Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8]([Cl:15])=[O:9]
Reactant: O=C(O)CCSCCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCSCCC(F)(F)F
Temperature: 36 °C
Yield: 91 %

Procedure:
A dry 5 L round bottom flask equipped with magnetic stirrer, nitrogen inlet, reflux condenser, and thermometer, was charged with 3-((3,3,3-trifluoropropyl)thio)propanoic acid (188 g, 883 mmol) in dichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) was then added dropwise over 50 minutes. The reaction mixture was heated to reflux (about 36° C.) for two hours, then cooled to room temperature. Concentration under vacuum on a rotary evaporator, followed by distillation (40 Torr, product collected from 123-127° C.) gave the title compound as a clear colorless liquid (177.3 g, 86%): 1H NMR (400 MHz, CDCl3) δ 3.20 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 2.78-2.67 (m, 2H), 2.48-2.31 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −66.42, −66.43, −66.44, −66.44.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>>[CH3:28][C:23]([CH3:29])([CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(C)(C)CCCCN
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Product: COC(=O)C(C)(C)CCCCNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
A mixture of 3.2 g of 2-chloro-4-phenyl-quinoline (prepared according to the method of S. Kwon and K. Isagawa, Yoki Gosei Kagaku Shi 973,31, 313) and 5.9 g of methyl 6-amino-2,2-dimethylhexanoate is heated to 100° C. for 8 hours. After cooling, the residue is purified by chromatography on silica gel (eluent: 98:2 dichloromethane/methanol) to give methyl 2,2-dimethyl-6-[(4-phenyl-2-quinolyl)amino]hexanoate obtained as an oil.
Reaction SMILES: [CH2:1]([C:5]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)=[C:8]2[C:9]([C:13]([O:15]C)=[O:14])=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)(C)(C)C>[CH2:1]([C:5]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)=[C:8]2[C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2cccc(C(=O)OC)c2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CCCCc1nn2cccc(C(=O)O)c2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the procedure of Example 15, 1.02 g of the product of Example 20, 50 ml. of terbutyl alcohol and 25 ml of potassium hydroxide were reacted to obtain after recrystallization from acetonitrile, 686 mg of the expected product melting at 214° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:40](Br)[C:41]#[CH:42].CCOC(C)=O>C1COCC1.O>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:42][C:41]#[CH:40])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: C#CCBr
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and K2CO3 (196 mg, 1.6 mmol) in THF (5 mL) was stirred for 1 hour at ambient temperature, and was treated with propargylbromide (120 μL, 1.6 mmol). The resulting reaction mixture was stirred for 24 hours at 60° C. AcOEt and water was added. The phases were separated. The aqueous layer was extracted with AcOEt. The organic layers were washed with water, combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, Toluene/AcOEt 7:3) afforded the title compound as a colorless crystalline solid. LC/MS: 506 (M+H)+, 528 (M+Na)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:33]=[CH:32][C:10]2[N:11]([CH2:14][C:15]3[CH:31]=[CH:30][C:18]4[N:19]=[C:20]([NH:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]5[OH:29])[S:21][C:17]=4[CH:16]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:6]([C:7]1[CH:33]=[CH:32][C:10]2[N:11]([CH2:14][C:15]3[CH:31]=[CH:30][C:18]4[N:19]=[C:20]([NH:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]5[OH:29])[S:21][C:17]=4[CH:16]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
A mixture of (1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (61 mg, 0.13 mmole) and Na2CO3 (177 mg, 1.3 mmole) in MeOH (2 mL) was stirred at rt for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and a Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((5-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (8 mg, 17%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.27-7.33 (m, 2H), 7.19 (m, 1H), 5.48 (s, 2H), 4.78 (d, J=4.9 Hz, 1H), 4.03 (s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.69 (m, 2H), 1.11-1.31 (m, 4H); LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: CCOC(=O)c1noc(Cc2cccc(Cl)c2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cccc(Cl)c2)n1
Yield: 21 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.115 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.0377 g (21%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-chlorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.Cl[C:35]1[CH:36]=[CH:37][C:38]2[C:39]3[N:56]=[C:55]([C:57]4[CH:58]=[N:59][C:60]([CH3:63])=[CH:61][CH:62]=4)[CH:54]=[C:53]([C:64]([O:66][CH3:67])=[O:65])[C:40]=3[N:41](CC3C=CC(OC)=CC=3)[C:42]=2[CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(OC)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([C:35]2[CH:36]=[CH:37][C:38]3[C:39]4[N:56]=[C:55]([C:57]5[CH:58]=[N:59][C:60]([CH3:63])=[CH:61][CH:62]=5)[CH:54]=[C:53]([C:64]([O:66][CH3:67])=[O:65])[C:40]=4[NH:41][C:42]=3[CH:43]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(-c2ccc(C)nc2)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Reactant: O=S1(=O)CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)nc2)nc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 100 °C
Yield: 72.8 %

