Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:32]([OH:33])=[C:31]([C:34]([NH:36][CH3:37])=[O:35])[CH:30]=[CH:29][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]3[CH2:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[O:19][C:14]=3[C:13]=2[CH2:26][CH2:27][CH3:28])[CH2:3][CH2:2]1.S(OC)(O[CH3:42])(=O)=O.[OH-].[K+]>C1COCC1>[CH:1]1([CH2:4][C:5]2[C:32]([O:33][CH3:42])=[C:31]([C:34]([NH:36][CH3:37])=[O:35])[CH:30]=[CH:29][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]3[CH2:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[O:19][C:14]=3[C:13]=2[CH2:26][CH2:27][CH3:28])[CH2:2][CH2:3]1
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 17 (20 mg, 0.04 mmol), dimethyl sulfate (0.5 mg, 0.12 mmol), and potassium hydroxide (4.5 mg, 0.08 mmol) were added to about 5 ml of THF, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to give the product.
Reaction SMILES: CN1CCCC1=O.[OH:8][C@H:9]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.[H-].[Na+].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([Cl:35])[N:26]=1>O>[Cl:35][C:27]1[N:26]=[C:25]([O:8][C@H:9]2[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10]2)[C:34]2[C:29]([CH:28]=1)=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(Cl)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.2 %

Procedure:
To a 25 mL microwave vial was added N-methyl-2-pyrrolidinone (10.00 mL) and tert-butyl trans-3-hydroxy-4-methylpyrrolidine-1-carboxylate (1.118 g, 5.55 mmol). The mixture was cooled to 0° C. under a nitrogen atmosphere. To this mixture was added portion-wise NaH (60% suspension in mineral oil, 0.202 g, 5.05 mmol). After 5 minutes the mixture was allowed to warm to RT and was stirred for 10 minutes. Next, 1,3-dichloroisoquinoline (1 g, 5.05 mmol) was added and the reaction mixture was heated in a microwave reactor at 135° C. for 30 minutes. The reaction mixture was subsequently diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated onto silica. The crude product was purified by flash column chromatography (SiO2) eluting with a gradient of 5-50% heptane in EtOAc to give the title compound as a white solid (1.066 g, 58.2%). 1H NMR (500 MHz, CDCl3) δ ppm 1.16 (d, 3H), 1.48 (s, 9H), 2.60 (br s, 1H), 3.23 (br s, 1H), 3.49 (br s, 1H), 3.74 (br s, 1H), 3.94 (br s, 1H), 5.38 (br s, 1H), 7.23-7.32 (m, 1H), 7.51 (ddd, 1H), 7.61-7.71 (m, 2H), 8.17 (d, 1H); ESI-MS m/z [M+H]+ 307.6.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[CH:6]1[C:15]2C=CC=C(S(Cl)(=O)=O)[C:10]=2[CH:9]=[CH:8][N:7]=1.N1C=CC=C(S(Cl)(=O)=O)C=1>C(N(CC)CC)C>[S:1](=[C:6]1[CH2:15][CH2:10][CH2:9][CH2:8][NH:7]1)(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Product: O=S(=O)=C1CCCCN1

Procedure:
Referring to the scheme for Method 9, an amine 25 is reacted with a sulfonyl chloride such as 5-isoquinolinesulfonyl chloride, 3-pyridinesulfonyl chloride, etc., in the presence of a base such as triethylamine to give a sulfonylpiperidine, 26. The amino nitrogen is then deprotected by removal of the Z group to afford a compound of formula IV.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9]Cl)=[CH:4][CH:3]=1.[CH3:11][NH:12][C:13]([F:15])=[O:14]>>[CH3:11][N:12]([S:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:13]([F:15])=[O:14]
Reactant: Cc1ccc(SSCl)cc1
Reactant: CNC(=O)F
Product: Cc1ccc(SSN(C)C(=O)F)cc1

Procedure:
Prepared by the procedure of Example II by reacting 4-methylphenylthiosulfenyl chloride with methylcarbamoyl fluoride. b.p. 92°-100° C/0.25 Torr ND22.5 1.5735.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:17]([C:27](=[O:45])[N:28]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=3)[CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:43][C:41]([F:42])([F:44])[C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=1)[CH2:30][N:28]([CH3:29])[C:27](=[O:45])[C:17]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1
Reactant: Cc1ccccc1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8.7 %

