Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH:15][C:16]([N:18]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[O:17])=[N:12][CH:11]=1)(=[O:9])=[O:8])C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC1C=C(C=CC=1F)N.C1(C=O)CCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:28]1([CH2:27][N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[C:16](=[O:17])[NH:15][C:13]2[S:14][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:33])=[O:3])(=[O:8])=[O:9])=[CH:11][N:12]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: Nc1ccc(F)c(F)c1
Product: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester the latter prepared in a similar manner as (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:17]=2[CH3:33])[OH:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:42]([NH2:45])(=[O:44])[CH3:43]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([CH:14]([OH:15])[C:4]3[CH:3]=[C:2]([NH:45][C:42](=[O:44])[CH3:43])[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[CH:5]=3)=[C:17]([CH3:33])[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:19]2)=[CH:24][CH:23]=1
Reactant: CC(N)=O
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(Cl)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(C(O)c2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure W by stirring palladium (II) acetate (1.5 mg, 6.70 μmol), tetramethyl tert-butyl XPhos (9.7 mg, 0.020 mmol), (3-chloro-5-morpholinophenyl)(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)methanol (0.031 g, 0.067 mmol), tripotassium phosphate (0.020 g, 0.094 mmol), acetamide (4.8 mg, 0.080 mmol), and tert-butanol (0.9 mL) at 110° C. for 1 hour. Purification by reverse-phase HPLC afforded N-(3-((7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)(hydroxy)methyl)-5-morpholinophenyl)acetamide as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (1H, s), 8.70 (1H, d), 8.39 (1H, m), 8.02 (1H, t), 7.80 (1H, d), 7.70 (1H, d), 7.52 (1H, m), 7.39 (1H, t), 7.32 (1H, s), 6.87 (1H, s), 6.60 (1H, s), 6.52 (1H, d), 6.48 (1H, s), 3.72 (4H, t, J=4.7 Hz), 3.03 (4H, d, J=3.3 Hz), 2.47 (3H, s), 1.91 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].Br[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Reactant: CC(C)(C)C(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)C(C)(C)C)CC3)c2n1
Temperature: 70 °C
Reaction time: 76 h
Yield: 32 %

Procedure:
To a stirred mixture of 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 4, Step 4, 150 mg, 0.446 mmol) and 1-bromo-3,3-dimethylbutan-2-one (72 μL, 0.670 mmol) in N,N-dimethylformamide (4.4 mL) were added sodium iodide (67 mg, 0.670 mmol) and triethylamine (0.156 mL, 1.12 mmol). The reaction mixture was stirred at 70° C. for 76 h. After removal of solvent, the residue was dissolved in ethyl acetate (100 mL), and washed with aqueous sodium bicarbonate (5 mL) and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Flash column chromatography (NH-silica gel) of the residue eluting with hexane/ethyl acetate (9:1 to 1:1) afforded a pale brown solid, which was recrystallized from ethyl acetate to afford 62 mg (32%) of the title compound as off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C>CO>[O:11]=[C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:10][CH2:9][CH2:8][CH:7]1[C:16]([O:15][CH3:14])=[O:17]
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2sccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCc2sccc2C1=O

Procedure:
To a solution of 5,6,7,8-tetrahydro-cyclohepta[b]thiophen-4-one (0.84 g, 5 mmol), prepared by the method of M. P. Cagniant (Bull. Soc. Chim. France, 1956, 1152-1163), in dimethylcarbonate (6 mL) was added a 60% dispersion of sodium hydride in oil (0.4 g, 10 mmol) and a few drops of dry methanol. The reaction mixture was heated at reflux for 4 hours, then cooled, quenched with 2 N hydrochloric acid solution, and the desired product was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and chromatographed on silica gel, eluting with 20% ethyl acetate:hexane to provide the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, J=5.42 Hz, 1H,), 7.28 (d, J=5.42 Hz, 1H), 4.04 (dd, J=10.8, 3.39 Hz, 1H), 3.66 (s, 3H), 3.80 (m, 4H), 3.14 (m, 2H); MS (DCI/NH3) m/z 225 (M+H)+, 242 (M+NH4)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:1]1([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccccc3)c21
Yield: 23.5 %

Procedure:
Using Method S above, phenyl boronic acid (86 mg, 0.70 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.47 mmol) (Starting Material 7) using (Ph3P)4Pd (27 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.47 mL, 0.94 mmol) and DME (10 mL) at reflux for 2 days to give (Z)-1,3-dihydro-4-phenyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 35 mg, 23%).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:37])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[C:31]1([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][C:16]([F:37])([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=3)[CH2:21][CH2:20]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: [H][H]
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCN(CCC(c2ccccc2)c2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Oc1cccc(C2(F)CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Yield: 64 %

