Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.O.[C:13]1([C:19]([CH:21]=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[Ni]>[C:13]1([C:19]2[N:1]=[C:2]3[N:3]=[C:4]([NH2:11])[CH:5]=[CH:6][C:7]3=[N:8][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])c(N)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
A solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210 ml of ethanol is hydrogenated with Raney nickel as catalyst at 50° C. and 5 bar. After the hydrogenation is complete, the catalyst is filtered off with suction through a glass fibre filter. Before the filtration, 1.68 g of phenylglyoxal hydrate (11.03 mmol) are introduced into 50 ml of ethanol in the receiver. The catalyst is then filtered off under nitrogen as protective gas, and the hydrogenation solution is sucked directly into the reaction flask. The greenish blue reaction mixture is heated under reflux under nitrogen for 30 min. The mixture is allowed to cool, and the solvent is removed in vacuo. A dark brown solid is finally obtained. Purification by column chromatography on silica gel (mobile phase dichloromethane/methanol mixture) affords a pale yellow crystalline solid.
Reaction SMILES: [CH2:1]([N+:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH3:24])([CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:4]=1[CH3:25])[CH3:2].Cl.[C:27]1([N:33]=[CH:34][CH2:35][CH:36]=NC2C=CC=CC=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[NH:33](/[CH:34]=[CH:35]/[CH:36]=[CH:25]/[C:4]1[C:5]([CH3:24])([CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([O-:15])(=[O:13])=[O:14])[CH:7]=2)[N+:3]=1[CH2:1][CH3:2])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC[N+]1=C(C)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21
Reactant: C(CC=Nc1ccccc1)=Nc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CC[N+]1=C(/C=C/C=C/Nc2ccccc2)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21

Procedure:
1-Ethyl-2,3-dimethyl-3-(4-sulphobutyl)-3H-indolium-5-sulphonate, crude (1.1 g), malonaldehyde bis(phenylimine) HCl (0.5 g) and acetic acid (20 ml) were heated under nitrogen at 130° C. for 8 hrs to give a dark orange-red solution. The solvent was then evaporated under vacuum; the residue was partitioned in a water/dichloromethane/methanol mixture. UV/Vis is analysis (ethanol) confirmed the presence of the product in the upper, aqueous layer (λmax=524 nm) while the malonaldehyde starting material was present only in the lower, organic layer (λmax=384 nm). The aqueous layer was evaporated under vacuum and purified by HPLC (water/0.1% TFA and acetonitrile/0.1% TFA eluants). Fractions containing the product were pooled and evaporated, with final drying under high vacuum over phosphorus pentoxide to give the title product.
Reaction SMILES: [C:1]([C:3]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH:24]=[CH2:25])[C:4]=1[CH3:26])#[N:2].Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.C(N(CC)CC)C>[C:1]([C:3]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)=[CH:10][C:6]([C:7]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[OH:35])=[O:9])=[C:5]([CH:24]=[CH2:25])[C:4]=1[CH3:26])#[N:2]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of 4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid (0.10 g), trans-2-aminocyclohexanol hydrochloride (0.06 g), 1-hydroxybenzotriazole (0.06 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g) in dichloromethane (5.00 mL) was added triethylamine (0.11 g), and the mixture was stirred for 16 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.10 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7].CO>[O-]S(C(F)(F)F)(=O)=O.[Ag+].O>[C:6]([O:9][CH:10]=[CH:11][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: C=CC(=C)C
Reactant: C=COC(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CO
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 6 %

Procedure:
4 mg (0.016 mmol) of (η6-benzene) ruthenium (II) dichloride, 15 mg (0.058 mmol) of silver triflate and 11.2 mg (0.052 mmol) of N-2-aminoethyl-p-toluenesulfonamide were placed in a sealed tube, which was then charged with 2 ml (20 mmol) of isoprene, 2 ml (22 mmol) of vinyl acetate and 2 ml of methanol. The mixture was heated with stirring at 100° C. for 6 hours in an argon atmosphere. The reaction mixture was poured into water and the organic layer was concentrated to obtain 0.17 g (yield: 6% based on isoprene) of a co-dimer (4-methylhexa-1,5-dien-1-yl acetate) (Purity: 75%, regioisomer: 17%, cyclic dimer of dienes: 8%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:23][CH:22]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccncc1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 10.8 %