Procedure:
A microwave vial containing a mixture of biphenyl-2-yldicyclohexylphosphine (13 mg, 0.037 mmol), thiomorpholine 1,1 dioxide (30 mg, 0.22 mmol), methyl 7-chloro-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (88 mg, 0.186 mmol), potassium phosphate, tribasic (59 mg, 0.28 mmol), and tris(dibenzylideneacetone)dipalladium(0) (8.5 mg, 9.3 μmol) was flushed with nitrogen. DME (0.4 mL) was added and the vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine and the product was captured on an SCX column, washed with EtOAc and MeOH and then removed with 2N NH3 in MeOH and DCM. The solvent was removed and the crude methyl 7-(1,1-dioxido-4-thiomorpholinyl)-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (74 mg). This was dissolved in TFA (5 mL), anisole (0.142 mL, 1.30 mmol) was added, and the reaction was heated at 75° C. for 4 hr. Solvents were removed and the product was captured on an SCX column, washed with MeOH, and released with 2N NH3 in MeOH to leave crude methyl 7-(1,1-dioxido-4-thiomorpholinyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (61 mg). It was suspended in 7 N NH3 in MeOH (7 mL) and heated at 85° C. for 17 hr in a sealed microwave vial. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=100:0 to A:B=40:60 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-(1,1-dioxido-4-thiomorpholinyl)-2-(6-methyl-3-pyridinyl)-5H-pyrido[3,2-b]indole-4-carboxamide (14 mg, 0.031 mmol, 23% yield) as a yellow solid. MS (ESI) m/z 436.10 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1H, br. s.), 9.31 (1H, d, J=2.01 Hz), 8.54 (1H, s), 8.49(1H, dd, J=8.18, 2.39 Hz), 8.35 (1H, s), 8.10 (1H, d, J=8.81 Hz), 7.87 (1H, s), 7.41 (1H, d, J=8.31 Hz), 7.31 (1H, d, J=2.27 Hz), 7.07 (1H, dd, J=8.81, 2.01 Hz), 3.87 (4H, d, J=4.78 Hz), 3.22 (4H, d, J=4.03 Hz), 2.55 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH:21][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2ccc3cc(O)ccc3c2)c1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 3-methoxy-benzylamine (commercially available) according to the procedure described for Example A. MS (m/e): 306.2 (MH−, 100%)
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH2:20][CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.C([N:36]([CH:39]([CH3:41])[CH3:40])[CH2:37]C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C1(CN)CC1>CN(C)C=O>[CH:39]1([N:36]([CH3:37])[C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([CH:21]3[CH2:20][CH2:19][N:18]([C:7]4[N:8]=[C:9]([NH:11][CH:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[C:10]5[S:2](=[O:1])[CH2:3][CH2:4][C:5]=5[N:6]=4)[CH2:23][CH2:22]3)[CH:25]=2)[CH2:40][CH2:41]1
Reactant: O=C(O)c1cccc(C2CCN(c3nc4c(c(NC5CCOCC5)n3)S(=O)CC4)CC2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccc(C2CCN(c3nc4c(c(NC5CCOCC5)n3)S(=O)CC4)CC2)c1)C1CC1
Temperature: 25 °C

Procedure:
59.8 mg 3-{1-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperidin-4-yl}-benzoic acid are placed in 2.3 ml dimethylformamide, then 91 l diisopropylethylamine and 60 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min a mixture of 15.5 mg cyclopropylmethylamine hydrochloride in 300 l dimethylformamide is added. The reaction mixture is stirred at ambient temperature until there is no further reaction, and the product is purified directly by preparative HPLC (method B). 50 mg Example 249 are obtained as a solid. Analytical HPLC-MS (method D): RT=1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])(=[O:13])=[O:12].OC1C2N=NNC=2C=CC=1.[OH:33][CH:34]([CH:37]1[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]1)[CH2:35][NH2:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:33][CH:34]([CH:37]1[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]1)[CH2:35][NH:36][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:15]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)c2)O1
Temperature: -10 °C
Reaction time: 6 h

