Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1>CN(C=O)C>[CH3:1][C:2]1([C:18]([NH:60][C:59]2[CH:61]=[CH:62][C:56]([CH3:55])=[CH:57][CH:58]=2)=[O:19])[CH2:3][CH2:4][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Reactant: Cc1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(C)CCN(c3ncnc4[nH]cc(C)c34)CC2)cc1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from example 6, step B, (0.020 g, 0.073 mmol) in DMF (1 mL) were added BOP reagent (0.065 g, 0.15 mmol), triethylamine (0.019 mL, 0.15 mmol), and 4-methylaniline (0.012 mL, 0.11 mmol). The reaction was stirred overnight and concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.0133 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]([CH3:22])[CH3:20])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Product: CN(C)c1nc(Cl)nc2c1COCC2c1ccc(Cl)cc1
Yield: 77.9 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and Dimethylamine (2.0 M in THF) (1.188 mL, 2.377 mmol) were combined an purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (400 mg, 1.234 mmol, 78% yield) as a white solid. LC-MS (M+H)+=324.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.20-7.31 (2 H, m), 7.04-7.15 (2 H, m), 4.70-4.89 (2 H, m), 4.17 (1 H, dd, J=11.60, 5.49 Hz), 4.05 (1 H, t, J=5.49 Hz), 3.87 (1 H, dd, J=11.60, 5.49 Hz), 3.05-3.19 (6 H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>[Pd+2].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCS2
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCS2
Temperature: 85 °C

Procedure:
A mixture of 624 mg (3.0 mmol) of 4,4,7-trimethyl-6-bromothiochroman, 314 mg (3.2 mmol) of trimethylsilylacetylene, 40 mg (0.21 mmol) of cuprous iodide, 80 mg (0.11 mmol) of bis-(triphenylphosphine) palladium (II) chloride and 1 ml of triethylamine was degassed under nitrogen and heated in a sealed tube at 85° C. for 15 hours. The mixture was then treated with a further 20 mg (0.11 mmol) of cuprous iodide and 40 mg (0.06 mmol) of the palladium (II) catalyst. The mixture was then heated under a nitrogen atmosphere in the sealed tube at 100° C. for a further 64 hours. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][C:33]([CH3:36])=[N:32]3)=[C:27]([F:37])[CH:26]=2)[N:20]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[F:37][C:27]1[CH:26]=[C:25]([NH:24][C:21]2[N:20]=[C:19]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:23]3[N:22]=2)[CH:30]=[CH:29][C:28]=1[N:31]1[CH:35]=[N:34][C:33]([CH3:36])=[N:32]1
Reactant: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OC(F)(F)F)c(F)c4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(OC(F)(F)F)c(F)c3)cc2F)n1
Yield: 22.8 %

Procedure:
A solution of 5-(5-chloro-1-(3-fluoro-4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (989 mg, 1.83 mmol), sodium iodide (1.37 g, 9.13 mmol), and diisopropylethylamine (1.60 mL, 9.13 mmol) in acetone (25 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (70% EtOAc/chloroform). The purified product was recrystallized from EtOAc/hexane to afford 211 mg (22% yield) of the titled compound as a white solid. LC-MS (M+H)+ 506.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.4 Hz), 7.68 (1 H, dd, J=13.9, 2.3 Hz), 7.62 (1 H, t, J=8.7 Hz), 7.31 (1 H, t, J=8.1 Hz), 7.08 (1 H, dd, J=11.0, 2.1 Hz), 7.03 (1 H, dd, J=8.9, 2.4 Hz), 6.98 (1 H, d, J=8.5 Hz), 6.68 (1 H, s), 4.20-4.33 (3 H, m), 2.50 (3 H, s), 2.08-2.22 (2 H, m), 1.94-2.06 (2 H, m), 1.84-1.93 (2 H, m).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH:9]2[C:14](=O)[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].NN.C(O)COCCO>O.CCCCC>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2CCN(CC2)C1CC(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
9.3 Parts of 2-(2,2-diphenylethyl-1-azabicyclo[2.2.2]octan-3-one, 1.3 parts of potassium hydroxide, 3.6 parts by volume of an 85% solution of hydrazine in water and 59 parts diethylene glycol are refluxed together, with stirring, under nitrogen for 2.75 hours. Stirring and heating are then discontinued and the reaction mixture is allowed to stand overnight. The mixture is then heated to distill under nitrogen until a head temperature of 235° C. is reached. After cooling to room temperature, the mixture is partitioned between 900 parts by volume of 5% sodium chloride solution and two 600 parts by volume portions of ethyl ether. The ethereal extracts are combined, washed with water, dried over anhydrous sodium sulfate and stripped in vacuo to give an residual oil which solidifies upon standing. This solid is dissolved in 300 parts by volume of hot n-pentane. The solution is then concentrated on the steam bath to 45 parts by volume and cooled to room temperature to give a solid precipitate which is filtered off, washed with n-pentane and dried in vacuo to give a white solid 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane, melting at about 87.5°-89° C. This compound is represented by the following structural formula ##STR4##
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4](SC)[C:5](=[O:12])[NH:6]2.ClN1C(=[O:21])CCC1=O.C1COCC1.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[C:5](=[O:12])[NH:6]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2ccc(C)c(Cl)c21
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1Cl)C(=O)C(=O)N2
Yield: 80.9 %

