, and any remaining 2-chloropyridine was removed by sublimation under high vacuum conditions. 7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]hept-1-yl)-(6-chloro-pyridin-3-yl)-methanone was obtained in a 62% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, infrared (IR) spectrophotometry and mass spectrum (MSES) as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH2:29])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH2:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: C=CC(=O)OC
Reactant: NC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Solvent: ClCCl
Product: COC(=O)CCNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: 100 °C

Procedure:
1-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-cyclopropanamine (0.067 g, 0.167 mmol) and methyl acrylate (0.5 mL, 5.5 mmol) were combined in a sealed tube and heated neat at 100° C. for 1 day, during which LC-MS indicated completion of reaction. The cooled reaction mixture was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 5% to 20% EtOAc/Hexanes afforded methyl 3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)cyclopropylamino)propanoate as a light golden yellow oil. MS (ESI) m/z: Calculated: 487.6; Observed: 488.1 (M++1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1)=[O:18].[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:29]([O:33][C:34](=[O:35])[NH:36][C@H:37]([C:38]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:19]1[C:17](=[O:18])[NH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])=[O:39])[CH:41]([CH3:42])[CH3:43])([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Nc1c(F)cccc1Cl)[C@H]1NCCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of (S)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide trifluoroacetate (80 mg, 191 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (41.5 mg, 191 μmol, Eq: 1.00) and HATU (79.9 mg, 210 μmol, Eq: 1.1) in DMF (500 μL) at 0° C. was added DIEA (74.1 mg, 100 μL, 573 μmol, Eq: 3). The reaction was stirred at RT for 1 h, diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give {(S)-1-[(S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (47 mg) as a white foam.
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].[CH:33](O)=[O:34]>>[CH:33]([N:15]([CH2:16][C:17]1[N:28]=[C:27]2[C:20]([N:21]=[C:22]([NH:24][C:25]2=[O:26])[NH2:23])=[N:19][CH:18]=1)[C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2][C:1]([OH:32])=[O:31])=[CH:30][CH:29]=1)=[O:34]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Reactant: O=CO
Product: Nc1nc2ncc(CN(C=O)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1

Procedure:
5-CHO- and 5-Me-(6R,S)-THF can be prepared in a known manner from folic acid. Formylation with formic acid produces 10-formyl-folic acid (10-CHO-FA). The latter can subsequently be catalytically hydrogenated to 10-formyl-tetrahydrofolic acid (10-CHO-THF). 5,10-Methenyl-tetrahydrofolic acid (I; 5,10-CH-THF; "anhydroleucovorin") can be obtained from the latter by dehydration: ##STR1##
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]([F:22])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][NH2:25]>>[F:22][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]2[O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:25][O:24][CH3:23])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CON
Product: CONCc1ccc(-c2nc3cc(F)cc(C(=O)OC)c3o2)cc1
Yield: 87 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxyamine, methyl 5-fluoro-2-(4-((methoxyamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 87%. LC-MS (ESI) m/z: 331 (M+1)+) was made.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[C:14]([CH3:26])=[N:15][N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[O:18][CH3:19])=[CH:11][C:10]([CH3:27])=[N:9]1)=O)(C)(C)C.C(OC(N1C(C)=CC(C2C(C)=NN(C3C=CC=CC=3)C=2OC)=N1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:17]1[N:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[C:14]([CH3:26])[C:13]=1[C:12]1[NH:8][N:9]=[C:10]([CH3:27])[CH:11]=1
Reactant: COc1c(-c2cc(C)nn2C(=O)OC(C)(C)C)c(C)nn1-c1ccccc1
Agent: COc1c(-c2cc(C)n(C(=O)OC(C)(C)C)n2)c(C)nn1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(-c2cc(C)n[nH]2)c(C)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of O-methylated products, compounds (C) and (D) (0.013 g 0.035 mmol), in dichloromethane (1 ml) add trifluoroacetic acid (1 ml). Stir this mixture at room temperature for 1 hour, and then evaporate the mixture to dryness. Dilute the residue with dichloromethane, wash sequentially with water, aqueous sodium bicarbonate solution, and water. Dry the organic layer (sodium sulfate) and concentrate to give 0.006 g (0.022 mmol) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][C:33](=[O:34])[C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:37][CH:36]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)Sc2cccn3c(=O)c(C(=O)OCC)cnc23)cc1
Yield: 51.3 %

