Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=4)=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: C#Cc1cnc(C)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3cnc(C)nc3)cc2c1=O
Temperature: 150 °C
Yield: 54 %

Procedure:
Compound D (50 mg, 0.13 mmol, 1.0 eq), 5-ethynyl-2-methyl-pyrimidine (30 mg, 0.26 mmol, 2.0 eq), copper(I) iodide (2.5 mg, 0.013 mmol, 0.010 eq), bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 0.0064 mmol, 0.050 eq) and triethylamine (53.6 μL, 0.38 mmol, 3.0 eq) were dissolved in DMF (1.3 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 15 minutes. The reaction was purified directly using reverse phase chromatography to afford 30 mg (55%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.47 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81-7.76 (m, 3H), 7.53 (t, J=8.7 Hz, 2H), 7.02 (d, J=8.80 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 428.2.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[C:11]([O:15][CH3:16])(=[O:14])C=C.C1(C=CC(O)=CC=1)O>>[CH3:16][O:15][C:11]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:14]
Reactant: C=CC(=O)OC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: COC(=O)C12C=CC(CC1)C2
Temperature: 220 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
DCPD (Aldrich, 256.5 mL, 1.9 mol), methyl acrylate (Aldrich, 405 mL, 4.5 mol), and hydroquinone (3.2 g, 0.03 mol) were put in a 2 L autoclave. After heating to 220° C., reaction was carried out for 2 hours while stirring the autoclave at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 50° C. to obtain the product (yield: 74.8%). The molar ratio (mol %) of exo/endo isomers of the product was 55.8:44.2.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[C:8]([O:19]C)=[C:9]([S:11]([NH:14]C(C)(C)C)(=[O:13])=[O:12])[CH:10]=1)(C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=C(C)C=1.C(OCC)C>O>[Cl:24][CH2:23][C:22]([NH:21][C:7]1[C:8]([OH:19])=[C:9]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:10]=[CH:5][CH:6]=1)=[O:25]
Reactant: COc1c(NC(=O)CCl)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1cccc(C)c1
Solvent: CCOCC
Product: NS(=O)(=O)c1cccc(NC(=O)CCl)c1O
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 5-t-butyl-2-methoxy-3-(chloroacetamido) phenyl-N-t-butyl-sulfonamide (8.0 g), aluminium chloride (16.4 g) and m-xylene (80 ml) was heated at 95° C. with stirring for 16 hours under nitrogen. The mixture was then poured into a beaker containing diethyl ether (300 ml) and water (300 ml) and stirred at ambient temperature for 15 minutes. The organic layer is separated and dried over sodium sulphate and concentrated under vacuum in order to remove all diethyl ether. The residual solution was cooled and hexane added to precipitate the title compound (4.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6](O)[C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Temperature: 50 °C

Procedure:
To 3.0 g of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-10-hydroxy-1,9(2H,10H)-acridinedione suspended in 30 ml of chloroform is added dropwise 2.1 g of phosphorous trichloride in 20 ml of chloroform. The suspension is warmed at 50° C. for 2 hrs and filtered while warm. The solid is suspended in aqueous ethanol and filtered to give 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)-acridinedione as a cream solid; mp >325° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]2=[C:17]3[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]3[C:8](=[O:22])[C:9]1[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[O:12][C:13]=12.[Br:23][CH2:24][CH2:25][CH2:26]Br>>[Br:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:16]=[CH:15][C:14]2=[C:17]3[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]3[C:8](=[O:22])[C:9]1[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[O:12][C:13]=12
Reactant: BrCCCBr
Reactant: O=C1c2c(oc3ccccc23)-c2ccc(O)c3cccc1c23
Product: O=C1c2c(oc3ccccc23)-c2ccc(OCCCBr)c3cccc1c23

Procedure:
Alternatively, the title compound is prepared by reaction of 3-hydroxy-7-oxo-7H-benzo[b]phenaleno[2,1-d]furan with 1,3-dibromopropane as previously described.
Reaction SMILES: [CH2:1]1[C:13]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH:3]([C:14]([O:16]C)=O)[CH2:2]1.[NH3:18]>CO>[CH2:1]1[C:13]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH:3]([C:14]([NH2:18])=[O:16])[CH2:2]1
Reactant: N
Reactant: COC(=O)C1CCc2cc3ccccc3nc21
Solvent: CO
Product: NC(=O)C1CCc2cc3ccccc3nc21
Reaction time: 8 h

