Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:31]=[C:30]([CH2:32]OS(C)(=O)=O)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:46])=[CH:40][CH:39]=2)[N:27]=1>C(#N)C>[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[N:27]=[C:28]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:45](=[O:46])[NH:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:42][CH:43]=2)[N:29]=[C:30]([CH2:32][S:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:31]=1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: CC(=O)NCCS
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCCSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-Acetylcysteamine (0.086 mL) was dissolved in acetonitrile (5 mL). DBU (0.120 mL) was then added to the solution and was allowed to stir at RT for 15 minutes. 1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (228 mg) in acetonitrile (5 mL) was added to the reaction and stirred for 30 minutes. The reaction was concentrated in vacuo and the crude residue purified on silica, eluting with 5% methanol in DCM, to give the desired compound (100 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)c1-c1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(-c2ccc3ncccc3c2)c1F
Yield: 70 %

Procedure:
The title compound was prepared by the method of Example 1B. A 5.00 g sample (70% yield) was made from 6-(2,6-difluorophenyl)-quinoline (6.02 g, 25 mmoles) and 50 ml of concentrated H2SO4 and 1.5 ml of concentrated HNO3. The product was isolated as an off white solid of m.p. 152°-153° C. NMR (DMSO-d6, 250 MHz): 9.05 (d of d, 1H), 8.50 (d, J=5 Hz, 1H), 8.40 (sextet, 1H), 8.24 (s, 1H), 8.20 (d, J=5.0 Hz, 1H), 7.87 (d, J=5.0 Hz, 1H), 7.60 (m, 2H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]([C:16]([CH:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])([CH:18]3[CH2:20][CH2:19]3)[CH3:17])[CH:12]=[CH:13][C:14]=2[Cl:15])=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[NH2:8][C:9]1[CH:10]=[C:11]([C:16]([CH:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])([CH:18]2[CH2:19][CH2:20]2)[CH3:17])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COC(=O)C(C(=O)OC)C(C)(c1ccc(Cl)c(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1)C1CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C(=O)OC)C(C)(c1ccc(Cl)c(N)c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
627 mg (1.11 mmol) of dimethyl (1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-1-cyclo-propylethyl)malonate were taken up in 60 ml of dichloromethane and 15 ml of water. 553 mg (2.44 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were then added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then added to about 50 ml of saturated aqueous sodium bicarbonate solution. The phases were separated, and the aqueous phase was extracted three more times with in each case about 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water). This gave 283 mg of the target product (78% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:62])([F:61])[CH2:40][NH:41][C:42]([C:44]1([CH2:57][CH2:58][CH2:59]Br)[C:56]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43]>CN(C=O)C.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH2:59][CH2:58][CH2:57][C:44]4([C:42](=[O:43])[NH:41][CH2:40][C:39]([F:38])([F:61])[F:62])[C:56]5[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=5[C:50]5[C:45]4=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[C:9]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(Cc2ccccn2)CC3)CC1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(N3CCN(CCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CCN1Cc1ccccn1
Temperature: 8 °C
Reaction time: 4.5 h
Yield: 44 %

Procedure:
The compound (50 mg, 0.16 mmol) prepared in step (b) of Example 125 was dissolved in anhydrous DMF. Potassium carbonate (44 mg) and 66 mg of the compound prepared in step (a) of Example 93 were added to the solution. The mixture was stirred at 50° C. for 20 hr and further at 8° C. for 4.5 hr. The reaction solution was diluted with ethyl acetate, and the dilution was washed twice with water, followed by drying over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography (development system, methylene chloride:methanol=30:1) to give the title compound (46 mg, yield 71%) as a white foam.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])([O-])=O.N.[H][H]>C(O)C.[Ni]>[NH2:1][CH2:4][CH:5]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:6][P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccccc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC

Procedure:
A solution of 5.7 g of ethyl 3-nitro-2-phenylpropyl(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 50 g of an 8% solution of ammonia in ethanol. To this are added 9 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+44.4 ppm (CDCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.CO[CH:16](OC)[CH2:17]Br>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:16]=[CH:17][N:8]=2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Cc1ccc(-c2nccs2)c([N+](=O)[O-])c1
Yield: 75 %

Procedure:
The procedure described in Example 15-1 was followed except that 4-methyl-2-nitro-thiobenzamide (56) was used instead of 4-trifluoromethyl-2-nitro-thiobenzamide, bromoacetaldehyde-dimethylacetal was used instead of 1-bromo-3-methyl-butan-2-one, and the reaction was acid catalyst with 5% acetic acid. This gave the title compound (66 mg, 75%). LC/MS: (Method I): tR=0.98 min, >90%, m/z (ESI+)=221 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].Cl.CCN(CC)CC.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:16]([NH:20][C:21]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)CN
Reactant: CCCCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Glycine ethyl ester·HCl (5.58 g, 40 mmol) was suspended in distilled CH2Cl2 (20 ml). After cooling in an ice bath, distilled Et3N (6.13 ml, 44 mmol) was added. Distilled n-butyl isocyanate (4.95 ml, 44 mmol) was added. The cooling bath was removed and the mixture was left stirring overnight at room temperature. Additional Et3N (3.05 ml) was added and the mixture was stirred 3 more hours. After diluting with more CH2Cl2, the solution was washed with water (50 ml), lN HCl (50 ml), saturated NaHCO3 solution (50 ml) and water (50 ml). After drying (MgSO4), the solvent was removed in vacuo leaving the title compound (7.641 g, 94%) which slowly crystallized. This was used without further purification.
Reaction SMILES: [C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]3[C:8]([C:6](=[O:7])[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:29])=[CH:9][C:10]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[C:11]32)=[CH:16][C:17]=1[O:22][CH3:23])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(cc1O)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of the product of example 52 (250 mg), bromo-acetic acid ethyl ester (81 μl) and Cs2CO3 (595 mg) in DMF (10 ml) was stirred at 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature, subsequently poured into water and extracted with dichloromethane. The organic layer was washed with an aqueous HCl solution (0.5 M), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/1 (v/v)] as eluent.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])[CH2:2][CH3:3].[Br:13]Br>C(Cl)Cl>[Br:13][CH:2]([CH3:3])[C:1]([C:5]1[S:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: BrBr
Reactant: CCC(=O)c1cc([N+](=O)[O-])cs1
Solvent: ClCCl
Product: CC(Br)C(=O)c1cc([N+](=O)[O-])cs1

Procedure:
Following the procedure of Example 12B, using 9.26 g. of 2-propionyl-4-nitrothiophene and 7.99 g. of bromine in 100 ml. of methylene chloride, there is obtained 13.0 g. of product m.p. 79°-82° C. which is recrystallized from ethanol affording 2-(2-bromopropionyl)-4-nitrothiophene m.p. 82.5°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:9]1.C1C(=O)N([Br:32])C(=O)C1>>[Br:32][CH2:19][C:12]1[NH:11][C:10]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1Cl
Yield: 60 %