Procedure:
This compound is prepared according to the procedure described in stage B of Preparation 1.10 from 0.72 g of 4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and 0.422 g of N-chlorosuccinimide in 72 ml of carbon tetrachloride and then from 58 ml of THF and 14 ml of water. The product obtained is chromatographed on silica gel, elution being carried out with DCM and then with the gradient of the DCM/AcOEt mixture up to (90/10, v/v). 0.5 g of the expected product is obtained.
Reaction SMILES: [C:1]1([C:7]2[C:8]3([CH2:14][CH3:15])[CH2:13][CH:11]([CH:12]=2)[CH2:10][CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][CH2:18][CH2:19]CC.C1(C)C=CC=CC=1.ClCCl>C1(C)C=C(C)C=C(C)C=1>[CH2:14]([C:8]12[CH2:13][CH:11]([CH2:10][CH2:9]1)[CH:12]=[CH:7]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:12]([C:11]12[CH2:13][CH:8]([CH2:9][CH2:10]1)[CH:14]=[CH:15]2)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC12CCC(C=C1c1ccccc1)C2
Reactant: C=CCCCC
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)cc(C)c1
Solvent: ClCCl
Product: C1=CC2(CCc3ccccc3)CCC1C2
Product: CCCCCCC12C=CC(CC1)C2
Temperature: 120 °C

Procedure:
HxNB (2.78 g, 0.0156 mol), Phenyl ethyl norbornene (PENB, CAS 29415-09-6) (7.22 g, 0.036 mol), 1-hexene (2.18 g, 0.026 mol) and toluene (57.0 g) were combined in a 250 mL serum bottle and heated to 120° C. in an oil bath. To this solution were added Pd1446 (3.0E-3 g, 2.1E-6 mol) and DANFABA (6.7E-3 g, 8.4E-6 mol) in concentrated solutions of dichloromethane. After addition, the resulting mixture was maintained at 120° C. for 1 hour. After cooling to room temperature, the copolymer was precipitated by adding methanol drop wise into the reaction mixture. The solid copolymer was collected by filtration and dried at 80° C. in a vacuum oven. The solid polymer was dissolved in an appropriate amount of mesitylene to give 10 wt % solid copolymer solution After drying, 8.0 g was obtained (80%). The molecular weight of the polymer was determined by GPC methods in THF poly(styrene) standard) Mw=127,332; Mn=39,206. The composition of the polymer was determined by 1H-NMR: HxNB/PENB=22/78. The composition of the copolymer was determined by 1H-NMR to be 54/46 HxNB/diPhNB. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5601 in TE mode and 1.5585 in TM mode at a wavelength of 633 nm. The dried copolymer was dissolved in sufficient mesitylene to result in a 10 wt % copolymer solution.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[C:5](=O)[NH:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[CH2:5][NH:6]2
Reactant: CC1(C)C(=O)Nc2ccc(F)c(F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CNc2ccc(F)c(F)c21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
0.15 mg (0.76 mmol) 4,5-difluoro-3,3-dimethyl-1,3-dihydro-indol-2-one were placed in 20 mL THF under argon. 0.91 mL (0.91 mmol) of a 1M lithium aluminium hydride solution in 10 mL THF were added dropwise. The reaction mixture was stirred for 1 h at 70° C., cooled and mixed with water. The reaction mixture was dried, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[O:27])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C)CCN
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Product: CN(C)CCNC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and N1,N1-dimethyl-1,2-ethanediamine were coupled to give 109bp. 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 1 H), 7.67 (s, 1 H), 7.56 (m, 1 H), 7.25 (m, 1 H), 6.88 (m, 2 H), 6.78 (m, 1 H), 6.69 (s, 1 H), 5.07 (s, 2 H), 3.78 (m, 2 H), 3.31 (s, 3 H), 3.27 (m, 2 H), 2.84 (s, 6 H). LCMS (ESI) m/z: 472.2
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH:13](I)([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CC(C)I
Product: CC(C)Oc1ccc(C(=O)O)c(Cl)c1

