Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CCO>[CH3:25][N:23]([CH3:24])[C:21](=[O:22])[CH2:20][N:12]([C@@H:7]1[C:8]2[C:4](=[C:3]([C:1](=[NH:2])[NH:27][OH:28])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: NO
Reactant: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C(=N)NO)cccc21
Temperature: 85 °C
Yield: 98.4 %

Procedure:
Prepared using General Procedure 3. To a solution of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-yl(2-(dimethylamino)-2-oxoethyl)carbamate (3.8 g, 11.07 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (1.92 g, 27.67 mmol) and triethylamine (2.8 g, 27.67 mmol). The reaction solution was heated to 85° C. for 2 h. The solvent was removed under vacuum and the residue partitioned between DCM (3×10 mL) and water (10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to produce 4.10 g (87.7%) of (S)-tert-butyl 2-(dimethylamino)-2-oxoethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate, which was 65% pure and used directly in the next experiment. LCMS-ESI (m/z) calculated for C19H28N4O4; 376.45. found 377.2 [M+H]+, tR=1.85 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([CH2:32][O:33][CH3:34])[CH2:29][CH2:30]I)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([CH2:32][O:33][CH3:34])[CH2:29][CH2:30][N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:12]=[CH:13][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:11]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: COC[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: Clc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of 3-(4-Chloro-phenoxy)-azetidine hydrochloride (0.669 g, 3.04 mmol), triethylamine (1.7 ml, 12.16 mmol) and [(S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester (1.0 g, 3.04 mmol) in dimethylformamide (10 ml) is stirred at ambient temperature for 18 hours, then partitioned between ethylacetate and water. The ethylacetate phase is washed with saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 5:95 methanol/dichloromethane) to afford {(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamic acid tert-butyl ester as a clear oil. [MH]+ 385.25.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20](O)=[O:21])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:24][CH2:25][C:26]([CH3:32])([OH:31])[C:27]([F:30])([F:29])[F:28]>>[F:28][C:27]([F:30])([F:29])[C:26]([OH:31])([CH3:32])[CH2:25][NH:24][C:20]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:4]=1)=[O:21]
Reactant: Nc1cc(C(F)(F)F)c(-c2ccc(Cl)cc2Cl)nc1C(=O)O
Reactant: CC(O)(CN)C(F)(F)F
Agent: Cl
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)cc1N)C(F)(F)F

Procedure:
The enantiomers of 3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide were prepared from 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate H) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride analogously to Example 1 and separated by chiral separation using Supercritical Fluid Chromatography:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:32]2[CH:31]=[C:30]([F:29])[CH:37]=[C:36]([F:38])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 525.4(M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][NH:13][C:14](=[O:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-:16].[Na+]>Cl>[OH:16][C:2]1[C:11]2[CH2:12][NH:13][C:14](=[O:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1NCc2c(Cl)nc3ccccc3c21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C1NCc2c(O)nc3ccccc3c21
Temperature: 80 °C
Yield: 88 %

Procedure:
8 g (24.9 mmoles) of Compound 3 was dissolved in 1 litre of 1N HCl and heated to 80° C. for 4 h with stirring. The reaction mixture was then cooled to 0° C., brought to pH 9 with 5N NaOH and extracted with chloroform. The organic extracts were dehydrated with anhydrous sodium sulphate, filtered and evaporated at reduced pressure to give 7 g of Compound 5 (yield 88%). Crystallization from ethyl acetate, gave a pure compound which melted at 245-246° C. 1H NMR (CDCl3): 1.46-1.61 (m, 4H), 2.16-2.23 (m, 5H), 2.43-2.58 (m, 2H), 3.27 (m, 2H), 4.35 (s, 2H), 4.61 (m, 1H), 7.28-7.36 (m, 2H), 7.55 (m, 1H), 8.84 (d, j=8.2, 1H), 10.63 (br s, 1H), MS: m/z 323 (M+, 28).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]5[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:34][CH2:33]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[CH2:49][C:50](Cl)=[O:51]>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:50](=[O:51])[CH2:49][C:45]5[S:44][CH:48]=[CH:47][CH:46]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH2:34][CH2:33]1
Reactant: COc1ccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)cc1N1CCN(CCS(C)(=O)=O)CC1
Reactant: O=C(Cl)Cc1cccs1
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)cc1N1CCN(CCS(C)(=O)=O)CC1
Yield: 47 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-(methyloxy)-3-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)-2-pyrimidinamine using 2-thienylacetyl chloride as described in Example 10, Step E to give a light brown solid in 47% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 4H) 2.7 (m, 3H) 2.9 (m, 4H) 3.0 (s, 3H) 3.7 (s, 3H) 3.9 (s, 2H) 6.4 (d, J=5.1 Hz, 1H) 6.8 (d, J=9.1 Hz, 1H) 7.0 (d, J=4.6 Hz, 2H) 7.1 (t, J=6.6 Hz, 1H) 7.3 (m, 3H) 7.4 (d, J=10.4 Hz, 1H) 7.4 (m, 2H) 7.7 (d, J=8.1 Hz, 1H) 7.9 (s, 1H) 8.2 (d, J=5.5 Hz, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.3 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 723 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:4]2[CH:3]=[CH:2]1.[CH3:18][C:19]1[C:23](B(O)O)=[C:22]([CH3:27])[O:21][N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:18][C:19]1[C:23]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[C:22]([CH3:27])[O:21][N:20]=1
Reactant: O=S(=O)(Oc1ccnc2[nH]ccc12)C(F)(F)F
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccnc2[nH]ccc12
Temperature: 110 °C
Reaction time: 5 h

