Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH:18]([CH3:20])[CH3:19])=[C:10]([CH2:12][C:13]([O:15]CC)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+]>O>[C:1]1([C:7]2[O:8][C:9]([CH:18]([CH3:20])[CH3:19])=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)oc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1oc(-c2ccccc2)nc1CC(=O)O
Yield: 97.6 %

Procedure:
2.73 g of ethyl 2-(2-phenyl-5-isopropyl-4-oxazolyl)acetate, 20 ml of methanol, 5 ml of water and 1.1 g of potassium hydroxide are treated in the same manner as described in Example 8. 2.39 g of 2-(2-phenyl-5-isopropyl-4-oxazolyl)acetic acid are thereby obtained. Yield: 97.4%.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH2:18][O:19][CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][CH2:18][C:8]1[O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:7]=1[CH:2]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-(methoxymethyl)-5-phenylfuran (439 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 60% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (63 mg, 9%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH2:8][C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:4][C:5]([OH:7])=[O:6].[CH3:13]C#N>>[NH2:1][CH2:2][C@@H:3]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH2:11][CH3:13])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC[C@@H](C)C[C@H](CN)CC(=O)O
Reactant: CC#N
Product: CCC[C@H](C)C[C@H](CN)CC(=O)O

Procedure:
A procedure similar to the preparation of example 10 (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid was followed giving example 11. 380 mg; 29.0%. 1H NMR (CD3OD) δ 2.90 (dd, J=3.9, 8.8 Hz, 1H), 2.80 (dd, J=7.6, 5.1 Hz, 1H), 2.40 (dd, J=3.2, 12.51 Hz, 1H), 2.20 (dd, J=8.8, 6.8 Hz, 1H), 2.05 (m, 1H), 1.55 (m, 1H), 1.30 (m, 3H), 1.10 (m, 2H), 0.85 (m, 6H); MS, m/z (relative intensity): 187 [M+1H, 100%], 211 [M+1H+CH3CN, 30%].
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]1[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.CO[CH:36]1[CH2:40][CH2:39][CH:38](OC)O1>C(O)(=O)C>[CH3:1][C:2]1([CH3:33])[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:36]=[CH:40][CH:39]=[CH:38]3)=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]1[CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: COC1CCC(OC)O1
Reactant: CC1(C)c2ccc(N)cc2S(=O)(=O)N1CCCN1CCN(c2cccc3ccccc23)CC1
Solvent: CC(=O)O
Product: CC1(C)c2ccc(-n3cccc3)cc2S(=O)(=O)N1CCCN1CCN(c2cccc3ccccc23)CC1
Yield: 86 %

Procedure:
The pyrrole ring was assembled by reacting 3,3-dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)prop-1-yl]-6-amino-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide with 2,5-dimethoxytetrahydrofuran in glacial acetic acid at 100° C. (1 h) in 86% yield.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:13]([OH:16])[CH2:14][CH3:15])[C:10]([O-:12])=[O:11])=O)(C)(C)C>Cl>[NH2:8][C@H:9]([C@@H:13]([OH:16])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CC[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: Cl
Product: CC[C@H](O)[C@@H](N)C(=O)O
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
In a 35 ml microwave vial, the diastereomeric mixture containing ethyl (2R*,3R*) and (2R*,3S*)-2-(tert-butoxy-carbonylamino)-3-hydroxy-pentanoate (0.2 g, 0.81 mmol) was dissolved in a 6.0 M HCl solution (15 mL) and stirred at 130° C. for 30 min. The reaction mixture was concentrated under reduced pressure giving a yellowish solid crude product, as a diastereoisomeric mixture (anti:syn=8:2), which was used without further purification in the following step. MS (ESI) m/z: 134 [M−H]+; (ESI) m/z: 132 [M−H]−. 1H NMR (DMSO-d6) δ 0.92 (t, J=7.36 Hz, 3H), 1.42-1.64 (m, 2H), 3.80 (ddd, J=3.25, 5.80, 11.72 Hz, 1H), 3.86 (d, J=3.02 Hz, 1H), 4.36 (s, 1H), 8.26 (s, 3H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:19][CH2:20][CH3:21])(=O)C>Cl>[OH:19][C:20]1[CH:21]=[C:3]2[C:2]([CH:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:12][C:13](=[O:15])[O:14]2)=[CH:1][CH:10]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Reactant: CCOC(C)=O
Agent: Cl
Product: O=C1CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Reaction time: 8 h