Procedure:
the title compound (13 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), C-pyridin-4-ylmethylamine (62 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 401.3 (M+1, 100%). Yield=11%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[C:5]2=[N:6][C:7]=1[Cl:8].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[C:9]([CH3:13])=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: Cc1nccc2nc(Cl)c(Cl)nc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc2nc(NC3CC3)c(Cl)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
2,3-Dichloro-5-methylpyrido[3,4-b]pyrazine (1.700 g, 7.94 mmol) was added to dioxane (15.88 mL), then cyclopropanamine (0.864 mL, 12.71 mmol) and DIPEA (2.24 mL, 13.50 mmol) were added sequentially. The mixture was stirred for 12 h at room temperature then concentrated under reduced pressure. Column chromatography using a gradient of 10% to 75% EtOAc in hexanes provided 3-chloro-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine (1.3 g) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18](OCC)=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25].Cl.[NH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(OC)c(Br)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1Br)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 95 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of ethyl 7-bromo-4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.28 g, 0.68 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.17 g, 1.0 mmol) in 5 mL dioxane was treated with DIPEA (0.26 g, 2.0 mmol). The mixture was warmed to 95° C. and stirred for 3 hours, M+1=496/498. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.28 g of the title compound as a white yellow solid. MS m/e=496/498 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[N:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30]>>[Cl:26][C:27]1[CH:35]=[N:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: O=C(O)c1ccncc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccncc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-chloroisonicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=10:10:1) to yield the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:28][C:4]1[C:3]([CH2:1][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CN2CCN(C)CC2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 48 h
Yield: 66.6 %

Procedure:
A mixture of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (27 mg, 0.073 mmol) and 1-methyl-piperazine (8.1 μl, 0.073 mmol) in CH2Cl2 (2.5 ml) was stirred for 48 h, then treated with NaBH(OAc)3 (46.4 mg, 0.2 mmol) and stirred for 24 h. The mixture was diluted with CHCl3, washed with saturated NaHCO3 and H2O, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (22 mg, 66%) (20% MeOH—CHCl3). It has a retention time of 4.90 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=453.1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl>CS(C)=O.O>[CH2:7]([NH:19][CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:21]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCNCCCCOc1ccc2ccccc2c1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-dodecylamine (0.48 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-dodecyl)-(4-(naphthalen-2-yloxy)-butyl)amine, solid. m.p. 129° C., (yield 0.78 gm, 95.5%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C:3]([O:5]C)=O.[NH2:15][CH2:16][CH2:17][SH:18].C(=O)([O-])[O-].[K+].[K+].COC(=O)CSC(C1C=CC=C(OC)C=1)CN>O.C(O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH:2]2[S:18][CH2:17][CH2:16][NH:15][C:3]2=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: NCCS
Reactant: COC(=O)C(Br)c1cccc(OC)c1
Agent: COC(=O)CSC(CN)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cccc(C2SCCNC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
In a 500 mL round-bottomed flask, methyl 2-bromo-2-(3-methoxyphenyl)acetate (5.2 g, 20.1 mmol), 2-aminoethanethiol (1.55 g, 20.1 mmol) and potassium carbonate (5.55 g, 40.1 mmol) were combined with ethanol (150 ml) to give a light yellow suspension. The resultant mixture was stirred at 85° C. (bath temp.) for 2.5 h. No starting material remained. The intermediate, [2-amino-1-(3-methoxy-phenyl)-ethylsulfanyl]-acetic acid methyl ester, was the major product with 25% of the cyclized product. The mixture was further heated at reflux for an additional 4.5 h. Complete by LCMS. Reaction mixture was allowed to cool to room temperature and sit overnight. The reaction mixture was poured into 500 mL H2O and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting pale yellow solid was triturated with cold ether and dried under vacuum to afford 2-(3-methoxyphenyl)thiomorpholin-3-one (3.7 g, 83%) as a yellow solid. (M+H)+=224 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.88 (td, J=5.81, 2.78 Hz, 2H) 3.67 (td, J=5.81, 3.54 Hz, 2H) 3.82 (s, 3H) 4.63 (s, 1H) 6.42 (br. s., 1H) 6.85 (ddd, J=8.34, 2.53, 0.76 Hz, 1H) 7.00 (t, J=2.15 Hz, 1H) 7.01-7.05 (m, 1H) 7.29 (t, J=7.93, 1H).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7](Cl)([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][OH:20])([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>CO>[C:1]([N:5]=[N:6][C:7]([O:20][O:19][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)CC(C)(Cl)N=NC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC(C)(N=NC(C)(C)C)OOC(C)(C)C