Procedure:
To a solution of trifluoro-methanesulfonic acid-1H-pyrrolo[2,3-b]pyridin-4-yl ester [4.05 g, Reference Example 18(g)] and 3,5-dimethylisoxazole-4-boronic acid (2.31 g) in dimethylformamide (100 mL) was added tetrakis(triphenylphosphine)palladium[0] (0.1 g) and saturated sodium bicarbonate solution (30 mL). The resulting mixture was stirred at 110° C. for 5 hours. The reaction mixture was cooled and filtered through celite. The filtrate was evaporated to dryness and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate and the combined organic fractions were washed twice with brine (30 mL), then dried over magnesium sulfate and then evaporated to afford the title compound as an orange oil which was used immediately without further purification for the preparation of Reference Example 9(i).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[CH3:32][O:33][C:34](=[O:44])[CH:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH3:32][O:33][C:34](=[O:44])[CH:35]([O:8][C:7]1[C:6]([Br:9])=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:14][CH:15]=2)=[CH:3][C:2]=1[Br:1])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(O)c(Br)c2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: COC(=O)C(Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)cc2)cc1Br

Procedure:
The title compound was prepared from 3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, and 3-phenyllactic acid methyl ester in substantially the same manner, as described in Example 7, and was obtained as a white solid, mp 70–72° C.; MS m/e 713 (M+);
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:14]([F:21])([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1COCC1.[Zn]>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH3:11])[C@@H:9]([OH:10])[C:14]([F:21])([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 44 %

Procedure:
tert-Butyl[(1S)-1-methyl-2-oxoethyl]carbamate (7.21 g) and ethyl bromodifluoroacetate (25.1 g) were dissolved in THF (65 mL), and the solution was added dropwise to a suspension of zinc powder (25.1 g) in THF (14 mL) at room temperature over 30 min. The suspension was heated under reflux for 30 min and cooled to 0° C. A 1 mol/L aqueous hydrochloric acid solution (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extracted organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10→3/10) to give the title compound as a pale-yellow oil (yield: 5.45 g, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: ClCCCOc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: ClCCCOc1ccc(-c2ccncc2)cc1
Yield: 85 %

Procedure:
Following the procedure described in example 24, but starting from 1-bromo-4-(3-chloropropoxy)benzene (2.5 g), potassium carbonate (4.14 g), 4-pyridylboronic acid (1.47 g) and palladium tetrakistriphenylphosphine (116 mg) in toluene (24 mL) affords 2.11 g of 4-[4-(3-chloropropoxy)phenyl]pyridine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][CH2:26][C:27]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:28][CH2:29]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:29][CH:28]=[C:27]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:26][O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: ClCC=C(COCc1ccccc1)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(CC=C(COCc3ccccc3)COCc3ccccc3)c2n1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
A mixture of 1.61 g 2-amino-6-chloropurine (9.5 mmol) and 1.31 g finely ground anhydrous K2CO3 (9.5 mmol) in 50 ml of dry dimethylformamide (DMF) was kept at 100° C. for 5 min. and cooled. At 10° C. the crude 1-benzyloxy-2-benzyloxymethyl-4-chlorobut-2-ene in 25 ml of dry DMF was added with stirring during 4 h. After 2 days at room temperature the mixture was evaporated in vacuum, the residue was extracted with 2×25 ml of chloroform and the extract evaporated to dryness. Chromatography (silica gel, CHCl3 +MeOH 19+1) afforded 0.25 g (18%) of 4-(2-amino-6-chloropurin-9-yl)-1-benzyloxy-2-benzyloxymethyl-2-butene (TLC on silica gel, CHCl3 +MeOH 13+1 parts by volume Rf 0.62).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C.O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:17](=[O:19])[CH3:18]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1

