Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]([OH:29])=O)=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:34][CH:32]([CH3:33])[CH2:31][NH:30][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:29]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Reactant: CC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 61.1 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-propyl)-amide (52 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 1-amino-2-propanol (15 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 484.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.93 (bs, 1H), 12.35 (bs, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.73 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.79 (s, 1H), 3.86-3.75 (m, 1H), 3.61 (bs, 3H), 3.29-3.17 (m, 2H), 1.10 (d, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C(O)CCCCCCC.[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCCCO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a mixture of 25.0 g (147 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 1-octanol was added 2.5 g (purity: 98.5%; 14.7 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 80.0 g of pure water and 90.0 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 2.81 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 69.2%) and 8.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][CH:18]=[CH:19]2)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indole-5-carbaldehyde to give the title compound.
Reaction SMILES: C(OC(N1CCC[C@H]1/C=C(/[C:15]1[CH2:21][C@H:20]2N([C:18](=O)[C@@H:19]2[C@H:22]([OH:24])C)[C:16]=1[C:26](OCC=C)=O)\C)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=[O:58])CC(=O)C1>O1CCCC1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:19]([C:22]([OH:58])=[O:24])=[CH:20][CH2:21][CH2:15][CH2:16][CH3:26]
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g) in a mixture of tetrahydrofuran (28 ml) and ethanol (14 ml) were added successively triphenylphosphine (0.51 g), 5,5-dimethyl-1,3cyclohexanedione (dimedone) (1.79 g), and tetrakis-(triphenylphosphine) palladium (0) (220 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with tetrahydrofuran (40 ml) and dissolved in water (150 ml). The solution was washed with ethyl acetate (50 ml×2), concentrated in vacuo and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[b 3.2.0]hept-2-ene-2-carboxylic acid (1.52 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.[CH:25]([C:28]1[C:29]([CH:34]=O)=[N:30][CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:22][C:21]1[C:16]([CH2:15][N:14]([CH2:34][C:29]2[C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][CH:32]=[CH:31][N:30]=2)[C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(CN[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CC(C)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)[C@H]2CC[C@H](N)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of {trans-4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester and 3-isopropyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave the desired amine as a white solid. Conversion to the HBr salt using General Procedure D gave COMPOUND 258 as an off-white solid. 1H NMR (D2O) δ 1.27 (d, 6H, J=7.0 Hz), 1.37-1.65 (m, 4H), 2.09-2.16 (m, 4H), 2.44 (s, 3H), 2.47 (s, 3H), 2.75 (t br, 1H, J=11.4 Hz), 3.16 (t br, 1H, J=11.4 Hz), 3.32 (h, 1H, J=7.0 Hz), 4.28 (s, 2H), 4.39 (s, 2H), 7.90 (dd, 1H, J=7.8, 5.1 Hz), 8.17 (s, 1H), 8.40 (s, 1H), 8.50 (d, 1H, J=7.8 Hz), 8.57 (d, 1H, J=5.1 Hz). 13C NMR (D2O) δ 17.22, 17.48, 22.15 (2), 25.97 (2), 28.28, 29.54 (2), 49.75, 50.31, 50.76, 60.49, 126.60, 137.17, 137.69, 138.19, 138.80, 144.83, 147.32, 148.03, 149.31, 150.12. ES-MS m/z 367 (M+H). Anal. Calcd. for C23H34N4.2.9HBr.1.7H2O: C, 43.72; H, 6.43; N, 8.87; Br, 36.68. Found: C, 43.94; H, 6.40; N, 8.48; Br, 36.43.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=[C:61]3C=2N=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[CH:83]=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.CN(C)[C@@H]1CCNC1>>[CH3:61][N:60]([CH3:59])[C@@H:74]1[CH2:78][CH2:77][N:79]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:3]=2)[CH2:83]1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (BA7) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethylamino)-pyrrolidine. After purification, the compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 624 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:24])([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C.C>C(O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:24])([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: O=P(c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
