Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2].[Na+].Cl[C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=2>CN(C=O)C>[C:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:21]2[S:22][C:23]3[C:28]([N:29]=2)=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=3)=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc([O-])cc1
Reactant: Cc1ccc2nc(Cl)sc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccc(C)nc3s2)cc1
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To sodium 4-{[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenolate (170 mg, 0.63 mmol) was added 2-chloro-5-methyl[1,3]thiazolo[5,4-b]pyridine (117 mg, 0.63 mmol) and DMF (6.3 mL). The solution was stirred for 16 h, filtered, and purified by preparative reverse phase HPLC to provide the desired product (140 mg, 56%). 1H NMR (400 MHz, CDCl3): 7.81 (d, J=8.2, 1H), 7.46-7.39 (m, 2H), 7.33-7.28 (m, 2H), 7.18 (d, J=8.3, 1H), 4.79 (s, 0.5H), 4.24 (s, 0.5H), 3.82-3.72 (m, 2.5H), 3.60-3.53 (m, 1.5H), 3.30 (ddd, J=13.3, 10.3, 2.1, 1H), 3.02 (dd, J=9.5, 2.1, 0.5H), 2.85 (dd, J=9.7, 2.2, 0.5H), 2.78 (d, J=9.7, 0.5H), 2.61 (s, 3H), 2.57 (dd, J=9.5, 1.2, 0.5H), 2.08 (s, 1.5H), 2.03-1.96 (m, 2H), 1.91 (d, J=9.8, 0.5H), 1.81 (d, J=9.7, 0.5H), 1.67 (d, J=10.0, 0.5H). MS (ESI): mass calcd. for C21H22N4O2S, 394.15; m/z found, 395.1 [M+H]+.
Reaction SMILES: N([C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)=C=S.CC(N)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H]([NH:43]C)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.CC(NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O.O.OS(O)(=O)=O>CO>[NH2:43][C:6]1[C:5]2[C:10](=[N:11][C:12]3[C:17]([CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](C(C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Reactant: S=C=Nc1c2ccccc2nc2ccccc12
Agent: CNC(C)[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@](C)(O)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1cccc2nc3ccccc3cc12
Reaction time: 0.5 h
Yield: 910.6 %

Procedure:
9-Isothiocyanatoacridin (100 mg) was dissolved in MeOH (5 mL), and added to the solution of gentamicin sulfate (250 mg) in 5 mL MeOH and some drops of water, followed by the solution of BaO (100 mg) in 5 mL MeOH. The suspension was stirred 30 min, neutralized with 3% H2SO4 in MeOH, filtered, evaporated to dryness and the residue was washed carefully with dichloromethane. Obtained 297 mg of yellow powder.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[C:26]([NH:34][NH2:35])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:11][C:10]1[C:9]([N:8]=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([NH2:13])[N:34]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[N:35]=1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: Nc1ccccc1
Solvent: N#CCC#N
Product: Nc1nn(C(=O)c2ccccc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
(3,5-diamino-4-phenylazopyrazol-1-yl)phenylmethanone was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and benzoic hydrazide (68 mg, 0.5 mmol). Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in methanol and then precipitated by the addition of water. The resulting solid was isolated by filtration and dried to yield 20 mg (13%) of the compound as an orange coloured solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[N:22]=[N:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH3:25])=[C:23]([C:26]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:27])[N:22]=[N:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C)c(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{2-(benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (3.95 g) obtained in Example 140a) in DMF (30 ml) were successively added cyclopropylamine (0.86 ml), triethylamine (1.73 ml), HOBt (1.91 g) and WSC (2.40 g), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a pale-yellow amorphous substance (3.30 g, 76%).
Reaction SMILES: C([O-])=O.[NH4+].O1CCCC1.C([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([S:23][CH3:24])=[N:18][CH:19]=2)[N:14]1[C:25]1[N:30]=[C:29]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])[CH:28]=[CH:27][CH:26]=1)C=C>C(Cl)(Cl)Cl>[CH3:24][S:23][C:17]1[N:16]=[C:15]2[N:14]([C:25]3[N:30]=[C:29]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])[CH:28]=[CH:27][CH:26]=3)[NH:13][C:21](=[O:22])[C:20]2=[CH:19][N:18]=1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2ccccc2=O)n1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CSc1ncc2c(=O)[nH]n(-c3cccc(-n4ccccc4=O)n3)c2n1
Temperature: 25 °C