Procedure:
To a cooled mixture of 2-aminoindan (1.2 mol, 160.00 g) in ethyl acetate (1019 mL) at about 5-7° C. was added a solution of Na2CO3 (2.4 mol, 254.65 g) in water (1528 mL) while stirring, followed by the addition of a solution of acetyl chloride (1.32 mol, 109.19 g) slowly over 2 hours. The reaction temperature was maintained below 10° C. by adjusting the addition rate. During the addition, a suspension was formed. After the addition of acetyl chloride, the mixture was stirred at the room temperature for 1 hour. The precipitated solid was collected by vacuum filtration and the filter cake was washed with water (200 mL), EtOAc (200 mL), and air-dried for 48 hours. The first crop of the product was obtained as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[N:4]=1.O(P(O[C:39]1[N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:42][O:43][CH:44]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[Cl-].[Li+]>C1COCC1.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>[CH3:1][O:2][C:3]1[N:4]=[C:5]([C:39]2[N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:42][O:43][CH:44]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2=COCCN2C(=O)OC(C)(C)C)n1
Yield: 29.7 %

Procedure:
A mixture of 2-methoxy-6-(tributylstannyl)pyridine (552 mg, 1.39 mmol) and tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate (300 mg, 0.69 mmol) were dissolved in THF (6 ml). Lithium chloride (90 mg, 2.1 mmol) and Pd(PPh3)4 (78 mg, 0.069 mmol) were added and the mixture heated at reflux for 18 hours. The mixture was concentrated and purified on silica gel, eluting with 0-10% ethyl acetate/petrol. This gave the title compound as a brown solid (60 mg, 30%); 1H-NMR (CDCl3) 1.26 (9H, s), 3.77 (2H, t), 3.92 (3H, s), 4.19 (2H, m), 6.55 (1H, d), 6.76 (1H, d), 6.80 (1H, s), 7.49 (1H, t); MS ES(+) 293.2 (M++1); HRMS m/z calcd for C15H20N2O4+H+ 293.1501 [M+H+]. Found 293.1512. IR λmax=1701 cm−1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1Cl)(=[O:3])[NH2:2].[NH2:19][C@H:20]1[C@@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:22]1[CH2:23][C@H:24]([CH3:25])[C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:21]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2c(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@@H]3C)c(C(N)=O)cnn2c1
Temperature: 100 °C
Yield: 99.6 %

Procedure:
A mixture of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (Intermediate 1, 375 mg, 1.401 mmol), (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (Intermediate 5, 361 mg, 1.541 mmol) and diisopropylethylamine (0.734 mL, 4.20 mmol) in DMA (5 mL) was heated to 100° C. for 3 hr. After cooling, the volatiles were removed in vacuo and the residue was triturated with water. Filtration and drying afforded a tan solid that was rinsed with hexane and redried to afford ethyl 4-(((3S,4S)-1-((benzyloxy)carbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (650 mg, 1.396 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (d, J=7.3 Hz, 1H), 8.34 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.50-7.06 (m, 7H), 5.15-4.96 (m, 2H), 4.81 (d, J=4.8 Hz, 1H), 4.35-4.20 (m, 2H), 3.85-3.63 (m, 2H), 3.45 (dd, J=10.9, 3.4 Hz, 1H), 3.09 (dt, J=16.1, 10.2 Hz, 1H), 2.72-2.58 (m, 1H), 1.34-1.27 (m, 3H), 1.07 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 466.3 (M+H); LC retention time: 3.095 min (analytical HPLC Method O).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([N:6]=[C:7]([N:10]([CH3:19])[N:11]=CC1C=CC=CC=1)SC)=O.[N:20]1([CH2:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.Cl>[CH3:19][N:10]1[C:7]([NH:35][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:36]=[CH:37][C:27]([CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:28][CH:29]=2)=[N:6][C:4]([CH2:3][S:2][CH3:1])=[N:11]1
Reactant: NCCCOc1ccc(CN2CCCCC2)cc1
Reactant: CSCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CSCc1nc(NCCCOc2ccc(CN3CCCCC3)cc2)n(C)n1
Yield: 73.7 %