Procedure:
Ethyl 4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (10 g, 27.6 mmol) was reacted with NBS (5.41 g, 30.4 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (7.3 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:26]=[CH:25][C:10]2[S:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]([C:14](=[O:17])[NH:15][CH3:16])[C:9]=2[CH:8]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[S:11][C:10]3[CH:25]=[CH:26][C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])=[CH:8][C:9]=3[C:13]=2[C:14](=[O:17])[NH:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl trifluoromethanesulfonate (0.32 g, 0.74 mmol), 3-boronobenzoic acid (0.18 g, 1.1 mmol), cesium carbonate (0.36 g, 1.1 mmol), dioxane (6.2 mL) and water (1.2 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.016 mmol). The solution was maintained at 95° C. for 90 min. The solution was cooled to room temperature, concentrated and suspended in ethyl acetate (20 mL) with stirring for 1 h. The mixture was filtered, washed with water (3×20 mL) and air dried to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid as a grey solid which was used without further purification. LCMS: retention time: 2.132 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 406 (MH+).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]([NH2:27])([CH3:26])[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)NCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 41.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.30 mmol), isopropylamine (30 μL, 0.36 mmol) and sodium triacetoxyborohydride (101 mg, 0.48 mmol) to afford 47 mg (42%) of the desired product after purification.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:38][CH3:39])[N:9]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:39][O:38][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][N:11]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I23) (2.694 g, 4.39 mmol) was dissolved in dichloromethane (150 mL), and TFA (15 mL) was added. The resulting mixture was stirred for 16 hours then concentrated. The residue was suspended in 10% sodium hydroxide (200 mL) then extracted with ethyl acetate (5×200 mL). The combined organic phases were washed with brine (300 mL), dried over sodium sulfate and evaporated to give the title compound (2) (2.252 g, 100% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 7.29-7.21 (m, overlaps with CHCl3), 6.87 (d, J=8.3 Hz, 1H), 6.80 (s, 1H), 5.43 (d, J=10.1 Hz, 2H), 3.92 (d, J=1.3 Hz, 3H), 3.70 (s, 2H), 3.20 (d, J=12.7 Hz, 2H), 3.15-3.05 (m, 4H), 2.75 (t, J=12.2 Hz, 2H), 2.61 (tt, J=12.0, 3.5 Hz, 1H), 1.89-1.76 (m, overlaps with water), 1.67 (qd, J=12.7, 3.9 Hz, 2H). LCMS Method C: rt 4.92 min; m/z 514.1 [M+H]+, 536.1 [M+Na]+; m/z 512.2 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([P:14]([O:19]CC)(=[O:18])[O:15]CC)[P:6]([O:11]CC)(=[O:10])[O:7]CC.[N+]([O-])(O)=O.C[C:27]1C=C(C)[N:29](C(N)=N)[N:28]=1>CN(C=O)C>[NH2:29][N:28]=[CH:27][NH:1][CH2:2][CH2:3][CH2:4][CH:5]([P:14]([OH:19])(=[O:18])[OH:15])[P:6]([OH:11])(=[O:10])[OH:7]
Reactant: CCOP(=O)(OCC)C(CCCN)P(=O)(OCC)OCC
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: NN=CNCCCC(P(=O)(O)O)P(=O)(O)O