Procedure:
A mixture of 3-(1-naphthyl)acrylic acid (50.0 g., 0.25 moles) in concentrated hydrochloric acid (1500 ml.) was stirred at reflux while a vigorous stream of hydrogen chloride was passed through the reaction for 6 hours. The solution was allowed to stand overnight at room temperature, then filtered to give a white solid which was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3×). The ethyl acetate solution was dried and removal of solvent gave the dihydrocoumarin as a white solid (43.5 g., 85% based on consumed starting material) m.p. 193°-196° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([N:11]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[N:28]=[CH:29][NH:30][C:26]=2[CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[N:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C@H:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:33])=[O:5])=[CH:25][C:26]=2[NH:30][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc3nc[nH]c3c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccc3nc[nH]c3c2)[C@@H](C(=O)O)C(C)C)cc1
Yield: 86.5 %

Procedure:
A solution of 2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid tert-butyl ester (74 mg, 0.156 mmol) in a 1:4 trifluoroacetic acid/methylene chloride mixture (5 mL) was stirred for 2 h. The reaction mixture was concentrated on a roto-evaporator and then on high-vac pump to give 2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid (approx. 0.135 mmol).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]#[N:30])=[CH:26][C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.[Li+].[BH4-]>O1CCCC1.O>[NH2:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:33])[N:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:32])(=[O:31])[C:20]=2[CH:26]=1
Reactant: N#CCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A solution of the product of Example 392A (39 mg, 0.084 mmol) in anhydrous tetrahydrofuran (2 mL) was treated with LiBH4 (1mL, 2M in tetrahydrofuran, 0.2 mmol), stirred at ambient temperature for 30 minutes, then 18 μl water was added and stirred overnight. The solution was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The slurry was filtered and the solvent removed under reduced pressure to give title compound (38 mg, 97%). 1H NMR (500 MHz, BENZENE-d6) δ 0.20 (d, J=3.05 Hz, 2 H) 0.46 (d, J=7.32 Hz, 2 H) 1.01 (m, 1 H) 2.74 (s, br, 2 H) 2.86 (m, 2 H) 4.19 (t, J=4.90 Hz, 2 H) 5.21 (s, br, 2 H) 6.04 (s, br, 1 H) 7.15 (s, br, 1 H) 7.24 (s, br, 2 H) 7.32 (s, br, 1 H) 7.59 (s, br, 1 H) 7.78 (s, br, 1 H) 8.11 (d, J=7.32 Hz, 1 H) 15.65 (s, br, 1 H). MS (ESI−) m/z 468 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[N:22]=[C:23]([NH2:26])[S:24][CH:25]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[N:22]=[C:23]([NH:26][C:13]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=[CH:11][CH:10]=2)=[O:15])[S:24][CH:25]=1)[CH3:17]
Reactant: O=C(O)c1cccn1Cc1ccccc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2cccn2Cc2ccccc2)n1
Yield: 65 %

Procedure:
(2-{[1-(Benzyl)-1H-pyrrole-2-carbonyl]-amino}-thiazol-4-yl) acetic acid ethyl ester (60 mg) was prepared from 1-benzyl-pyrrole-2-carboxylic acid (50 mg, 0.25 mmol) and 2-aminothiazol-4-yl acetic acid ethyl ester (47 mg, 0.25 mmol) following general procedure F.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8].C(O)C.[NH2:20][NH2:21]>O>[F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([NH:20][NH2:21])=[O:8]
Reactant: COC(=O)c1ccccc1OCC(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccccc1OCC(F)(F)F

