Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9]/[N:10]=[C:11](\[C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])/[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].O>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18](=[O:19])[CH:17]=[C:16]([OH:22])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC(=O)/C(=N\Nc1ccc(Cl)c(Cl)c1)C(=O)OC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1O
Reaction time: 1 h
Yield: 61.3 %

Procedure:
(E)-Dimethyl 2-(2-(3,4-dichlorophenyl)hydrazono)-3-oxopentanedioate (6.7 g, 19.3 mmol) in 1, 2 dichlorobenzene (20 mL) was heated at 180° C. overnight. After cooling, the reaction to room temperature, water 50 mL was added to the reaction mixture and it was stirred for 1 hour. The product was collected by filtration and further washed with water 20 mL and methanol (10 mL×3), then dried overnight under reduce pressure to yield 3.73 g (55.2%) of methyl 1-(3,4-dichlorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate as a tan solid. MS (ESI) 315 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 3-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A27) (4 g, 16 mmol, 1 equiv) in MeOH/H2O (9:1, 40 ml) was added 10% palladium on charcoal (50% wet, 800 mg, 0.1 equiv w/w). The resulting mixture was stirred for 6 h at atmospheric pressure under an atmosphere of hydrogen. The catalyst was removed by filtration through a pad of celite and the solvent was removed in vacuo. The residue was dried at 60° C. under vacuum for 16 h to give 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (3.34 g, 15.2 mmol, 95%) as a pale brown solid. [M−H]−=218.8, RT=1.86 min
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][N:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:8]=2[N:24]=1.[CH3:25]I>CC(N(C)C)=O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][N:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:8]=2[N:24]=1
Reactant: CI
Reactant: CC1(C)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
60% Sodium hydride in mineral oil (0.210 g, 5.24 mmol) was added to a mixture of (R)-2-chloro-9-(3,3-difluorocyclopentyl)-7,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.65 g, 4.99 mmol) and methyl iodide (0.34 ml, 5.49 mmol) in dimethylacetamide (18 mL). The reaction mixture was stirred at room temperature for 25 minutes. Ice was added to the reaction mixture and the resultant precipitate collected and rinsed with water. The solid was dried in a pistol in vacuo for 3 hours. The title compound was obtained as a white solid (1.68 g, 98% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH:20]([Li])([CH3:22])[CH3:21]>C1COCC1.CCCCC>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:20]([CH3:22])[CH3:21])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2]
Reactant: [Li]C(C)C
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1cccc(C(C)C)c1/C=N/C(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.8 g (3.1 mmol) (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a)) in 3 ml dry THF cooled to −20° C. were added 9.62 ml of a 0.7M solution of isopropyl lithium in pentane drop-wise to keep temperature below 0° C. Then the mixture was stirred at −20° C. for further 30 min and the reaction quenched by addition of water. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification of the crude product by flash chromatography on silica gel with heptane as eluent provided 0.220 g (E)-[1-(2-ethyl-6-isopropyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine as colourless liquid: MS (ISP): 274.1 (M+H+.).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35](B(O)O)[CH:36]=1)#[N:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=4[O:40][CH3:41])[C:29]#[N:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:19]=1
Reactant: COc1ccc(C#N)cc1B(O)O
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C#N)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 100 °C