Procedure:
2,3-Dihydro-1H-cyclopenta[b] quinoline in ether is added to isopropylmagnesium bromide (prepared from magnesium and isopropylbromide in ether). The mixture is heated at 120° C for several hours adding toluene when necessary as the ether distilled off to maintain the contents liquid. The mixture is cooled and ether is added. The resulting solution of 2,3-dihydro-1H-cyclopenta[b]-quinoline-3-magnesium bromide is added to stirred ice-cooled ether while a stream of dry CO2 gas is bubbled through until the red colour is discharged. The resulting solid (the magnesium bromide salt of 2,3-dihydro-1H-cyclopenta[b] quinoline-3-carboxylic acid) is dried and added to methanol saturated with HCl. The solution is stirred overnight and then evaporated to dryness. The residue is dissolved in water and extracted with ether. The aqueous phase is basified with sodium carbonate, any solid filtered off and the aqueous solution is extracted with ether (3 times). The ether extracts are dried and evaporated to dryness leaving an oil which is purified by distillation under reduced pressure to give methyl 2,3-dihydro-1H-cyclopenta[b] quinoline-3-carboxylate. This ester is dissolved in methanol saturated with ammonia in a bomb and kept overnight at 80° C. The solution is then cooled and evaporated to dryness. Purification and recrystallisation of the product gives 2,3-dihydro-1H-cyclopenta [b] quinoline-3-carboxamide.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.[C:52]([O:56][C:57](=[O:66])[CH2:58][C@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:63]([C@H:61]3[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]3)=[O:64])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (113 mg, 0.30 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (100 mg, 0.27 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (63.8 mg, 0.30 mmol) and DIEA (0.053 mL, 0.30 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(trans-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (150 mg, 0.27 mmol, 98%) as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:9]=[C:10]([C:15]#[C:16][Si](CC)(CC)CC)[C:11]([NH2:14])=[N:12][CH:13]=1>CN1CCCC1=O.CCOC(C)=O.O>[Br:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:16][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC[Si](C#Cc1nc(Br)cnc1N)(CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Brc1cnc2[nH]ccc2n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
Potassium tert-butoxide (6.612 g, 58.92 mmol) was suspended/dissolved in dry N-methylpyrrolidinone (15 mL) and stirred at 80° C. while a solution of 5-bromo-3-(2-triethylsilylethynyl)pyrazin-2-amine (9.1992 g, 29.46 mmol) in dry N-methylpyrrolidinone (50 mL) was added slowly drop wise over 10 minutes. The dropping funnel was washed out with a further aliquot of dry N-methylpyrrolidinone (10 mL). The resultant was stirred at 80° C. for 1.5 hours. Reaction mixture cooled to ambient then diluted with EtOAc and water and EtOAc layer washed with small portions of water (×6). Organic layer dried (MgSO4), filtered and concentrated in vacuo to give a dark brown solid (4.1 g, 70.3%). 1H NMR (400.0 MHz, DMSO) δ 12.50 (s, 1H), 8.37 (s, 1H), 8.01 (s, 1H) and 6.64 (q, J=1.7 Hz, 1H) ppm; MS (ES+) 198.10.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:30])=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>>[F:30][C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:31]=[N+:32]=[N-:33])[O:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:20][C:19]=1[F:29]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(F)c(F)c2c1OC(CN=[N+]=[N-])C2
Yield: 90.1 %

Procedure:
Treatment of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.3 g, 3.02 mmol) with sodium azide (0.983 g, 15.11 mmol) generally according to the procedure described for intermediate 98 gave 0.82 g (90%) of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide as a colorless oil. Rf=0.69 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 7.25 (d, 2H); 7.14 (m, 3H); 5.06 (m, 1H); 3.67 (dd, 1H); 3.55 (dd, 1H); 3.46 (dd, 1H); 3.11 (dd, 1H); 2.15 (s, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][CH2:10][C:11]([NH-:13])=[O:12]>>[C:2]1([C:10](=[CH2:9])[C:11]([NH2:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH-]C(=O)CCCl
Reactant: Nc1ccccc1
Product: C=C(C(N)=O)c1ccccc1