Procedure:
A solution of 0.69 g (2 mmol) of tetraethyl 4-aminobutane-1,1-bisphosphonate (according to DE 3,225,469 A1, 01.05.1984) and 0.402 g (2 mmol) of 3,5-dimethylpyrazole-1-carboxamidine nitrate in 10 ml of DMF is heated at boiling point for 3 hours. The DMF is then distilled off in vacuo and the residue is dissolved in a little water. After extraction with diethyl ether and ethyl acetate (the organic extracts are discarded), the aqueous phase is distilled in vacuo. A dark oil (0.89 g) remains. This is heated at boiling point for 8 hours in 15 ml of concentrated hydrochloric acid. The excess hydrochloric acid is distilled off and the residue is treated with a little water, DMF and acetone. The precipitate is filtered off with suction and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[NH2:37][C:38]1[CH:48]=[CH:47][C:46](Br)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41].C([O-])(O)=O.[Na+]>C(#N)C>[NH2:37][C:38]1[CH:48]=[CH:47][C:46]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.6 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.167 g, 0.331 mmol), 2-amino-5-bromo-N,N-dimethyl-benzamide (0.088 g, 0.364 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (14 mg, 0.017 mmol), acetonitrile (5 mL) and saturated aqueous NaHCO3 (5 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 5 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and adsorbed onto silica gel. The crude material was purified by silica gel chromatography in an EtOAc (containing 10% MeOH) and hexane gradient. The purified material was dissolved in a MeOH/acetone solution (5 mL) and 200 uL of a 50% KOH solution was added and the solution was stirred at room temperature for 3 hours. The reaction was quenched by adding 1 M citric acid dropwise until pH=5. The quenched reaction mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous phase was extracted 2× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and adsorbed onto silica gel. The material was purified on amino silica in an EtOAc (containing 10% MeOH) and hexane gradient to afford the title compound as a pale yellow powder (13.5 mg, 11% yield). 1H-NMR (500 MHz, d6-DMSO) δ=11.80 (br. s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.68 (d, J=2.5 Hz, 1H), 7.58 (dd, J =1.5, 6.0 Hz, 1H), 7.44 (dd, J=2.0, 6.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.04 (t, J=7.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 2.95 (s, 6H). MS: m/z 387.1 [MH+].
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][OH:24]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][OH:24])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: OCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: OCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridone (15 g), freshly distilled 3-bromo-1-propanol (16.5 cc), silver carbonate (8.4 g) and toluene (600 cc). The reaction mixture is refluxed for 144 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 7-3). (white solid; m.p.=94° C.)
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].CC1C=C(C)[N:11]([C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[S:19])=N)N=1>CS(C)=O>[NH2:11][C:15]1[N:17]=[C:18]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:19][C:2]=1[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Reactant: O=C(CBr)C1CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCNc1nc(N)c(C(=O)C2CC2)s1
Temperature: 100 °C

Procedure:
A solution of 404 mg (2.48 mmol) of 2-bromo-1-cyclopropylethanone in 15 ml of DMSO is added dropwise to 845 mg (2.48 mmol) of the crude mixture from Example 72A while cooling in ice, and the mixture is then heated at 100° C. for 1 h. The crude mixture is poured into ice-water and extracted three times with ethyl acetate. After the combined organic phases have been dried, the solvent is completely removed and the residue is purified by subsequent purification by preparative HPLC. 428 mg (48% of theory) of the product are obtained as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:10]1[C:15]([NH:16][C:17]([C:19]2[S:20][CH:21]=[C:22]([CH:24]=[CH2:25])[N:23]=2)=O)=[C:14]([Cl:26])[C:13]([O:27][CH3:28])=[CH:12][CH:11]=1)(=[O:9])[CH3:8]>C(O)(C)(C)C.C(OCC)C>[Cl:26][C:14]1[C:13]([O:27][CH3:28])=[CH:12][CH:11]=[C:10]2[C:15]=1[N:16]=[C:17]([C:19]1[S:20][CH:21]=[C:22]([CH:24]=[CH2:25])[N:23]=1)[CH:8]=[C:7]2[OH:9]
Reactant: C=Cc1csc(C(=O)Nc2c(C(C)=O)ccc(OC)c2Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: C=Cc1csc(-c2cc(O)c3ccc(OC)c(Cl)c3n2)n1
Temperature: 100 °C
Yield: 73 %

Procedure:
Potassium tert-butoxide (2.13 g, 2.2 eq.) was added to a suspension of compound 272 (2.91 g, 1 eq.) in tert-butanol (30 mL). The reaction mixture was heated to 100° C. for 5 hrs. After one night at room temperature, the mixture was diluted with diethyl ether and the precipitate filtered, washed with diethyl ether, and solubilized in water. The pH was adjusted to 6-7 by addition of 1N HCl and the precipitate was filtered, washed with water, and triturated with diethyl ether to yield compound 273 in 73% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.06 (s, 3H), 5.54 (d, J=10.82 Hz, 1H), 6.25 (d, J=17.31 Hz, 1H), 6.74 (s, 1H), 6.79 (dd, J=17.31 and 10.82 Hz, 1H), 7.06 (d, J=9.10 Hz, 1H), 7.32 (s, 1H), 8.28 (d, J=9.10 Hz, 1H), 9.97 (br s, 1H).