Procedure:
A degassed mixture of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate B) (0.337 mmol), 5-cyano-2-methoxyphenylboronic acid [612833-37-1] (0.675 mmol), Pd(PPh3)4 (0.067 mmol) and K3PO4 (1.350 mmol) in 2:1 dioxane/H2O (4.5 mL) was heated at 100° C. for 4 h. After cooling to rt, the reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in CH2Cl2 and filtered through a PL-thiol MP SPE cartridge (StratoSpheres), washing through with additional CH2Cl2. The filtrate was re-concentrated and the residue purified using a RediSep® silica gel column to afford the title compound as a yellow solid. tR: 5.43 min (HPLC 1); ESI-MS: tR=1.37 min, [M+H]+ 530/532/534 (LC-MS 1); TLC: Rf=0.29 (1:1 EtOAc/heptanes); 1H-NMR (d6-DMSO, 600 MHz): 8.15 (br s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.37 (m, 2H), 7.31 (d, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 3.85 (m, 1H), 3.85 (s, 3H), 1.91 (s, 3H), 1.29 (m, 3H), 0.46 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 2 L, 3-neck round-bottom flask equipped with an overhead stirrer was added 4-ethynylaniline (30 g, 256 mmol) and pyridine (42.5 ml, 525 mmol) in dichloromethane (512 ml) to give an orange solution. The mixture was cooled to 5° C. and methanesulfonyl chloride (19.96 ml, 256 mmol) was added drop wise over 15 min. The reaction solution was stirred at 5° C. for 2 h and washed with 1M aqueous HCl (3×250 mL). The dichloromethane layer was then washed sequentially with saturated aqueous NaHCO3, water, and saturated aqueous NaCl. The dichloromethane layer was dried over sodium sulfate and treated simultaneously with decolorizing charcoal for 30 min, the solution then filtered through Celite and the filtrate was concentrated. The pink/orange solid was dissolved in a minimal amount of hot ethyl acetate (50-75 mL) and slowly diluted with hexanes (500-600 ml) to give orange crystals that were collected by filtration and dried to provide the title compound (40.0 g, 80%).
Reaction SMILES: [CH2:1]([CH:8]1[NH:12]C(=O)N[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+]>O.CCOCCO>[NH2:12][CH:8]([C:9]([OH:14])=[O:15])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: NC(Cc1ccccc1)C(=O)O
Reaction time: 48 h
Yield: 77 %

Procedure:
95.1 g (0.5 mole) of 5-benzyl-hydantoine are dissolved in a solution of 87 g of sodium hydroxide and 400 ml of water, whereupon 300 ml of cellosolve are added. The reaction mixture is heated to boiling for 48 hours, the water and the cellosolve are distilled off in vacuo (30 Hgmm, 80° C.), the solid residue is dissolved in a small amount of water and acidified with concentrated hydrochloric acid (pH 2). The solution is treated with activated charcoal and the pH is adjusted to 6 with a concentrated ammonium hydroxide solution. The mixture is allowed to stand for some hours at 5° C. The precipitated product is filtered off, washed with cold water and cold ethanol. Thus 63.4 g of the desired airdry compound are obtained, yield 77%, mp.: 245°-255° C. Purity: 97.9% according to HPLC.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][CH2:35][C:36]#[N:37]>C1COCC1>[C:36]([CH2:35][CH2:34][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:34][CH2:35][C:36]#[N:37])=[CH:28][CH:29]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH2:34][CH2:35][C:36]#[N:37])=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13]([S:16][CH2:34][CH2:35][C:36]#[N:37])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)#[N:37]
Reactant: Sc1ccc(C(=C(c2ccc(S)cc2)c2ccc(S)cc2)c2ccc(S)cc2)cc1
Reactant: N#CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCSc1ccc(C(=C(c2ccc(SCCC#N)cc2)c2ccc(SCCC#N)cc2)c2ccc(SCCC#N)cc2)cc1
Temperature: 85 °C

Procedure:
1,1,2,2-tetrakis(4-mercaptophenyl)ethylene (0.5 mmol) made in Example 2 was added to 30 ml of THF, and 160 mg (4.0 mmol) of sodium hydride and 0.35 mL (4.0 mmol) of 3-bromopropionitrile were added with stirring in an ice-cooled bath followed by being refluxed at 85° C. for 24 hours. After solvent was evaporated, ice-cooled water was added to the residue, the mixture was acidified with hydrochloric acid, and then was extracted with dichloromethane. The extract was dehydrated with anhydrous magnesium sulfate. Subsequently, it was subjected to a silica gel column chromatography (φ=40 mm, height=50 mm, developing solvent: ethyl acetate:chloroform=1:15), and was recrystallized from chloroform and carbon tetrachloride to afford the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][C:21]2=[O:24])=[CH:17][CH:16]=1.[H-].[Na+]>C1COCC1>[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20]3([C:21]2=[O:24])[CH2:2][CH2:3][C:4]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[C:9]=2[F:10])[CH2:12]3)=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)c(CCBr)c1F
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCc1c(ccc(F)c1F)C2
Yield: 45.8 %