Procedure:
Phenyl acrylamide was synthesized via the acylation reaction of aniline followed by the β-elimination of the 3-chloropropionyl amide intermediate product (intermediate product 1).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)=O)=CC=1.C[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=2)[NH:28][CH:29]=[O:30])=[CH:23][CH:22]=1.C(N)=O.B(Br)(Br)Br>C(Cl)Cl>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:31]2[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=2)[NH:28][CH:29]=[O:30])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(NC=O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: NC=O
Product: O=CNC(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Following the procedure in step C of Example 1, 4,4'-dimethoxybenzophenone was converted to N-[bis-(4-methoxyphenyl)methyl]formamide. To a solution of the above formamide (2.2 g, 8.1 mmol) in anhydrous CH2Cl2 (50 ml) at 0° C. under N2 was added 1.0M solution of BBr3 in CH2Cl2 (20.0 ml). After warming to 20° C. and stirring for one hour, the reaction mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The EtOAc fractions were washed with brine, dried over MgSO4 and then stripped to obtain 1.9 g of N-[bis-(4-hydroxyphenyl)methyl]formamide.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[O:20][C:21]([CH3:24])=[CH:22][N:23]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[O:20][C:21]([CH3:24])=[CH:22][N:23]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ncc(C)o3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)o1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of 125b (114 mg, 0.20 mmol) and lithium hydroxide (120 mg, 5.0 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at 35° C. for 30 mins. The mixture was concentrated under reduced pressure and the residue was diluted with water (5 mL). The resulting mixture was extracted with dichloromethane three times. The combined organic layer was then concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 125 (52 mg, 49%). MS-ESI: [M+H]+ 530.9. 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.53 (d, J=3.0 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 7.78 (dd, J=1.0, 13.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.50 (d, J=5.0 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H), 4.92 (bs, 1H), 4.40 (d, J=7.0 Hz, 2H), 3.60 (s, 3H), 2.22 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>>[Cl:24][C:23]1[C:18]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: Oc1ccccc1-c1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1

Procedure:
2-(Benzo[d]thiazol-2-yl)phenol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 2-(2-(3-chloro-5-nitropyridin-2-yloxy)phenyl)benzo[d]thiazole which was further converted to 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine as per the procedure described in preparation 2.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](I)[CH3:39]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][CH3:39])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCI
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.79 g) and ethyl iodide (0.12 mL) as starting materials, 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:38]1([O:37][C:35](=[O:36])[NH:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:10]3[CH:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][CH:11]=3)=[CH:24][N:23]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed C-[5-(3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methylamine (P-596, 115 mg, 0.307 mmol), dichloromethane (1.5 mL) and triethylamine (85.6 uL, 0.614 mmol). The solution was cooled to 0° C. and then phenyl chloroformate (57.8 uL, 0.461 mmol) was added and the mixture was stirred at 0° C. for 15 minutes. The reaction was quenched with water (3 mL) and then the organic portion was removed. The aqueous portion was extracted with dichloromethane (2 mL), the organic portions were combined, washed with brine (3 mL), dried (MgSO4), concentrated and purified by silica gel column chromatography utilizing 70% ethyl acetate/hexanes as the eluent to produce 78 mg of I-149 as a yellow viscous oil in 51% yield.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:17][NH:18][C:19](=O)[CH2:20][CH:21]2[CH2:23][CH2:22]2)=[N:5][CH:6]=[CH:7][C:8]=1OCC1C=CC=CC=1)#[N:2].O(Cl)[Cl:26].[P+5]>ClCCCl.C(Cl)Cl>[Cl:26][C:8]1[CH:7]=[CH:6][N:5]2[C:19]([CH2:20][CH:21]3[CH2:23][CH2:22]3)=[N:18][N:17]=[C:4]2[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1c(OCc2ccccc2)ccnc1NNC(=O)CC1CC1
Reactant: ClOCl
Agent: [P+5]
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1c(Cl)ccn2c(CC3CC3)nnc12
Yield: 64.3 %