Procedure:
Methyl 2-(2,2,2-trifluoroethoxy)benzoate (1.22 g. 5.2 mmole), ethanol (15 ml.) and 5 ml. of 95 per cent hydrazine (4.75 g., 158 mmole) are refluxed for two hours, cooled, diluted with water (100 ml.) and cooled. The white solid product, 2-(2,2,2-trifluoroethoxy)benzoic acid hydrazide is recrystallized from ethanol, m.p. 102°-104°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[CH3:24]/[C:25](=[CH:29]\[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:26](Cl)=[O:27]>CC(C)=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:26](=[O:27])/[C:25](/[CH3:24])=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C/C(=C\c1ccccc1)C(=O)Cl
Reactant: Nc1cc(OCCN2CCCCC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C/C(=C\c1ccccc1)C(=O)Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-chloro-5-(2-piperidinoethoxy)aniline (705 mg, 3.9 mmol, 1 eq.) was placed in a mixture of acetone (653 μL) and water (852 μL) in the presence of K2CO3 (1.1 g, 7.8 mmol, 2 eq.). (E)-2-methyl-3-phenylacryloyl chloride (705 mg, 3.9 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford (E)-N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)-2-methyl-3-phenylacrylamide (500 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.C(OC(=O)C)(=[O:15])C>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2cc(F)ccc21
Product: O=c1ccc2cc(F)ccc2[nH]1
Reaction time: 8 h

Procedure:
A solution of 6-fluoroquinoline 1-oxide from Step B (5.0 g, 30.65 mmol) in acetic anhydride (30 mL) is heated at 110° C. for 6.5 hours. The reaction is allowed to stand at room temperature overnight. The solid (1.1 g) is collected and recrystallized from anhydrous ethanol (75 mL). The reddish crystals are collected by filtration and dried under high vacuum to give the title compound (0.653 g), m.p. dec. 269–270° C.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][C:21]#[C:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][CH2:8]1)([OH:4])([OH:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[O-:46][P:47]([O:50][P:51]([O-])([O-:53])=[O:52])(=[O:49])[O-:48].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][C:21]#[C:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][CH2:8]1)([O:3][P:51]([O:50][P:47]([OH:49])([OH:48])=[O:46])([OH:53])=[O:52])(=[O:4])[OH:2]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Reactant: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Without being limiting in any way, monophosphate (6) can optionally be formed by treatment of 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′dideoxyuridine (5) with, for example, POCl3. 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′-dideoxyuridine-5′-monophosphate (6) can then optionally be treated with, for example, carbonyldiimidazole (CDI) followed by tetrabutylammonium pyrophosphate (TBAPP) under appropriate conditions to form 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′-dideoxyuridine-5′-triphosphate (7). It will be recognized by one of skill in the art that conversion of 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′dideoxyuridine (5) to triphosphate (7) can be accomplished by any method known in the art.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6′-bromo-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine] (89 mg, 0.33 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (90 mg, 0.33 mmol) and hydrochloric acid in 1,4-dioxane (83 μL, 0.330 mmol) in NMP (2.0 mL) and heating in the microwave at 150° C. for 2 h. After purification 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] was obtained as a yellow film. Mass Spectrum (ESI) m/e=505 [(M+1) (79Br)] and 507 [(M+1) (81Br)].
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:62])[N:54]([CH3:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:62])[N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C(=O)OCCCBr)c1ccccc1
Product: CCCCc1nn(CCCOC(=O)N(C)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 86 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with 3-bromopropyl-N-methyl-N-phenylcarbamate was carried out as described in Example 3, Step A, except that only 2.4 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (35 mL for 0.162 mmole, gradient elution using 0.75-2.5% MeOH/CH2Cl2) to give the desired material as a white foam in 86% yield, mass spectrum (FAB) 809 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:25][N:26]1[C:30]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:35][C:32]5[CH:33]=[CH:34][C:29]6[N:28]=[CH:27][N:26]([CH3:25])[C:30]=6[CH:31]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Reactant: Cn1cnc2ccc(N)cc21
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)CC6CC6)c5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (50.0 mg, 0.340 mmol) at 105° C. for 90 h to afford the title compound. Yield of TFA salt: 25 mg (22%) of brown powder; LC/MS: 459 (M+H); HPLC: 97% pure, RT=2.49 min; 1H NMR: (DMSO, δ) 10.01 (s, 1H), 9.24 (s, 1H), 9.12 (s, 1H), 8.55 (m, 2H), 8.27 (s, 1H), 7.92 (d, J=7.8, 1H), 7.85 (t, J=7.8, 1H), 7.79 (d, J=9.0, 1H), 7.74 (d, J=9.0, 1H), 7.32 (d, J=4.7, 1H), 7.06 (d, J=4.7, 1H), 3.79 (s, 3H), 3.29 (d, J=7.0, 2H), 0.83 (m, 1H), 0.41 (m, 2H), 0.07 (m, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([NH:11][NH2:12])=[O:10])[CH2:2]2.[C:13](OCC)(OCC)(OCC)[CH3:14]>>[CH3:13][C:14]1[O:10][C:9]([CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[N:11][N:12]=1
Reactant: NNC(=O)C1CN2CCC1CC2
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(C2CN3CCC2CC3)o1
Temperature: 140 °C
Yield: 72 %