Procedure:
A solution of 4-(3-benzyloxyphenyl)-1-(3,3-diphenyl-propyl)-4-fluoropiperidine hydrochloride (40 mg, 0.08 mmol) in methanol (5 mL) was treated with palladium on carbon (10 mg, 10% Pd, 50% H2O) and the mixture rapidly stirred under 1 atmosphere of hydrogen gas for 8 hours. After this time the hydrogen was replaced by nitrogen and the reaction mixture filtered through a celite pad. The pad was washed with additional methanol (10 mL) and the filtrate concentrated under reduced pressure. Trituration of the residue with a 1:1 mixture of 2-butanone/ethyl acetate (10 mL) and subsequent filtration and drying afforded a 64% yield of 1-(3,3-diphenylpropyl)-4-fluoro-4-(3-hydroxyphenyl)piperidine hydrochloride as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:49][C@:50]1([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52][C@H:51]1[CH:53]=[CH2:54]>C(Cl)Cl.[Au]>[C:2]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([OH:16])[CH2:11][C@H:12]1[C:13]([NH:49][C@:50]1([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52][C@H:51]1[CH:53]=[CH2:54])=[O:15])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: [Au]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 94 %

Procedure:
A stirred slurry of Boc-L-4-hydroxyproline (N-Boc (2S,4R)-hydroxyproline) (10 g, 43.3 mmol) in 400 mL of methylene chloride was treated sequentially with N-methyl morpholine (9.3 mL, 84.7 mmol), HATU (19.5 g, 51.3 mmol), and ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate hydrochloride (9.1 g, 47.5 mmol). The gold homogeneous solution was stirred at rt under N2 for 18 h, and then concentrated in vacuo to give a brown oil. This was partitioned between ethyl acetate and sat. aq. NaHCO3. The organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo to give 15 g (94%) of ethyl 1(R)-[1-tert-butoxycarbonyl-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate as a off-white solid: LC-MS (Xterra HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 3 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.09 min), MS m/z 369 (M++1).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[CH:26]=[N:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][N:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.87 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.5 g, 8.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.25 g, 2.1 mmol) was added and stirred for further 5 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch) then further purified through preparative TLC to provide the desired compound as yellow solid (0.05 g, 16% yield). 8-Isopropyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.143 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.018 g, 0143 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.02 g, 32% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C@H:61]1([C:68](O)=[O:69])[CH2:64][C@@H:63]([C:65]([OH:67])=[O:66])[CH2:62]1>CN(C=O)C.O.C(#N)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:68]([C@@H:61]2[CH2:64][C@H:63]([C:65]([OH:67])=[O:66])[CH2:62]2)=[O:69])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
HATU (82 mg, 0.22 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (70 mg, 0.18 mmol), DIEA (0.061 mL, 0.36 mmol) and cis-cyclobutane-1,3-dicarboxylic acid (78 mg, 0.54 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (29.7 mg, 0.057 mmol, 32.1%) as a white solid.
Reaction SMILES: [C:1]([NH:5]C(NCC1C=C(C2C=CC=C(C=O)C=2OCOCCOC)C(OCOCCOC)=CC=1)=O)(C)(C)C.Cl.[NH2:39][C:40]1[C:41](N)=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH2:45])=[NH:44].C1(=O)C=CC(=O)C=C1>CO>[NH:5]1[C:48]2[CH:47]=[CH:46][C:42]([C:43]([NH2:45])=[NH:44])=[CH:41][C:40]=2[N:39]=[CH:1]1
Reactant: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC
Reactant: N=C(N)c1cccc(N)c1N
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: N=C(N)c1ccc2[nH]cnc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl-3-[3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea (0.6 g, 1.15 mmol), prepared as in Reference 19, diaminobenzamidine hydrochloride (0.3 g, 1.6 mmol) and 1,4-benzoquinone (0.124 g, 1.15 mmol) were combined in methanol (15 mL) and the mixture was heated at 60° C. and stirred for 2 hours. The mixture was cooled to room temperature and the solvent was removed by evaporation to yield 2-[5′-3-tert-butylureidomethyl)-2,2′- bis-(2-methoxyethoxymethoxy)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[N:9]1([C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:17]=[C:16]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[N:9]1([C:14]2[N:15]=[C:16]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:22][CH2:21]3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OCCCCCCBr
Reactant: C1CCN(c2nc(N3CCCC3)nc(N3CCNCC3)n2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1

Procedure:
A mixture of 6-bromohexanol (0.905 g), 2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)-1,3,5-triazine (PCT 86/01797, PREPARATION A-45, 1.517 g), potassium carbonate (0.346 g) and sodium iodide (0.075 g) in acetonitrile (165 ml) are stirred under reflux for 4.5 hr. The mixture is concentrated and the residue is partitioned between methylene chloride and potassium bicarbonate (1N). The phases are separated, the organic phase is washed with water and saline, then filtered through sodium sulfate and concentrated. The residue is chromatographed on silica gel (230 g) packed in methanol/methylene chloride (5/95). Elution is performed with 5% methanol/methylene chloride (3 l) followed by 10% methanol/methylene chloride (2 l). 50 ml fractions are collected, fractions 61-78 are pooled and concentrated to give the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl-].[Ti+4:8].[Cl-].[Cl-].[Cl-].[Ti].[NH4+].[OH-].[C:15]([OH:20])(=[O:19])[CH:16]([CH3:18])[OH:17]>C([O-])(=O)C(C)O.[Zr+4].C([O-])(=O)C(C)O.C([O-])(=O)C(C)O.C([O-])(=O)C(C)O.O>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Ti+4:8].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[C:15]([O-:20])(=[O:19])[CH:16]([CH3:18])[OH:17].[Ti+4:8].[C:15]([O-:20])(=[O:19])[CH:16]([CH3:18])[OH:17].[C:15]([O-:20])(=[O:19])[CH:16]([CH3:18])[OH:17].[C:15]([O-:20])(=[O:19])[CH:16]([CH3:18])[OH:17]
Reactant: CC(O)C(=O)O
Reactant: O=C(O)C(=O)O
Agent: [Ti+4]
Agent: [Ti]
Agent: [Zr+4]
Solvent: O
Product: O=C([O-])C(=O)[O-]