Procedure:
A solution of D4 (1.4 g, 4.343 mmol) and phosphorous(V)oxychloride (0.810 ml, 8.686 mmol) in DCE (15 ml) was heated at 150° C. under microwave irradiation for 5 min. After cooling, the mixture was diluted with DCM and washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D5 (0.650 g, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[N:11]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)CCC(=O)O)c3ccccc32)[nH]1

Procedure:
The title compound was prepared from 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one and succinic anhydride (modification of procedure used to prepare (3Z)-1-acetyl-3-[(3,5-dimethyl-4-1H-pyrrol-2-yl)-methylidene]-1,3-dihydro-2H-indol-2-one).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.[C:14](N1C=CN=C1)(N1C=CN=C1)=O.[Mg+2].C[CH:28]([C:32]([O-:34])=[O:33])C([O-])=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11](=[O:13])[CH2:28][C:32]([O:34][CH3:14])=[O:33]
Reactant: CC(C(=O)[O-])C(=O)[O-]
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 2,4,5-trifluorophenyl acetic acid (42.2 g, 222 mmol) in THF (400 mL) was added 1,1′-carbonyldiimidazole (39.5 g, 244 mmol) in portions at 0° C. The mixture was warmed to room temperature for 1 h, stirred at room temperature for another 1 h, and transferred to another flask containing 1.1 equivalent of methyl malonic acid magnesium salt. The stirring was continued for 24 h and quenched with 1N HCl. The mixture was extracted with dichloromethane and the organic phase was washed with saturated sodium bicarbonate, then brine, then dried over sodium sulfate, filtered and evaporated. The residue was crystallized from isopropanol/water to give 42.2 g (77.3%) of off-white solid. 1H NMR (300 MHz, CDCl3) 7.10-6.90 (m, 2H), 3.85 (s, 2H), 3.78 (s, 3H), 3.55 (s, 2H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:13][CH2:12]1>>[CH:11]1([CH2:10][NH:9][C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: Clc1ccc(I)cn1
Reactant: NCC1CC1
Product: Ic1ccc(NCC2CC2)nc1
Yield: 77 %

Procedure:
A solution of 500 mg (2.09 mmol) of 2-chloro-5-iodo pyridine in 1.64 g (23.1 mmol) of aminomethylcyclopropane was heated to 100° C. in a sealed tube for 48 h. The mixture was then concentrated, dissolved in EtOAc, washes with water and brine, dried with MgSO4, filtered, and concentrated. Recrystallization from hexanes provided 440 mg (1.61 mmol; 77%) of cyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine. ESI MS m/z 275 [C9H11IN2+H]+.
Reaction SMILES: C(#N)C.C(N(CC)C(C)C)(C)C.[CH3:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([CH3:23])[CH:17]=[CH:16][N:15]=1.Cl[CH2:25][N:26]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][C:32]([O:41][CH3:42])=[CH:33][C:34]=2[CH:38]([CH3:40])[CH3:39])[S:27]1(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:13][C:14]1[C:19]([C:20]([O:22][CH2:25][N:26]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][C:32]([O:41][CH3:42])=[CH:33][C:34]=3[CH:38]([CH3:40])[CH3:39])[S:27]2(=[O:28])=[O:29])=[O:21])=[C:18]([CH3:23])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1c(C)ccnc1C)C2=O
Reaction time: 0.08 h
Yield: 58 %

Procedure:
Acetonitrile (20 ml), followed by N,N-diisopropylethylamine (5.8 ml, 33 mmol) were added to 2,4-dimethyl-3-pyridinecarboxylic acid (5.1 g, 33 mmol). The mixture was stirred for 5 minutes, then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (4.3 g, 14 mmol) was added. The reaction mixture was stirred at room temperature for 47 hours, then at 80° C. for 1 hour. The mixture was diluted with ethyl acetate (100 ml), washed with saturated NaHCO3, and the organic layer was dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized from ether to afford 3,4 g (57%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 2,4-dimethylpyridine-3 carboxylate, m.p. 132.1°-133.5° C.