Procedure:
Using methyl 2-chloro-4-hydroxybenzoate and isopropyl iodide, 2-chloro-4-isopropoxybenzoic acid was obtained in the same method as in Production Example 277b).
Reaction SMILES: N12CCCNC1=NCCC2.[CH3:11][C:12]1[CH:24]=[CH:23][C:15]([CH:16]=[C:17]([CH2:21]C)[N+]([O-])=O)=[CH:14][CH:13]=1.[CH2:25]([O:27][C:28](=[O:32])[CH2:29][N+:30]#[C-:31])[CH3:26]>C(O)(C)C.C1COCC1>[CH2:25]([O:27][C:28]([C:29]1[NH:30][CH:31]=[C:17]([CH3:21])[C:16]=1[C:15]1[CH:23]=[CH:24][C:12]([CH3:11])=[CH:13][CH:14]=1)=[O:32])[CH3:26]
Reactant: CCC(=Cc1ccc(C)cc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Agent: C1CN=C2NCCCN2C1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
1,5,7-Triazabicyclo[4.4.0]dec-5-ene on polystyrene (5.36 g, 2.6 mmol/g, 13.9 mmol) was added to a reaction mixture of 4-methyl-β-ethyl-β-nitrostyrene (1.23 g, 6.94 mmol) and isocyanoacetic acid ethyl ester (788 mg, 6.90 mmol) in isopropanol (5 mL) and THF (5 mL) and the reaction mixture was stirred overnight at RT under nitrogen as protective gas. The reaction mixture was filtered out and the residue washed with isopropanol and THF. The desired product 4-methyl-3-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.42 g, 85% of theoretical) was obtained.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[CH3:11][C:12]([O:15][C:16](=[O:27])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O)([CH3:14])[CH3:13].[C:28]([O:34][CH3:35])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>C(O)(C)C>[CH3:11][C:12]([CH3:14])([O:15][C:16](=[O:27])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:29]([C:30](=[O:31])[CH3:32])[C:28]([O:34][CH3:35])=[O:33])[CH3:13]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccccc1C=CC(=O)OC(C)(C)C)C(C)=O
Yield: 57.9 %

Procedure:
A solution of piperidine (0.11 g) and acetic acid (0.078 g) in isopropanol (1 ml) was added to a solution of 3-(2-formylphenyl)propenoic acid 1,1-dimethylethyl ester (5.2 g) and methyl acetoacetate (2.55 g) in isopropanol (15 ml). The mixture was stirred at 60° C. for 1h, then the solvent was evaporated and the residue taken up with ether (100 ml). The solution was washed with 1N HCl, water, with saturated bicarbonate solution, then water again and dried over Na2SO4. Evaporation of the solvent gave an oil which was purified by column chromatography (gradient Petrol/Ether, 7:3-1:1) to give the title compound as a pale oil (4.2 g; mixture E/Z isomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:41])[C:32]3[N:36]=[C:35]([CH:37]4[CH2:39][CH2:38]4)[NH:34][C:33]=3[CH:40]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:37]1([C:35]2[NH:34][C:33]3[CH:40]=[C:29]([O:28][C:24]4[N:25]=[CH:26][N:27]=[C:22]([N:17]5[CH2:18][CH2:19][CH:14]([N:10]6[CH2:9][CH2:8][C:7]7[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=7[NH:12][C:11]6=[O:13])[CH2:15][CH2:16]5)[CH:23]=4)[CH:30]=[C:31]([CH3:41])[C:32]=3[N:36]=2)[CH2:38][CH2:39]1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C6CC6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
44 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]imidazole and 0.06 mL (0.32 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(F)cc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Yield: 15 %