Procedure:
Ammonium formate (964 mg) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)/dichloromethane complex (208 mg) were added to a tetrahydrofuran (10 mL) solution of 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one (1 g), and heated overnight under reflux. The reaction liquid was cooled to room temperature, then diluted with chloroform, and washed with water and saturated saline water in order. The organic layer was dried with anhydrous magnesium sulfate. The insoluble matter was dissolved, and then the solvent was evaporated away to give crude 6′-[6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one.
Reaction SMILES: C=O.[CH3:3][NH:4][C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6].C(N(CC)CC)C.[O:18]1[CH2:23]COC[CH2:19]1>C1(C)C=CC=CC=1>[CH3:3][N:4]1[C:5](=[N:7][N+:8]([O-:10])=[O:9])[NH:6][CH2:23][O:18][CH2:19]1
Reactant: C1COCCO1
Reactant: CNC(=N)N[N+](=O)[O-]
Agent: C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1COCNC1=N[N+](=O)[O-]

Procedure:
30.5 g of paraformaldehyde are added, at room temperature, to a mixture of 20 g of N-methyl-N′-nitroguanidine, 17 g of triethylamine, 100 ml of dioxane and 100 ml of toluene, and the mixture is refluxed for 16 hours and subsequently evaporated in vacuo. The residue is purified by column chromatography [silica gel; dichloromethane/methanol (95:5)], giving the title compound which melts at 137 to 139°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O([CH2:51][CH3:52])S(C(F)(F)F)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH2:51][CH3:52])[C:9]1=[O:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@@H](C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of (5S)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.0 mmol) in THF (50 mL) at −78° C. was added LHMDS (1.0 M in THF, 12.6 mL, 12.6 mmol). The mixture was stirred for 30 min before ethyl triflate (1.78 mL, 1.25 equiv.) was added. The reaction was stirred between −78° C. to −40° C. for 45 min. It was quenched with 5% citric acid at −50° C., extracted with ethyl acetate. The combined organic phases were washed with 5% NaHCO3, brine, and dried over MgSO4NaHCO3, brine, and dried over MgSO4. Evaporation of the solvent and flash column chromatography (hexanes/EtOAc, 4:1) gave the desired product (90% yield) as viscous oil. 1HNMR (400 MHz, CDCl3) δ 7.63 (m, 4 H), 7.41 (m, 6 H), 4.13 (m, 2 H), 3.86 (m, 1 H), 3.74 (d, 1 H), 2.71 (m, 1 H), 2.24 (t, 1 H), 1.95 (m, 1 H), 1.78 (q, 1 H), 1.46 (s, 9 H), 0.95 (t, 3 H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:14]2[CH:17]=[CH:21][CH:20]=[CH:19]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)OC1Cc2cccc(N)c2C1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OC1Cc2cccc(-n3cccc3)c2C1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A stirred solution of 0.70 g (0.004 mole) of 4-amino-2-indanyl acetate and 0.56 g (0.004 mole) of 2,5-dimethoxytetrahydrofuran in 1.5 mL of acetic acid was heated under reflux for 3 hours. The reaction mixture was cooled to ambient temperature and poured into 30 mL of chloroform. The mixture was stirred with 30 mL of an aqueous saturated solution of sodium chloride. The organic layer was removed, and the aqueous layer extracted with two portions of 30 mL each of chloroform. The combined organic phases were washed with two portions of 30 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 0.89 g of 4-(1-pyrrolyl)-2-indanyl acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=2[O:21][CH3:22])[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].Cl>CC#N>[CH3:22][O:21][C:12]1[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(OC)c2OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: COc1ccc(-c2cccc(C(=O)O)c2)c(OC)c1OC