Procedure:
To a mixture of 0.8 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1, 0.5 g of powdery potassium carbonate and 25 ml of acetone is added 0.7 g of 4-n-butoxybenzoyl chloride with stirring, and the resultant mixture is stirred at room temperature for 2 hours. The resultant precipitate is filtered and distributed in water-chloroform. The chloroform layer is washed with saturated brine, dried over sodium sulfate and concentrated. The residue (1.1 g) is chromatographed on a column of silica gel, eluting with ethyl acetate. Concentration of the eluate affords 0.7 g of the titled compound.
Reaction SMILES: ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Br:34])[C:28]([OH:30])=O.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C(N(CC)C(C)C)(C)C>O1CCOCC1.CO>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Br:34])[C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:30]
Reactant: NCCCCCC(=O)O
Reactant: O=C(O)c1ccc(Br)c(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)CCCCCNC(=O)c1ccc(Br)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
Added N-hydroxysuccinimide (0.69 g, 6 mmol) followed by 1,3-dicyclohexylcarbodiimide (1.24 g, 6 mmol) to a stirred solution of 3,4-dibromobenzoic acid (1.4 g, 5 mmol) in anhydrous dioxane (40 mL). Stirred suspension for 6 hours at room temperature. Filtered precipitate from solution and washed with dioxane (3×5 mL). Combined filtrate and washes and concentrated in vacuo to afford a white solid. Dissolved solid in methanol (50 mL) and added 6-aminohexanoic acid (1.31 g, 10 mmol) and N,N-diisopropylethylamine (1.74 mL, 10 mmol). Stirred for 24 hours at room temperature. Concentrated solution on a rotary evaporator and dissolved residue in 0.1 N NaOH (150 mL). Filtered precipitate from solution and washed with water (2×10 mL). Combined filtrate and washes and acidified with conc. HCl (1.5 mL). Extracted filtrate with ether (2×50 mL), washed extract with brine (2×30 mL) and dried over anhydrous MgSO4. Removed solvent in vacuo to afford a white solid. Obtained 1.78 g (91% yield) of N-(3,4-di-bromobenzoyl)-6-aminohexanoic acid. 1H NMR (300 MHz, DMSO-d6): δ11.99 (s, 1H), 8.61 (triplet, J=6 Hz, 1H), 8.16 (doublet, J=1.8 Hz, 1H), 7.84(doublet, J=8.1 Hz, 1H), 7.73(doublet of doublets, J=1.8, 8.1 Hz, 1H), 3.2 (doublet of triplets, J=6,6, 6.0 Hz, 2H), 2.18 (triplet, J=7.3 Hz, 2H), 1.49 (multiplet, 4H), 1.28 (multiplet, 2H). 13C NMR (300 MHz, DMSO-d6): δ174.71, 164.03, 135.64, 133.98, 132.31, 128.22, 127.20, 124.14, 33.60, 28.65, 26.00, 24.22.
Reaction SMILES: C(#N)C.[CH:4]1([C:7](=[O:25])[CH:8](C(OCC)=O)[C:9]([C:11]2[S:15][C:14]([CH3:16])=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[O:10])[CH2:6][CH2:5]1>O>[CH:4]1([C:7](=[O:25])[CH2:8][C:9]([C:11]2[S:15][C:14]([CH3:16])=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[O:10])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C(=O)c1sc(C)c(OC)c1F)C(=O)C1CC1
Solvent: CC#N
Solvent: O
Product: COc1c(C)sc(C(=O)CC(=O)C2CC2)c1F

Procedure:
The above compound was also prepared in a similar manner, but using acetonitrile without addition of water, from 3-cyclopropyl-2-ethoxycarbonyl-1-(4-fluoro-3-methoxy-2-methylthiophenyl)propane-1,3-dione. In this experiment the reaction mixture was heated for 20 hours at reflux, resulting in a clean conversion to the title compound (as shown by nmr), but after this time 60% of the starting ethyl ester still remained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[I:13][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Solvent: CC(=O)O
Product: COc1nc(N)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A suspension of 6-methoxy-3-nitro-2-pyridineamine (14.6 g, 86.4 mmol) and N-iodosuccinimide (29.2 g, 130 mmol) in acetic acid (280 ml) was stirred at room temperature for 21 hours and 30 minutes. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and 0.5N sodium hydroxide. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and a saturated brine solution, dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in hexane, and a resulted precipitate was filtered and washed with hexane, thereby yielding the title compound (25.2 g, 85.5 mmol, 98.9%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[I-].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
4-Chloromethylbenzoic acid methyl ester (1.66 g), 1-methylpiperazine (1.8 g) and sodium iodide (0.67 g) were added into acetone (50 ml). The reaction mixture was stirred at 60° C. for 9 hours. More 1-methylpiperazine (0.9 g) and sodium iodide (0.34 g) were added and after stirring additional 1½ hours at 60° C. the reaction mixture was allowed to cool into room temperature. The mixture was filtered and acetone was evaporated. The residue was dissolved in ethyl acetate and washed with water. The solvent was dried with NaSO4 and evaporated to yield 4-(4-methyl-piperazin-1-ylmethyl)benzoic acid methyl ester. 1H NMR (300 MHz, d6-DMSO) δ: 2.18 (s, 3H), 2.37 (bs, 8H), 3.53 (s, 2H), 3.84 (s, 3H), 7.44 (d, 2H, J 8.1 Hz), 7.91 (d, 2H, J 8.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6]2.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: CCOC(=O)C=C1CCCc2cc(OC)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of the alkene (512) (0.792 g, 3.22 mmol) in ethanol (53 mL) was added Pd/C (100 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, then filtered through a pad of celite and concentrated in vacuo to give ethyl 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (513) (0.708 g, 88.7%) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][C:30](=[O:32])[CH3:31])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
2-{[1-(Phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 24, 9.6 g, 30 mmol) in DCM (100 mL) was treated with triethylamine (12.8 mL, 91.0 mmol) and 4-dimethylaminopyridine (1.9 g, 15 mmol). The solution was cooled to 0° C. and acetyl chloride (4.3 mL, 61 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and washed with saturated aqueous NaHCO3 (50 mL) and 1 M HCl (2×50 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (10.3 g). MS m/z 359 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][CH2:22]Br)[CH2:20][CH2:19]3)=[C:8]2[CH3:24])=[CH:4][CH:3]=1.[C-:27]#[N:28].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][CH2:22][C:27]#[N:28])[CH2:19][CH2:20]3)=[C:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C1(CCBr)CC1)c(C)n2Cc1ccc(Br)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C1(CCC#N)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 75 °C
Yield: 97.2 %