Procedure:
A precipitate of zirconium lactate was prepared by mixing an aqueous solution of 0.3 mole zirconium oxychloride (ZrOCl2) assaying 17.9% ZrO2 with 0.9 mole of lactic acid (H6C3O3). The resulting thick slurry was filtered and the precipitate was washed with distilled water and reslurried therein. To the second slurry, which had a pH of about 1.85, there was slowly added 0.1 mole calcium oxide with stirring. During this addition, the pH increased and was finally adjusted to 7.5 by addition of NH4OH. The calcium ammonium trilactatozirconate formed was completely soluble in the water present. A solution of titanium oxalate was prepared by stirring 0.15 mole of oxalic acid into 100 ml of an aqueous titanium chloride solution containing approximately 0.1 gram atom of titanium. Sufficient water was added to ensure complete solution of the oxalic acid. This solution was run into about 4 times its volume of water simultaneously with a 50% NH4OH solution at such a rate as to maintain the pH of the mixture at 9.0. The resulting precipitate was filtered and washed with distilled water and was then dissolved in 0.37 mole of lactic acid (H6CO3), as an 85% aqueous solution, to form a titanium lactate solution.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[CH:4]=1)=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.C(OCC)(=O)C>[CH3:11][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[C:8]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:10]
Reactant: C1COCCN1
Reactant: Cc1cc(C=O)[nH]c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cc(C=O)[nH]c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (306.3 mg, 2 mmol) in DMF (5 mL) was added HOBt (324.3 mg, 2.4 mmol), EDC (460.1 mg, 2.4 mmol) and then morpholine (0.21 mL, 2.4 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was diluted with ethyl acetate and washed with sodium bicarbonate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried, concentrated and column chromatographed (MeOH/DCM) to give 395 mg (89%) of 4-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde as a light yellow foam solid. 1H NMR (360 MHz, DMSO-d6) δ 12.18 (br s, 1H, NH), 9.46 (s, 1H, CHO), 6.79 (s, 1H), 3.43 (m, 4H, 2×CH2), 2.29 (m, 4H, 2×CH2), 2.17 (s, 3H, CH3), 2.01 (s, 3H, CH3).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(OCC)=O.C(=O)([O-])[O-].[K+].[K+].BrC[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:1][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: BrCc1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: O=C1CCCCC1Cc1ccco1

Procedure:
2-carboethoxycyclohexanone, finely powdered potassium carbonate, 2-bromomethyl furan, and tetrabutylammonium iodide are reacted by the method of Example 38 to generate the title material.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[C:12]([I:14])[C:11]([OH:15])=[C:10]([I:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl[CH2:18][C:19]([CH3:21])=[CH2:20].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.[Na+].[I-]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O:15][CH2:20][C:19]([CH3:21])=[CH2:18])=[C:12]([I:14])[CH:13]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2cc(I)c(O)c(I)c2)CC1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1c(I)cc(C2(C(=O)OC)CC2)cc1I
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of 1-(4-hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid methyl ester (3.2 g, 7.2 mmol), 3-chloro-2-methyl-propene (1.0 g, 11 mmol), K2CO3 (1.2 g, 8.6 mmol), NaI (0.1 g, 0.7 mmol) in acetone (20 mL) was stirred at 20° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum to give 1-[3,5-diiodo-4-(2-methyl-allyloxy)-phenyl]-cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 2 H), 5.26 (s, 1 H), 5.06 (s, 1 H), 4.38 (s, 2 H), 3.65 (s, 3 H), 1.98 (s, 3H), 1.62-1.58 (m, 2 H), 1.18-1.15 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.[F-].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.CN(C=O)C>[CH2:61]([O:60][C:58]([C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1)=[CH2:59])[CH3:62]
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1.34 g, 5.59 mmol) was added DMF (8 mL), dioxane (48 mL), cesium fluoride (2.55 g, 16.78 mmol), X-Phos (0.258 g, 0.559 mmol), palladium (II) acetate (0.126 g, 0.559 mmol), and tributyl(1-ethoxyvinyl)stannane (2.64 mL, 7.83 mmol) (Aldrich), and the resulting mixture was stirred at 110° C. for 1.5 h. The reaction mixture was cooled to ambient temperature and purified via flash chromatography (neutral alumina) with 100% DCM (to remove the stannane), then 100% EtOAc to give the title compound (>99% yield). m/z (ESI, +ve ion) 276.0 (M+H)+.