Procedure:
To a solution of 2-(2-bromoethyl)-1-(bromomethyl)-3,4-difluorobenzene (3 g, 9.62 mmol) and 6-bromo-2,3-dihydro-1H-inden-1-one (2.03 mg, 9.62 mmol) in THF (20 mL) was added NaH (0.58 mg, 14.43 mmol), and the mixture was refluxed for 2 hour. The reaction was cooled and quenched with ice-water. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative TLC to afford 6-bromo-5′,6′-difluoro-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (1.6 g, 46%). 1H NMR (CDCl3): 1.68 (m, 1H), 2.01 (m, 1H), 2.47 (d, 1H), 2.72 (m, 2H), 2.89 (d, 1H), 3.07 (m, 2H), 6.71 (m, 1H), 6.86 (m, 1H), 7.22 (d, 1H), 7.63 (d, 1H), 7.92 (s, 1H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]2[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[CH2:31]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]3[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH2:31]2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C#N)cn5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 60.9 mg (0.25 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 19A) and 0.21 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 39 mg (33% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[Cl-].[NH4+]>[Zn].O>[NH2:17][C:16]1[C:11]([NH:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Nc2ncccc2N)cc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-4-[(3-nitropyridin-2-yl)amino]benzonitrile (C14) (5.4 g, 21 mmol) in a 1:1 mixture of tetrahydrofuran and water (40 mL) was added ammonium chloride (8.9 g, 170 mmol), followed by zinc (10.8 g, 165 mmol). The mixture was stirred at 60° C. for 30 minutes, whereupon it was filtered through a pad of Celite. The organic layer from the filtrate was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo; the residue was washed with heptane to afford the product as a brown solid. Yield: 4.2 g, 18 mmol, 86%. LCMS m/z 229.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (br s, 1H), 7.82 (dd, J=13.6, 2.0 Hz, 1H), 7.66 (dd, J=8.4, 8.3 Hz, 1H), 7.61 (dd, J=4.8, 1.6 Hz, 1H), 7.37 (dd, J=8.8, 2.0 Hz, 1H), 7.03 (dd, J=7.8, 1.6 Hz, 1H), 6.82 (dd, J=7.8, 4.8 Hz, 1H), 5.24 (br s, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[NH:22][C:21]=1[C:28](O)=[O:29]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:28]([C:21]3[NH:22][C:23]([CH2:26][CH3:27])=[C:24]([Cl:25])[C:20]=3[Cl:19])=[O:29])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: CCc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: CCc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 3,4-dichloro-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 73).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3'-methylacetophenone (0.87 g, 6.46 mmol), trimethylsilyl triflate (1.44g, 6.46 mmol), triethylamine (0.653 g, 6.46 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.0 g, 3.23 mmol). m.p. 161°-162° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 2.39 (s, 3H), 3.42 (m, 1H), 6.86 (s, 1H), 6.92 (d, 1H), 7.07 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.4 (t, 1H), 7.64 (d, 1H), 7.67 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>CC#N>[Br:12][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH2:9])[C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Nc1cccc(Br)c1N
Temperature: 70 °C
Reaction time: 14 h
Yield: 119.9 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (2.0 g, 11.59 mmol) and 1-bromopyrrolidine-2,5-dione (2.3 g, 12.75 mmol) in MeCN (30 mL) was stirred at 70° C. for 14 h. The reaction mixture was poured into water (100 mL) and stirred at RT for 1 h. The precipitate was filtered and washed with water. The solid was dried under vacuum to afford 3-bromobenzene-1,2-diamine as a yellow solid (2.6 g, 86.7%).
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CN(CCN(C)C)C.[Li]CCCC.[CH3:19][Sn:20](Cl)([CH3:22])[CH3:21]>CCCCCC>[CH3:19][Sn:20]([CH3:22])([CH3:21])[C:2]1[Se:1][C:5]([Sn:20]([CH3:22])([CH3:21])[CH3:19])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc[se]c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Sn](C)(C)c1ccc([Sn](C)(C)C)[se]1
Temperature: 0 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of selenophene (7.4 g, 56.5 mmol) in a solution of anhydrous hexane (90 ml) and TMEDA (17.4 g, 150 mmol) at 0° C. under nitrogen is added a solution of n-BuLi (55 ml of a 2.5M solution in hexanes, 137.5 mmol) dropwise over 5 min. The resulting solution is refluxed for 30 min and then cooled to 0° C. and trimethyltin chloride (25.6 g, 129 mmol) is added at once as a solid. The resulting solution is allowed to warm to room temperature and stirred at that temperature for 20 h. The solution is quenched with water (100 ml), and ethyl acetate (100 ml) is added. The layers are separated and the organic layer is washed with further water (4×100 ml), brine (100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting solid is recrystallized from acetonitrile four times to afford the product as white needles (25.8 g, 83%). M/Z cluster centered at 456 (M+). Found C, 26.3; H, 4.6. Calc. for C10H20SeSn2 C, 26.3; H, 4.2. 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 2H), 0.37 (s, 18H). 13C NMR (75 MHz, CDCl3) δ 150.2, 138.7, −7.7.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=[O:22])=[CH:17][CH:16]=3)[C:10]([CH3:14])=[C:11]([F:13])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[Cl:25][CH2:26][C:27](OCC)(OCC)OCC>>[Cl:25][CH2:26][C:27]1[O:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:9]3[C:10]([CH3:14])=[C:11]([F:13])[CH:12]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[CH:8]=3)=[CH:16][CH:17]=2)=[N:23][N:24]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1