Procedure:
To a solution of (S)-tert-butyl 3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (0.45 g, 1.12 mmol) in dioxane (10 mL) was added CDI (0.72 g, 2.24 mmol) under N2. The mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (70 mg, 40%). ESI-MS m/z [M+H-Boc]+ 316.
Reaction SMILES: O.NN.[Cl:4][C:5]1[C:6]([N:20]([CH2:25][CH2:26][N:27]2C(=O)C3=CC=CC=C3C2=O)[S:21]([CH3:24])(=[O:23])=[O:22])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2>ClCCl.CO>[Cl:4][C:5]1[C:6]([N:20]([CH2:25][CH2:26][NH2:27])[S:21]([CH3:24])(=[O:23])=[O:22])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)c2nc1OC
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)c(N(CCN)S(C)(=O)=O)c2nc1OC
Reaction time: 48 h
Yield: 69.4 %

Procedure:
Hydrazine hydrate (696 μl, 716 mg, 14.3 mmol) was added dropwise to a solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide (3.76 g, 7.15 mmol) in a mixture of dichloromethane (71 ml) and methanol (5 ml) at room temperature under nitrogen. The mixture was heated at reflux for 4 days and then further methanol (20 ml) was added. After a further 2 days the mixture was allowed to cool and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and this was extracted 3 times with 10% aqueous citric acid. The combined acid extracts were adjusted to pH 9 with solid potassium carbonate and extracted 3 times with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 95:5 dichloromethane:methanol to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide (1.96 g, 69%) as a pale yellow solid.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:25]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[S:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: c1cnc2sccc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a cold (−78° C.) solution of thieno[2,3-b]pyridine (2.000 g, 14.79 mmol) in anhydrous THF (50 mL) was added n-butyllithium (10.17 mL, 16.27 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (4.79 mL, 17.75 mmol) in anhydrous THF (10 mL) was added and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a period of 2 to 3 hours. Saturated aqueous sodium bicarbonate was added. The aqueous phase was extracted with ether (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The desired fractions were collected and the solvent removed in vacuo to give the title compound (4.5 g, 72%) 1H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (t, J=7.32 Hz, 9H), 1.13-1.20 (m, 6H), 1.32 (dq, J=14.64, 7.32 Hz, 6H), 1.52-1.64 (m, 6H), 7.34-7.42 (m, 1H), 7.51 (s, 1H), 8.25 (dd, J=7.81, 1.46 Hz, 1H), 8.50 (dd, J=4.39, 1.46 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.S(Cl)([Cl:13])=O>ClCCCl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: ClCCCl
Product: ClCc1cccnc1Cl

Procedure:
To 10.24 g(0.065 mole) of 2-chloronicotinic acid were added 20 ml of 1,2-dichloroethane and 9.5 ml of thionyl chloride and the mixture was refluxed for 1 hour. The reaction mixture was concentrated to give 11.9 g of 2-chloronicotinyl chloride as an orange-colored oil. When left standing at room temperature, this product solidified thoroughly.
Reaction SMILES: NC1SN=C(/[C:7](=N/OCF)/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([O-:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([CH2:25][C:26](=[O:28])[NH2:27])([CH2:23]C)[CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])N=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:45]1(OC)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[C:45]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([OH:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:25]([C:26](=[O:28])[NH2:27])[CH3:39])([CH3:22])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COc1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCF)c3nsc(N)n3)[C@H]2SC1)CC(N)=O
Product: C[C@H](C(N)=O)[N+](C)(C)C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Product: O=C([O-])C(F)(F)F

Procedure:
In a similar manner as in Example 5, the compound (34.5 g) of Example 14 was suspended in anisole (210 ml), followed by an addition of trifluoroacetic acid (230 ml) to obtain the target compound (25.9 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]#[N:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26]([NH:28][NH2:29])=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:18]=[C:26]([CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:28][N:29]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)sc1C(=O)NCc1ccccc1
Reactant: NNC(=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A mixture of N-benzyl-5-cyano-3-methylthiophene-2-carboxamide (0.15 g, 0.59 mmol), phenylacetic hydrazide (0.09 g, 0.59 mmol) and potassium carbonate (0.12 g, 0.87 mmol) in 1-butanol (4 mL) was stirred in a sealed tube at 150° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was purified by column chromatography (0-70% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (0.10 g, 42%): mp 168-171° C.; 1H NMR (300 MHz, CDCl3) δ 7.40-7.18 (m, 12H), 6.20 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.11 (s, 2H), 2.47 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 142.2, 137.8, 135.2, 130.7, 130.6, 129.0, 128.8, 128.8, 127.7, 127.6, 127.4, 44.1, 33.1, 15.9; MS (ES+) m/z 389.3 (M+1).