Procedure:
Dissolve 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (43) (566 mg, 1.87 mmol) in MeCN (19.0 mL) at rt and add 1M aqu LiOH (9.36 mL, 9.36 mmol). Stir reaction mixture overnight at rt. Quench reaction mixture (cooling bath) with 1M aqu. HCl (to get pH ca. 3). Extract the mixture with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4. Recrystallize crude product from EtOAc/CyH 1+3 to obtain 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid (44) as a white solid (392 mg, to 72%). 1H NMR (400 MHz, CD3OD: 3.68 (s, 3H); 3.93 (br.s, 6H); 6.92 (d, 1H, J=8.6 Hz); 7.11 (d, 1H, J=8.6 Hz); 7.54 (t, 1H, J=7.7 Hz); 7.75 (d, 1H, J=7.6 Hz); 8.01 (d, 1H, J=7.8 Hz); 8.18 (br.s 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3O[C:13](=O)[C:14]4[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)(O)O.[NH2:30][NH:31][C:32]([NH2:34])=[NH:33]>N1C=CC=CC=1>[NH2:34][C:32]1[N:33]=[C:13]2[N:30]([C:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:16][C:15]3[CH:17]=[C:18]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:19]=[CH:20][C:14]=32)[N:31]=1
Reactant: N=C(N)NN
Reactant: NS(=O)(=O)c1ccc2c(=O)oc(Cc3ccc4c(c3)OCO4)nc2c1
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Nc1nc2c3ccc(S(N)(=O)=O)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Temperature: 180 °C
Yield: 36.3 %

Procedure:
A mixture of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4-sulfamoyl-benzoic acid (0.10 g, 0.26 mmol), acetic acid (1.5 mL) and acetic anhydride (0.10 mL, 1.06 mmol) was stirred at reflux for 1 h. The reaction was diluted with ethyl acetate and washed with NaHCO3 satured solution, then with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-benzo[1,3]dioxol-5-ylmethyl-4-oxo-4H-benzo[d][1,3]oxazine-7-sulfonic acid amide intermediate (0.032 g) as yellow oil. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-4-oxo-4H-benzo[d][1,3]oxazine-7-sulfonic acid amide (0.032 g, 0.09 mmol) in dry pyridine (1 mL) was added aminoguanidine hydrogencarbonate (0.013 g, 0.098 mmol) and the mixture was heated under microwave condition at 180° C. for 1.5 h. The solvent was then evaporated and the crude was taken up in methanol to give the title compound (0.013 g, 12% yield).
Reaction SMILES: [H][H].[CH:3]1([P:9]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([S:17]([O-:20])(=[O:19])=[O:18])[CH2:12]2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:27].C1(P(C2CCCCC2)(C2CCCC(S(OCC)(=O)=O)C2)=O)CCCCC1>CO>[C:21]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:11]2[CH:12]=[C:13]([S:17]([O-:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[Na+:27]
Reactant: O=P(C1CCCCC1)(C1CCCCC1)C1CCCC(S(=O)(=O)[O-])C1
Reactant: [H][H]
Agent: CCOS(=O)(=O)C1CCCC(P(=O)(C2CCCCC2)C2CCCCC2)C1
Agent: [Na+]
Solvent: CO
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc(S(=O)(=O)[O-])c1