A mixture of bis(4-methoxyphenyl)phenyl phosphine oxide (59.83 g, 0.1768 mol), 48% hydrobromic acid (400 ml, 3.536 mol), and glacial acetic acid (215 ml) was refluxed for 24 hrs. As the solution cooled to room temperature, the crude product remained in solution. The hydrobromic acid/glacial acetic acid mixture was added to stirred distilled water at room temperature to afford a light pink solid. The crude solid was washed several times in water and dried at ˜105° C. to afford 46.4 g (˜85% yield). The solid was dissolved in ethanol, treated with activated charcoal, and filtered through Celite 545. Distilled water was added to the stirred warm solution until a 50% aqueous ethanol solution was obtained. The mixture was then allowed to cool to ambient temperature. The product was recovered by filtration and dried under vacuum at 50° C. This recrystallization procedure was repeated an additional time to afford 22.66 g (41% yield) of a white solid, DSC (heating rate of 10° C./min) exotherm at 157° C. with sharp peaks at 227 and 233° C. [literature 233–234° C. (A. E. Senear, W. Valent, and J. Wirth J. Org. Chem. 25, 2001, 1960. )]
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([NH:20][CH:21]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[C:22]([NH:24][C:25]3([C:28]([O:30]CC)=[O:29])[CH2:27][CH2:26]3)=[O:23])=[O:19])[N:8]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([NH:20][CH:21]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:40])[F:42])[CH:34]=3)[C:22]([NH:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]3)=[O:23])=[O:19])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(NC(=O)C(NC(=O)Cn2nc(-c3ccc(Cl)s3)n(CCOC)c2=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NC(C(=O)NC2(C(=O)O)CC2)c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
43 mg (68 μmol) of the compound of Example 7 were dissolved in 3 ml of methanol, and 273 μl of a 1M aqueous lithium hydroxide solution (0.27 mmol) were added. The mixture was stirred at RT overnight and then acidified by addition of 1N hydrochloric acid and diluted with water. The precipitated solid was filtered off with suction, washed with a little water and dried in a vacuum drying cabinet at 50° C. This gave 32 mg (74% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:21][C:20](=[O:26])[N:19]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:33][CH:34]=1)[CH3:18])([CH3:25])([CH3:23])[CH3:24]
Reactant: CN(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Yield: 59.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.4 g, 7.6 mmol) was reacted with tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamate (4.2 g, 11 mmol) to afford the desired product (2.1 g, 40%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[Cl:13])[CH:10]=O)=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[Cl:13])[CH:10]=[N:23][OH:24])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C(Cl)=C(C=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(Cl)=C(C=NO)c2ccc(OC)cc2)cc1

Procedure:
30.2 g of 2,3-bis(4-methoxyphenyl)-3-chloro-acrylaldehyde (0.1 mol) were dissolved in 250 ml of pyridine and heated for half an hour on the steam bath together with 30 g of hydroxylamine hydrochloride. Then the solution was evaporated; the remaining solid substance was taken up with ethanol. The whole was boiled, suction-filtered and dried. The 2,3-bis(4-methoxyphenyl)-3-chloro-acrylaldoxime had a melting point of from 207° to 208° C (decomposition). The following compounds were prepared according to the same process:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][C:12]#[CH:13])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[C:15]([OH:20])(=[O:19])[CH2:16][C:17]#[CH:18]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[C:1]([O:5][C:6]([N:7]1[CH2:8][C:9]2[C:12](=[CH:13][CH:18]=[C:17]([CH2:16][C:15]([OH:20])=[O:19])[CH:10]=2)[CH2:11]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN(CC#C)C(=O)OC(C)(C)C
Reactant: C#CCC(=O)O
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(CC(=O)O)cc2C1
Temperature: 0 °C

Procedure:
A mixture of di-prop-2-ynyl-carbamic acid tert-butyl ester (4.78 g, 24.7 mmol) and ethanol (120 mL) was prepared under argon and cooled to 0° C. for 15 min. 3-Butynoic acid (3.64 g, 43.3 mmol) and tris(triphenylphosphine)rhodium (I) chloride (1.14 g, 1.23 mmol) were added and reaction was gradually warmed to room temperature over 1.3 hr. The reaction was then heated to 45° C. for 17 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with 1N NaOH and extracted with diethyl ether (3×). The aqueous layer was acidified to pH˜1 with 1N HCl and extracted with EtOAc (3×). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc:Hexane, 5-100%). ESI-MS m/z 278 (MH)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([Br:23])[CH:25]=3)[C:8]=2[N:9]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(Cc3cccc(Br)c3)c2n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 38 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.65 mmol). The mixture was heated at 50° C. for 20 minutes resulting in a clear solution. The heating mantle was removed, and 3-bromobenzyl bromide (240 μL, 0.96 mmol) was added. After 10 minutes, the reaction mixture was poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate, then dried in vacuo to provide 178 mg (58%) of 2-amino-8-(3-bromobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp softens at 195° C., melts at 215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:39])[NH:7][C:8]([CH:12]([N:18]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:39])[N:7]([CH2:40][C:41]3[CH:48]=[CH:47][CH:46]=[C:43]([CH3:44])[CH:42]=3)[C:8]([CH:12]([N:18]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)[nH]2)cc1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate (29 mg, 1 eq.) in dimethyl formamide (1 ml), was added 3-methylbenzyl bromide (8 μl, 1.2 eq.) and potassium carbonate (22 mg, 3 eq.). The reaction mixture was stirred at room temperature overnight. Water was added and the material was extracted into ethyl acetate. Ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated. The product was purified by flash chromatography to give tert-butyl 3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[NH:11][N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:14]=1)=[O:8].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[N+:26]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[NH:11][N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:14]=1)=[O:8])([O-:28])=[O:27]
Reactant: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-yl)benzamide (120 mg, 0.29 mmol, 1.00 equiv) in N,N-dimethylformamide (1 mL) was added piperidine (1 mL) and the resulting solution was stirred for 2 h at 100° C. in an oil bath. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 130 mg (97%) of product as yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[CH:30]=[C:31](/[CH:36]=[CH:37]/B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:33]([F:35])[CH:34]=1>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.O>[F:28][C:29]1[CH:30]=[C:31](/[CH:36]=[CH:37]/[C:2]2[N:7]=[N:6][C:5]3[O:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[O:11][C:4]=3[CH:3]=2)[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: CC1(C)OB(/C=C/c2cc(F)cc(F)c2)OC1(C)C
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
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
Solvent: O
Product: Fc1cc(F)cc(/C=C/c2cc3c(nn2)Oc2ccccc2O3)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Under an argon atmosphere, to 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (500 mg) were added 1,2-dimethoxyethane (7.5 ml), 2M aqueous sodium carbonate solution (3.0 mL), 2-[(E)-2-(3,5-difluorophenyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (720 mg) and tetrakis(triphenylphosphine)palladium (130 mg). The reaction mixture was stirred at 100° C. for 3 hr and cooled to room temperature. Water was added, and the obtained solid was collected by filtration and dried under reduced pressure to give 3-[(E)-2-(3,5-difluorophenyl)vinyl][1,4]benzodioxino[2,3-c]pyridazine (700 mg).
Reaction SMILES: C(OC(P(O)(O[C@@H](CCCCNC(OCC1C=CC=CC=1)=O)C([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=O)=O)CC1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCC(C)(C)C([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27]
Reactant: O=C(NCCCC[C@H](OP(=O)(O)C(Cc1ccccc1)OC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(CCCl)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reaction time: 8 h

Procedure:
1-[(S)-2-[[[1-(Benzoyloxy)-2-phenylethyl]hydroxyphosphinyl]oxy]-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester from Example 5(d) is suspended in dry dimethylformamide and treated with chloromethylpivalate. After several hours, additional chloromethylpivalate and anhydrous potassium carbonate are added and the resulting mixture is stirred overnight. The mixture is then diluted with ethyl acetate and washed successively with water, 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride solution, dried (Na2SO4), and evaporated. The residue is purified by flash chromatography (silica gel) to give 1-[(S)-2-[[[(2,2-dimethyl-1-oxopropoxy)methoxy][1-(benzoyloxy)-2-phenylethyl]phosphinyl]oxy]-1-oxo]-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.CON(C)[C:12](=[O:14])[CH3:13]>C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:12](=[O:14])[CH3:13])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CON(C)C(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
A round bottomed flask was charged with 5-bromo-2-chloropyridine (5.30 g, 27.6 mmol) in THF under N2 and cooled at 0° C. A solution of 1 M iso-propylmagnesiumchloride-lithium chloride complex in THF (40 mL) was added drop wise over 15 min. After 70 min N-methoxy-N-methylacetamide (4.1 mL, 38 mmol) was added drop wise. After stirring for 5 min at 0° C. the cooling bath was removed. The mixture was left stirring overnight and was then quenched by the addition of 100 mL saturated aqueous NH4Cl solution. The mixture was extracted with 3×100 mL EtOAc. The combined organic layers were washed with water followed by brine and dried over MgSO4. Evaporation of the volatiles at 80° C. 10 mbar for 1 h gave the title compound (3.596 g, 84) sufficiently pure for the next step.