Procedure:
5.96 g (18 mmol) of 3-[N-(2,4,6-trifluorophenyl)sulfamoyl]-benzoic acid is dissolved in 50 ml of dry dimethylformamide under argon atmosphere, 2.76 g (18 mmol) of hydroxybenzotriazole and 2.9 (18 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine are added and the solution is cooled to -10° C. At this temperature, 3.71 g (18 mmol) of dicyclohexylcarbodiimide is added to the solution. Then it is stirred for 1 hour at -10° C. and 6 hours at room temperature. The turbid reaction solution is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is dissolved in 100 ml of ethyl acetate, the solution is shaken out five times with saturated sodium bicarbonate solution and twice with water, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 4.91 g (10.35 mmol)=57.5% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C[O:20][C:21]1[CH:41]=CC2N=C(NC(=O)CC(=O)C3C=CC=CC=3)SC=2[CH:22]=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:22][C:21](=[O:20])[CH3:41])(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCC(C)=O)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and acetone (II), MS (m/e) 358, 316, 301, 288, 261, 233, 221, 179 and 152; CMR (CDCl3) 207.5, 62.4, 41.4, 34.8, 19.4 and 16 δ.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:4].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[C:21]([NH:20][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Anhydrous citric acid (5 mmoles, 960 mg) and dicyclohexyl carbodiimide (10 mmoles, 2.06 g) were stirred in 30 ml anhydrous tetrahydrofuran for one hour. Dicyclohexylurea crystals formed during the ensuing dehydration reaction were removed by filtration, and the filtrate was dried in vacuo, yielding the dicitrate cyclic diester-containing solid residue.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](O)=[O:31].CN(C)CCCN=C=NCC.O>O1CCCC1>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: CC(C)CCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (0.226 g, 0.645 mmol) in tetrahydrofuran (10.0 mL) was added 4-methylpentanoic acid (0.500 g, 4.30 mmol) followed by (3-dimethylaminopropyl)-ethyl carbodiimide (1.0 mL). The mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried with Na2SO4, concentrated, and the residue was dissolved again in a small amount of ethyl acetate. The solid, which precipitated by dropwise addition of hexane was filtered off and dried in vacuum to give the title product (0.070 g) as a white solid in 24% yield. 1H NMR (300 MHz, CDCl3) δ 9.15, 8.36, 7.74, 7.63, 7.56, 7.36, 7.05, 4.03-3.98, 3.93-3.89, 3.69-3.62, 3.55-3.53, 3.33-3.31, 2.51, 1.63-1.61, 0.91.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][CH3:33])(C)(C)C.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(OC)c3)nc2c1
Temperature: 150 °C
Yield: 7.8 %

Procedure:
NaH (0.12 g, 0.0050 mol, 60% in mineral oil) was added to 4-hydroxy-3-methoxylbenzalde (0.636 g, 4.18 mmol) in anhydrous DMF (15 mL) and then (2-bromoethoxy)-tert-butyl-dimethylsilane (1.0 g, 4.18 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The mixture was extracted with dichloromethane and the combined organic layers were passed through a column to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (170 mg, 13%). 2-Amino-4,6-dimethoxy-benzamide (101 mg, 0.515 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (160 mg, 0.515 mmol), sodium hydrogen sulfite (100 mg, 58.5%) and p-toluenesulfonic acid monohydrate (10 mg) were mixed with N,N-dimethyl acetamide (15 mL) and heated to 150° C. for 16 h. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and further purified by column chromatography to yield 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (15 mg, 7.8%). Selected data: MS (ES) m/z: 373.1; MP 246-248° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([CH3:15])[CH:9]=[C:10]([CH2:11][C:12]([OH:14])=O)[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([C:33]2[N:34]=[C:35]([NH2:38])[S:36][CH:37]=2)[CH:23]=[C:24]([F:32])[C:25]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.ClCCCl>[F:19][C:20]1[CH:21]=[C:22]([C:33]2[N:34]=[C:35]([NH:38][C:12](=[O:14])[CH2:11][C:10]3[C:6]4[C:5](=[O:16])[N:4]([CH3:17])[C:3](=[O:18])[N:2]([CH3:1])[C:7]=4[N:8]([CH3:15])[CH:9]=3)[S:36][CH:37]=2)[CH:23]=[C:24]([F:32])[C:25]=1[O:26][CH2:27][C:28]([F:31])([F:29])[F:30]
Reactant: Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1
Reactant: Cn1c(=O)c2c(CC(=O)O)cn(C)c2n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4cc(F)c(OCC(F)(F)F)c(F)c4)cs3)cn(C)c2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7 (100 mg, 0.398 mmol) with 4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (123 mg, 0.398 mmol) in the presence of EDCI hydrochloride (91 mg, 0.475 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (4 mg, 0.032 mmol) in 1,2-dichloroethane (5 mL) to give 70 mg of the product as an off white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 3.21 (s, 3H), 3.73 (s, 3H), 3.80 (s, 5H), 3.94 (s, 2H), 4.85 (q, J=8.7 Hz, 2H), 6.35 (s, 1H), 7.69 (d, J=9.3 Hz, 2H), 7.82 (s, 1H), 12.55 (br s, 1H, exchangeable with D2O); ESI-MS (m/z) 544.11 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C(=O)([O-])[O-].[K+].[K+].[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1)#[N:29]>O1CCCC1>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=2[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:38])=[O:37])[CH:35]=1)#[N:29]
Reactant: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
To a solution of 0.125 g of ethyl N-[2-(2-aminoethyl)-5-isopropylphenyl]oxalamate in tetrahydrofuran (4 mL)-water (2 mL) were added successively 0.149 g of potassium carbonate and 0.125 g 5-cyano-2-methoxybenzenesulfonyl chloride, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.21 g of ethyl N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]oxalamate.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: N#Cc1csc(Br)n1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C#N)cs3)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared as described for Example 321 from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and 2-bromo-1,3-thiazole-4-carbonitrile (prepared as described in J. Am. Chem. Soc. 1952, 74, 5799).