Procedure:
To a solution of 6.60 g (104 mmol) 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (Example 43) and 8.40 ml (207 mmol) methanol in 50 ml ethyl acetate 14.7 ml (207 mmol) acetyl chloride were added dropwise at 0° C. After 4 h the reaction mixture was diluted with ethyl acetate and treated with 1 N sodium hydroxide solution. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated to give 5.36 g of crude product. Flash column chromatography afforded 4.86 g (87.4%) of the title compound as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([O:28]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]=2[N:3]=1.[H][H].ClCCl.[OH-].[NH4+]>C(O)C.[Pd].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([OH:28])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccc(O)cc3c2n1CC(C)(C)NS(C)(=O)=O
Yield: 60 %

Procedure:
N-[2-(4-Amino-8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.16 g, 2.33 mmol) was dissolved in 50 mL of ethanol and 10% palladium on carbon (0.46 g) was added. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. Dichloromethane (100 mL) and methanol (100 mL) were added and reaction was filtered through CELITE filter agent. The filter cake was washed with 200 mL of 1:1 dichloromethane:methanol. The filtrate was concentrated under reduced pressure to give a white solid. The solid was precipitated from a minimum amount of ethanol and then redissolved in dichloromethane containing a minimum amount of methanol. Aqueous ammonium hydroxide was added. The two phases were mixed by shaking and then separated. The organic fraction was discarded and the aqueous fraction was extracted with four portions of dichloromethane followed by two portions of ethyl acetate. The combined organic fractions were concentrated. The volume of the aqueous fraction was reduced, and a precipitate formed. The aqueous fraction was made basic by the addition of aqueous ammonium hydroxide and the resulting precipitate was recovered by filtration. The solid precipitate was combined with the residue from the organic fraction to give 0.75 g of crude product. This material was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used with the eluent being a gradient of 30-50% CMA in chloroform to provide 0.57 g of N-[2-(4-amino-2-ethoxymethyl-8-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, m.p. 252-254° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:25]4)=[O:23])[C:17]=3[CH3:34])[CH:11]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4cccc(Cl)c4)c3)c2C)C1
Yield: 56 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and 3-chlorophenylboronic acid gave [5-(3′-chloro-biphenyl-3-yl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 56% yield as light brown oil. MS: 451.0 (MH+, 1 Cl).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([O:11]C)=[CH:4][CH:3]=1.[ClH:13].N1C=CC=CC=1>>[Cl:13][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2ccsc12
Reactant: Cl
Solvent: c1ccncc1
Product: Oc1ccc(Cl)c2ccsc12
Yield: 40.6 %

Procedure:
4-Bromo-7-methoxybenzo[b]thiophene (prepared as described in J. Chem. Soc. (Perkin Trans I), 1983, 2973-2977) (1.2 g, 4.96 mmol) and pyridine hydrochloride (1.95 g, 16.87 mmol) was heated at 210° C. in a microwave for 15 min. The mixture was partitioned between HCl (aq.) (20 mL) and EtOAc (20 mL). The aqueous phase was washed with additional EtOAc (3×20 mL) and the organic phase was dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography on silica gel with EtOAc:heptane (1:10 to 1:5, v/v) as eluent to give the title compound as a red oil (372 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:16])[CH:10]=[C:11]2[OH:13]
Reactant: CCOC(=O)CC(=O)Nc1ccccc1F
Solvent: ClCCl
Product: O=c1cc(O)c2cccc(F)c2[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of the product from step 1 (20.27 g) in DCM (100 ml) was added to polyphosphoric acid (43.7 ml). Dichloromethane was distilled from the reaction mixture by increasing the temperature slowly and then the brownish gummy solution was stirred at 120° C. for 3 hours and then left at room temperature for 16 hours. The reaction mixture was quenched by adding ice cooled water and the product was filtered. The filter cake was stirred with 500 mL of water and filtered to give the desired product (9.38 g) as a colorless solid. LRMS (ES+) m/z 180.1 (M+H)+.
Reaction SMILES: [Cl-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)CS
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To sodium chloride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added methyl thioglycolate (160 ul) dropwise at 0° C. After 30 minutes added 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) as a solution in DMF (1.5 ml) and the reaction mixture was warmed up to room temperature over 5 hours. Aqueous work-up and purification on silica yielded 4-methoxycarbonylmethylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Br:10])=[CH:4][C:3]=1[NH:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Br:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:12]=3[NH:11][C:3]=2[CH:4]=1
Reactant: COc1cc(N)c(Nc2cc(Cl)ccc2C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1Br)Nc1cc(Cl)ccc1C(=O)N2
Yield: 102.3 %