Procedure:
(±) 1-Azabicyclo[2.2.2]octane-3-carboxylic acid hydrazide (D8) (0.36 g; 2.1 mmoles) and triethyl orthoacetate (3 ml) were heated at 120° C. for 2 h. Excess triethyl orthoacetate was evaporated in vacuo and the residue was heated for a further 2 h at 140° C. The reaction was diluted with water (10 ml), saturated with potassium carbonate and extracted into ether (3×15 ml). Combined organic extracts were dried (Na2SO4) and concentrated to give the title compound as an oil (0.29 g; 72%), which was purified as the oxalate salt. m.p. 147°-8° (Acetone-methanol).
Reaction SMILES: C(OC([N:11]([CH2:28][C:29]([N:31]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]1[C:37]#[N:38])=[O:30])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:22]3[CH2:27][CH2:26]C[CH2:24][CH2:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>C(O)C.ClCCl.[C].[Pd]>[N:22]1([C:20]([C:15]23[CH2:18][CH2:19][C:12]([NH:11][CH2:28][C:29]([N:31]4[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]4[C:37]#[N:38])=[O:30])([CH2:13][CH2:14]2)[CH2:17][CH2:16]3)=[O:21])[CH2:23][CH2:24][CH2:26][CH2:27]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCCCC3)(CC1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)N3CCCC3)(CC1)CC2
Yield: 70.6 %

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 10% palladium carbon (3.0 mg) were dissolved in ethanol (1.0 mL) and dichloromethane (0.5 mL). The mixture was stirred at room temperature for 8 hours in a hydrogen atmosphere. The mixture was then filtered through a Celite pad and the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-(pyrrolidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (15.2 mg).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])=[C:8]([OH:23])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33].[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:9]2[CH:10]=[N:11][C:5]3[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][OH:34])=[N:7][C:6]=3[C:8]=2[OH:23])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cnc(Br)nc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cnc(C#CCO)nc2c1O
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-N-(4-chlorobenzyl)-8-hydroxypyrido[3,2-d]pyrimidine-7-carboxamide (Preparation 6, 1.97 g), (Ph3P)2PdCl2 (175 mg), and triethylamine (5.0 mL) in DMF (50 mL) is heated to 90° C. Propargyl alcohol (2.5 mL) is slowly added to the mixture over 20 h. The reaction mixture is allowed to cool to room temperature, poured into saturated aqueous NH4Cl solution (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1>O1CCCC1>[Cl:1][C:2]1([C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(Cl)C1(Cl)CC1
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(NC(=O)C3(Cl)CC3)cc2)=NN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
A solution of 4.45 g (32.0 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride in 20 ml of absolute tetrahydrofuran is added dropwise to a stirred suspension of 5.0 g (26.4 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 100 ml of absolute tetrahydrofuran. The mixture is then stirred for 20 hours at room temperature followed by 1 hour under reflux. The product is filtered off at 10° C., washed first with tetrahydrofuran and then with water, and recrystallized from dimethylformamide/water. 6.3 g (82% of theory) of 6-[p-(1-chlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone are isolated as colorless crystals, of melting point 231°-232° C.