Procedure:
The 2-t-butylazo-2-(t-butylperoxy)-4,4-dimethylpentane was prepared in 78% crude yield from 3.36 grams (.02moles) of 2-t-butylazo-2-chloro-4,4-dimethylpentane, 2.77 grams (.0277 moles) of 90% t-butyl hydroperoxide and 2.0 grams (.025 moles) of 50% NaOH in 20 ml. of methanol. The procedure was the same as that described in Example X.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([N:47]=[N+:48]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N+:47]=[N-:48])(=[O:17])=[O:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C(Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(=O)c3ccccc3)cc2)cc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=C(S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1)S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 37 %

Procedure:
The bis(4-benzoyloxyphenylsulfonyl)methane in Synthesis Example 6, 10 g (0.019 mol), was dispersed in 200 g of dichloromethane. To the dispersion was added 5.6 g (0.029 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring under ice cooling, 4.0 g (0.026 mol) of DBU was added to the dispersion, and after 5 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 15 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 40 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 37%) of fine yellow crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH2:39][C:40]1[O:41][C:42]([CH3:46])=[C:43]([CH3:45])[CH:44]=1>CN(C)C=O.C(Cl)Cl>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH2:39][C:40]1[O:41][C:42]([CH3:46])=[C:43]([CH3:45])[C:44]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2ccc3ccccc3c2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.93 g, 3.95 mmol, RN-117439-59-5), oxalyl chloride (0.377 mL, 4.33 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.507 mL, 4.33 mmol) and 2-naphthalen-2-ylmethyl-4,5-dimethylfuran (0.93 g, 3.94 inmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2 & 4% EtOAc/pet. ether step gradient gave 0.357 g (20%) of the title compound. 1H NMR (DMSO-d6) δ 1.14 (d, 12 H), 1.82 (s, 3 H), 2.20 (s, 3 H), 3.27 (septet, 2 H), 3.74 (s, 3 H), 4.02 (s, 2 H), 7.19 (dd, 1 H), 7.45-7.52 (m, 5 H), 7.76-7.79 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7](F)(F)F)[N:6]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=[O:16].Cl>C1COCC1.N1C=CC=CC=1>[Br:11][C:4]1[S:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[N:6][C:5]=1[CH3:7]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1Br
Temperature: 0 °C
Yield: 83 %

Procedure:
2-Amino-5-bromo-4-trifluoromethylthiazole (0.8 g) was dissolved in 3 mL of 1:1 mixture of THF and pyridine. 2,6-difluorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on silica gel gave the title compound as a white solid. Yield 83%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:6]2[C:7]([CH3:13])=[N:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+]>COCCOCCOC>[F:40][C:36]([F:41])=[CH:11][C:10]1[CH:9]=[N:8][C:7]([CH3:13])=[C:6]2[O:14][C:2]([CH3:15])([CH3:1])[O:3][CH2:4][C:5]=12
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: Cc1ncc(C=C(F)F)c2c1OC(C)(C)OC2

Procedure:
A mixture of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde, 0.11 mole of triphenylphosphine and 0.11 mole of sodium chlorodifluoroacetate in 100 ml. of diglyme is heated under nitrogen at 90° for 24hours. The reaction mixture is then filtered and concentrated in vacuo. Chromatography of the residue on silica gel and elution with etherpetroleum ether (10-50%) gives 5-(2,2-difluorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:20])([F:19])[C:14]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:15]
Reactant: Brc1ccoc1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccoc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (20 g) was added to a solution of n-butyllithium (2.5M in hexanes, 60 ml) in diethyl ether (200 ml) at -70° C. After 30 minutes, ethyl trifluoroacetate (28.6 g) was added slowly. After a further 1 hour the mixture was allowed to warm to room temperature and was then left to stir overnight. 1M Hydrochloric acid (100 ml) was added and the mixture stirred for 5 minutes. The organic layer was separated,
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: Clc1ncccn1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(c2ncccn2)C3)cc1

Procedure:
Compound gs was synthesized using the general procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-chloropyrimidine: LC-MS: m/z=+489 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:45][CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.95 (m., 14 H) 2.52 (t, J=7.38 Hz, 2 H) 2.92 (br. d., 1 H) 3.07 (br. d., 1 H) 3.39 (s, 3 H) 3.81 (br. s., 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.64 Hz, 2 H) 4.45 (m, 1 H) 7.34-7.55 (m, 2 H) 7.90 (s, 1 H) 8.03 (d, J=7.58 Hz, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). [M+H] calculated for C27H35F2N7O3, 544; found 544.