Procedure:
A mixture of Example 223F (0.35 g, 0.94 mmol), HATU (0.430 g, 1.13 mmol), and excess Et3N in 4 mL of DMF was stirred overnight. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), filtrated and concentrated to give 0.34 g of the title compound. MS (DCI) m/e 248 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.90 (s, 1H), 7.67 (d, J=8.42 Hz, 1H), 7.19 (s, 1H), 7.00 (d, J=1.87 Hz, 1H), 6.93 (dd, J=8.42, 2.18 Hz, 1H), 6.75 (s, 1H), 5.22 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34](Br)[CH:33]=[CH:32][C:31]=3[F:37])[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O.[OH-].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:31]([F:37])=[CH:32][CH:33]=[C:34]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[CH3:41])[CH:35]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(Br)ccc1F
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-bromo-2′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (79 mg, 0.123 mmol), (2-methylphenyl) boronic acid (25 mg, 0.182 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (10 mg, 0.0122 mmol), aqueous potassium hydroxide (82 μL, 3M, 0.246 mmol) and 1,4-dioxane (1 mL) were placed in a sealed tube and subjected to microwave irradiation at 140° C. for 15 minutes to complete the reaction. The crude reaction mixture was purified by preparative TLC on SiO2 (eluted with 30% Ethyl Acetate in hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6′-fluoro-2″-methyl-4-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a ckcar glass. LCMS calc.=655.16; found=656.11 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.73 (s, 1H), 7.72-7.66 (m, 2H), 7.48 (d, J=8 Hz, 1H), 7.41-7.36 (m, 1H), 7.29-7.23 (m, 4H), 7.19-7.23 (m, 3H), 5.56 (br s, 1H), 4.96 (br s, 1H), 4.13 (br d, J=46.5 Hz, 1H), 3.83 (br d, J=43.5 Hz, 1H), 2.29 (s, 3H), 0.56, 0.51 (br s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.[Pd]>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)N(CC(=O)O)c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 150 °C
Yield: 5.1 %

Procedure:
A solution of [(4-bromophenyl)(methylsulfonyl)amino]acetic acid (intermediate 3, 20 mg, 65 μmol) in dimethoxyethane (1 mL) was added in one portion to a mixture of 4-cyanophenyl-boronic acid (9.5 mg, 65 μmol) and fibrecat FC1001 (2.71% Pd; 25 mg, 6.5 μmol) in a Smith microwave reaction vial. Aqueous sodium carbonate solution (1.0 M; 130 μL, 130 μmol) was added and the vial capped. The crude reaction mixture was heated at 150° C. for 15 min using a Smith Synthesiser microwave reactor. On cooling the vial was opened and the contents were filtered through a Whatman 5 μM filter tube, washing the filter cake with methanol (2×1 mL). The filtrate was evaporated and the resulting residue was purified using mass directed auto-preparative reverse phase HPLC to give the title compound (1.1 mg, 5%) as a white solid. LC/MS: 2.94 min; z/e 329, calcd (M−1) 329. 1H NMR (400 MHz: MeOD): 7.80 (4H), 7.75 (2H), 7.65 (2H), 4.45 (2H), 3.10 (3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[N:22]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc2ccc(Cc3nnc4ccc(-n5ccnc5)nn34)cc2c1

Procedure:
A mixture of 6-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline, imidazole, and potassium carbonate were stirred in DMF (3 mL) for 8 h at 100° C. Aqueous HCl (0.5 N) was added and the volatiles were removed in vacuo. Purification by HPLC (5-35% B over 45 min) yielded the product as a TFA salt. The residue was dissolved in aq 1N HCl (5 mL) and the volatiles removed in vacuo. After two repetitions, the product-dihydrochloride was dried under high vacuum to yield a glassy solid (53 mg, 44% yield). 1H-NMR (CD3OD): δ 9.60 (1H, s), 9.17 (1H, dd, J=1.5, 5.3 Hz), 9.10 (1H, m), 8.58 (1H, d, J=9.9 Hz), 8.38 (1H, m), 8.36 (1H, m), 8.27 (1H, m), 8.23 (1H, m), 8.05 (1H, dd, J=5.3, 8.3 Hz), 7.98 (1H, d, J=9.9 Hz), 7.72 (1H, s), 5.12 (2H, s), 4.98 (2H, m). ESI-MS (m/z): Calcd. for C18H13N7: 327.1; found: 328.3 (M+H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][NH:11][C:12]3[CH:18]=[CH:17][N:16]=[CH:15][C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([Cl:27])=[O:26])[CH:20]=1>>[ClH:27].[C:25]([N:11]1[C:12]2[CH:18]=[CH:17][N:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[NH:10]1)(=[O:26])[C:21]1[CH:22]=[CH:23][CH:24]=[N:19][CH:20]=1
Reactant: Oc1ccc(C2=Nc3cnccc3NN2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(c1cccnc1)N1NC(c2ccc(O)cc2)=Nc2cnccc21
Yield: 79 %