Procedure:
To a r.t. solution of bromide from Step 9 (166 mg, 0.35 mmol) in 4 mL DMF was added NaH2PO4H2O (138 mg, 1 mmol) followed by NaCN (49 mg, 1 mmol) and the resulting mixture was warmed to 75° C. for 2 h. After diluting with excess H2O, the mixture was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4 and evaporated to provide 144 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.Cl[P:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:30]1([P:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COc1cccc(-n2c3ccccc3c3ccccc32)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-n2c3ccccc3c3ccccc32)c1P(c1ccccc1)c1ccccc1
Yield: 72.9 %

Procedure:
Title compound (1-3) (6.1 g) was obtained as a colorless powder by the same procedure as in the second step of Example 1, except that the reaction was conducted by use of the toluene solution of the crude product of N-(3-methoxyphenyl) carbazole (4-1) in an amount equivalent to 18.3 mmol, that chlorodiphenylphosphine was used instead of Cy2PCl, and further that the product was isolated and purified by crystallization from toluene/n-hexane. Two Steps Overall Isolated Yield: 72.9%.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=O)[NH:4][C:3]=1[CH3:15].O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([Cl:18])=[N:4][C:3]=1[CH3:15]
Reactant: COc1ccc2c(=O)[nH]c(C)c(Br)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(C)c(Br)c2c1
Temperature: 25 °C

Procedure:
A suspension of 4-bromo-6-methoxy-3-methyl-2H-isoquinolin-1-one (9.3 g, 35 mmol) in POCl3 (50 ml) is refluxed for 1 h. After cooling to room temperature, POCl3 is removed. The residue is diluted with water (50 ml) and neutralized with saturated NaHCO3. The resulting solid is filtered and dried to give 9.8 g of 4-bromo-1-chloro-6-methoxy-3-methyl-isoquinoline. 1H NMR (CDCl3) 8.17 (d, 1H), 7.43 (s, 1H), 7.25 (d, 1H), 4.01 (s, 3H), 2.80 (s, 3H).
Reaction SMILES: I.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([NH:12][NH2:13])=[NH:11].FC1C=C(F)C=CC=1C(N)=S.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH:33]=O)=[CH:28][C:27]=1[C:36]([F:39])([F:38])[F:37]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:12]=[N:13][CH:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([C:36]([F:39])([F:37])[F:38])[CH:28]=2)[N:11]=1
Reactant: O=CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: N=C(NN)c1ccc(F)cc1F
Agent: I
Agent: NC(=S)c1ccc(F)cc1F
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(C(F)(F)F)c3)n2)c(F)c1

Procedure:
2,4-Difluorobenzenecarboximidic hydrazide hydriodide salt was made from 2,4-difluorothiobenzamide using the method described in Example 24. (4-Fluoro-3-trifluoromethylphenyl)oxoacetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt using the method described in Example 1 to give 3-(2,4-difluorophenyl)-5-(4-fluoro-3-trifluoromethylphenyl)-[1,2,4]triazine as a yellow solid (795 mg): δH (400 MHz, CDCl3) 7.01-7.13 (2H, m), 7.45 (1H, t, J 9.2 Hz), 8.32-8.38 (1H, m), 8.46-8.50 (1H, m), 8.55 (1H, dd, J 2.3, 6.7 Hz), 9.66 (1H, s); m/z (ES+) 356.