Procedure:
DPPOBS-Na (7.0 g; 18.4 mmoL), prepared as above, is dissolved in dry methanol (70 mL) and placed into a Parr reactor (150 mL) containing 7 g of catalyst comprising Ru (5 wt percent) on carbon. Hydrogenation is carried out at 1,000 psi (6,895 kPa) hydrogen and at 100° C. The reaction is monitored by 31P and 1H NMR. After 2 weeks, resonances for the aromatic protons in the 1H NMR spectrum disappear, and new resonances appear in the 31P NMR spectrum. The mixture is filtered; a black solid on the filter is washed with methanol. The solvent is evaporated, and the residue is dried in vacuum to give a white solid identified as sodium 3-(dicyclohexylphosphinyl)cyclohexane-1-sulfonate (DCHPOCHS-Na). Yield 4.0 g (55%). 31P{1H} NMR (CD3OD, ppm): 5.68 (major, ca. 87%) and 57.99 (minor, ca. 13%). (3) Step 3 of Example 1 is repeated using the intermediate product from step (2) of this example. Subsequently, steps 4 to 6 of Example 1 are also reproduced to yield Ligand 1 of this invention, namely, the sodium salt of 3-(dicyclohexylphosphino)cyclohexane-1-sulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]3)=[C:10]([CH3:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[C:37]([OH:39])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]([CH3:21])[C:37]([C@@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][N:31]4[C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])=[O:39])[CH2:16][CH2:15]3)=[C:10]([CH3:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: CNC1CCN(c2nnc(-c3ccc(F)cc3)c(C)c2C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
Sequentially treat a solution of 1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-N-methylpiperidin-4-amine (100 mg, 0.318 mmol) in CH2Cl2 (3.2 mL) with (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (109 mg, 0.477 mmol), triethylamine (0.067 mL, 0.477 mmol) and EDCI (92 mg, 0.477 mmol). Stir the resulting mixture at ambient temperature for 2 d. Pour the reaction mixture into H2O containing NaHCO3. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to afford the title compound as a white solid (82 mg, 49%). ES/MS m/z 526.2 (M+1).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:34])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:68]([O:70][C:71]([N:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1)=[O:72])[CH3:69]>CN(C=O)C.ClCCl>[CH2:68]([O:70][C:71]([N:73]1[CH2:74][CH2:75][N:76]([C:31](=[O:32])[CH2:30][NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:34])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:77][CH2:78]1)=[O:72])[CH3:69]
Reactant: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid in 2 ml DMF were added 0.15 ml DIPEA, 81 mg HATU and 0.03 ml 1-ethoxycarbonylpiperazine. After stirring for 1 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1)(=O)=O.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+]>[C:35]([NH:39][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:10]=[C:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCOS(C)(=O)=O)CC3)c21
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCNC(C)(C)C)CC3)c21
Temperature: 50 °C
Yield: 55 %

Procedure:
Add (R)-2-(2-(1-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl methanesulfonate (0.50 g, 0.99 mmol), tert-butylamine (0.52 mL, 7.1 eq), and triethylamine (0.69 mL, 5.0 eq) in dimethylformamide (5 mL). Heat to 50° C. in a sealed tube for 48 hours. Dilute the solution with saturated aqueous sodium chloride. Add the mixture into ethyl acetate. Wash the organics with saturated aqueous sodium chloride and concentrate in vacuo. Purify by silica gel chromatography, eluting with 20% ethanol/acetone, to give the title compound (0.27 g, 55%). MS (ES) m/z=480 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:24][C:16]1[C:17](=[CH:23][C:13]([F:12])=[CH:14][CH:15]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: CCOC(=O)c1cc(F)ccc1N
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)ccc1NC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 2,4-dichlorophenyl isocyanate (47.0 g, 0.25 mol) in xylene (130 ml) is metered at room temperature into a solution of ethyl 5-fluoroanthranilate (45.2 g, 0.25 mol) in xylene (210 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. Triethylamine (3.5 ml, 2.55 g, 0.025 mol) is metered in. The mixture is stirred at 90° C. for a further 2 hours. After cooling, the product is filtered off with suction and washed with 3×30 ml of xylene and dried. 86.9 g of ethyl N-(2,4-dichlorophenylcarbamoyl)-5-fluoroanthranilate of melting point 219° to 223° C. (decomposition) are obtained. The cyclization product 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione cannot be detected by thin-layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4](Cl)[N:3]=1.CC(C)([O-])C.[K+].[OH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1
Reactant: OCc1cccnc1
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(N)nc(OCc2cccnc2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
102 mg (0.4 mmol) of 2-amino-6-chloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] and 54 mg (0.48 mmol) of potassium tert-butoxide are dissolved together in 1.696 g (=1.5 ml, 15.55 mmol) of 3-hydroxymethylpyridine, and the mixture is stirred at 60° C. for about 16 h. The resulting suspension is acidified with two drops of glacial acetic acid. The product which crystallizes out is filtered off with suction, washed with water and dried under reduced pressure.