Procedure:
2.75 g (0.01 moles) of 3-(p-hydroxyphenyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with pyridine-3-carbonyl chloride as described in Example 2 to obtain 1-nicotinoyl-3-(p-hydroxyphenyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 79%; m.p.: 212°-213° C.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.50 g, 9.09 mmol), thionyl chloride (20 ml) and a catalytic amount of DMF (2 drops) was stirred under reflux for 1.5 h to give a homogeneous mixture. It was evaporated under reduced pressure at 50° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3,4-dichloroaniline (1.62 g, 10.0 mmol) in dry DMA (15 mL). The residue of 3,4-dichloroaniline was washed down with more DMA (2×2 ml). The reaction mixture was stirred at room temperature for 20 h. It was poured into water (200 mL). The pH was adjusted to ca. 8 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether. The solid was collected by filtration and washed with water (5×25 mL). It was dried in vacuum over silica gel/KOH overnight to give N-(3,4-dichlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (204) (2.81 g, 100%) as a yellow/orange solid, mp 262-264° C.; 1H NMR δ [(CD3)2SO] 10.17 (s, 1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.26 (poorly resolved d, J=0.7 Hz, 1H), 7.92 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H). Anal. Calcd for C13H7Cl2FN4: C, 50.51; H, 2.28; N, 18.12. Found C, 50.50; H, 2.27; N, 18.42.
Reaction SMILES: C(OC(=O)C)(=O)C.[P:8]([OH:11])([OH:10])[OH:9].O[CH2:13][NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(=O)C>[C:15]([NH:14][CH2:13][P:8]([OH:11])(=[O:10])[OH:9])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCO)c1ccccc1
Reactant: OP(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(NCP(=O)(O)O)c1ccccc1
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
561 g (5.5 mol) of acetic anhydride were cooled to 10° C. Then, a solution of 164 g (2.0 mol) of phosphorous acid and 300 ml of acetic acid were added dropwise in the course of one hour, with stirring and cooling. 302 g (2.0 mol) of N-hydroxymethylbenzamide were then added in portions in the course of 50 minutes at 10°-15° C., with cooling. Stirring was continued at 10° C. for 20 minutes. The reaction mixture was subsequently kept under reflux for 2.5 hours, followed by cooling. 61 g (3.39 mol) of water were then added dropwise at 25°-30° C., with cooling and stirring. After this, the mixture was refluxed again. After cooling, the mixture was stirred overnight and solids were then filtered off with suction. 320 g (approx. 75% of theory) of crude benzoylaminomethanephosphonic acid were obtained. Further crude acid could be obtained from the mother liquor.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)(C)[C:12](O)=O)=[CH:7][CH:6]=1.OO>>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[CH2:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(C)(C(=O)O)c2ccc(N3CCCC3)cc2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: C=C(c1ccc(OC)cc1)c1ccc(N2CCCC2)cc1
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Into 50 ml of 5% aqueous solution of sodium hydroxide was dissolved 5 g of 2-(4-methoxyphenyl)-2-(4-pyrrolidinophenyl)propionic acid. Thereto was gradually added dropwise 2.4 g of 35% aqeous solution of hydrogen peroxide and the mixture was reacted at room temperature with stirring for 2 hours, and further at 60° C. with stirring for one hour. The reaction mixture was cooled and the precipitated crystal was collected by filtration. The crystal was recrystallized from methanol to give 3.0 g (yield 69.9%) of 1-(4-methoxyphenyl)-1-(4-pyrrolidinophenyl)ethylene, having a melting point of 159°~162° C.