Procedure:
N-Cyclopropyl-5-fluoro-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 29) (580 mg) in 2-chloro-1,1,1-triethoxyethane (2.5 ml) was heated at 80° C. for 20 hours. The reaction was absorbed onto silica and purified by chromatography on a biotage column (silica, 40 g), eluting with cyclohexane and then with ethyl acetate/cyclohexane (2:3). The product fractions were reduced to dryness under vacuum to give 4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][C:20]=1[Cl:37])\[C:13]([OH:15])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)c(Cl)s1
Yield: 91.8 %

Procedure:
A solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (70 g, 147 mmol) and NCS (23.50 g, 176 mmol) in N,N-Dimethylformamide (DMF) (735 mL) was stirred at 40° C. for 2.5 h. The reaction was quenched by addition of H2O (2 L), EtOAc (1 L) and 5% aq. sodium thiosulfate soln (400 mL). The organic layer was separated, and washed with H2O (2×), brine, dried and evaporated to afford (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (69 g, 91% purity, 135 mmol, 92% yield) as a light yellow foaming solid. LCMS: (M+H)+: 464.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:19]3[CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23][CH:18]3[N:6]3[CH2:7][CH:8]([CH3:17])[N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([CH:11]=1)=[C:5]23.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C:2]1[CH:3]=[C:4]2[CH:19]3[CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23][CH:18]3[N:6]3[CH2:7][CH:8]([CH3:17])[N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (100 mg, 0.22 mmol) in DMF (10 mL) was added 2,4-dichlorophenyl boronic acid (63 mg, 0.33 mmol) and Na2CO3 (58 mg, 0.55 mmol, in 0.4 mL of H2O). The mixture was degassed with a stream of nitrogen for 20 min and then there was added Pd(PPh3)4 (35 mg, 0.03 mmol) and the mixture was stirred at 100° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes/ethyl acetate) to afford diethyl 5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (30 mg, 29% yield) MS [M+H]+517.