Procedure:
Methyl N-[2-(methylthio)acetyl]-1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (1.2 g) and 3-[4-(1-piperidinylmethyl)phenoxy]propanamine (0.9 g) were heated at 55° under water vacuum for 2 h. Additional carboximidothioate (0.09 g) was then added and the mixture heated for a further 1 h. The reaction mixture was dissolved in toluene (5 ml) and 5N hydrochloric acid (4 ml), stirred at room temperature for 18 h and the phases separated. The aqueous phase was basified to pH 10 with sodium carbonate and extracted with ethyl acetate to give an oil, which was chromatographed using ethyl acetate-methanol (3:1) to give the title compound (1.04 g) as an orange brown oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCCN)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(CCCNC(C)=O)OCC
Reaction time: 4 h
Yield: 96 %

Procedure:
97 g. of 3-aminopropanephosphonic acid diethyl ester is dissolved in 400 ml. of dry pyridine and 55 g. of acetic anhydride is added with stirring. The mixture is then boiled for 4 hours with refluxing and freed of the low-boiling components by evaporation in a light vacuum. Gaschromatographically pure N-acetyl-3-aminopropanephosphonic acid diethyl ester is obtained in a 96% yield by shortcut distillation in vacuo. It is a pale yellow, highly viscous oil with a boiling point of 166° to 160° C (0.4 Torr).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12]([O:14][CH2:15]C(C)C)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]>CO>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)OC(C)OCC(C)C
Temperature: 60 °C
Yield: 92 %

Procedure:
0.5 g (0.012 mole) of sodium borohydride was suspended in 10 ml of methanol at room temperature. Thereto was added 2.5 g (0.01 mole) of isobutyl (R)-(+)-2-(1-isobutoxyethoxy)propionate with stirring. The resulting mixture was stirred at room temperature for 6 hours but no change was seen. Therefore, the mixture was heated to 60° C. and stirred for 4 hours to give rise to a reaction. The crude reaction mixture was analyzed. As a result, the raw material remained by 7% and the main product included 92% of a title compound formed by conversion (ester exchange) of the raw material isobutyl ester to the corresponding methyl ester, and no 2-(1-isobutoxyethoxy)-1-propanol was detected. After the reaction, 20 ml of water was added, followed by stirring for 0.5 hour. Then, 50 ml of toluene was added and the organic layer was separated. The water layer was subjected to extraction with 20 ml of toluene. The two organic layers were combined and washed with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 1.8 g (yield: 90.8%) of an oily methyl ester compound. The GC−MS spectrum of this compound agreed with that of the compound obtained in Reference Example 5.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:32])[C:11](=[O:31])[CH2:12][N:13]([C:18]1[CH:23]=[C:22]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH2:14][C:15](O)=[O:16].Br.[Br:34][CH2:35][CH2:36][NH2:37].C(N(CC)C(C)C)(C)C>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[N:10]([CH3:32])[C:11](=[O:31])[CH2:12][N:13]([C:18]1[CH:23]=[C:22]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH2:14][C:15]([NH:37][CH2:36][CH2:35][Br:34])=[O:16]
Reactant: NCCBr
Reactant: Cc1nc(-c2ccc(C)c(N(CC(=O)O)CC(=O)N(C)N3Cc4ccccc4C3)c2)no1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccc(C)c(N(CC(=O)NCCBr)CC(=O)N(C)N3Cc4ccccc4C3)c2)no1
Yield: 70 %

Procedure:
Using the compound (1.24 g, 2.85 mmol) of Example 15, step A, 2-bromoethylamine hydrobromide (786 mg, 3.84 mmol), and N,N-diisopropylethylamine (0.70 ml, 4.1 mmol), and according to the method of Example 1, step B, the title compound (1.08 g, yield 70%) was obtained as a colorless solid.