Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10](OCC)=[O:11])=[CH:8][C:7]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:6]1=2.[O-]CC.[Na+]>C(O)C>[CH3:18][C:16]1([CH3:19])[CH2:15][C:7]2[CH:8]=[C:9]3[N:5]([CH2:4][CH2:3][NH:2][C:10]3=[O:11])[C:6]=2[CH2:17]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CC(C)(C)C2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Temperature: 55 °C
Yield: 23.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with crude 110d (˜18 mmol), sodium ethoxide (6.2 g, 92 mmol) and ethanol (120 mL). The mixture was stirred at 55° C. over night. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The solution was filtered. The solid was washed with ethyl acetate (15 mL) to give 850 mg of desired product 110e. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to near dryness. The solution was filtered and the solid (1.44 g) was washed with ethyl acetate (15 mL). The combined solids were dried under vacuum a afford 61% yield (2.3 g) of 110e.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][C:23]([OH:25])=[O:24])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][C:23]([O:25][C@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:49][CH2:50]2)[CH:37]=1)[CH2:33][C:32]1[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=1[Cl:26])=[O:24])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1cccc2c1ccn2CC(=O)O)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Yield: 80.3 %

Procedure:
To a solution of 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (250 mg, 0.679 mmol) in DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (285 mg, 0.679 mmol), EDC (390 mg, 2.036 mmol) and DMAP (41.5 mg, 0.339 mmol) were added, and the mixture was reacted at room temperature overnight. The mixture was partitioned between DCM and 1N HCl and the aqueous phase was extracted with DCM (3×20 ml); the solvent was removed to give (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (420 mg, 0.545 mmol, 80% yield). MS/ESI+ 770.9 [MH]+. This intermediate was used in the following steps without purification.
Reaction SMILES: C(N1C2=NC=C(C(O)=O)[C:11]([N:12](C)[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=C2C=N1)C.[C:23]([NH:26][NH:27][C:28]([C:30]1[C:31](NC2CCCC2)=[C:32]2[CH:38]=[N:37][N:36]([CH2:39][CH3:40])[C:33]2=[N:34][CH:35]=1)=[O:29])(=[O:25])[CH3:24]>>[C:23]([NH:26][NH:27][C:28]([C:30]1[CH:31]=[C:32]2[C:38]([N:12]([CH3:11])[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:37][N:36]([CH2:39][CH3:40])[C:33]2=[N:34][CH:35]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: CCn1ncc2c(N(C)C3CCOCC3)c(C(=O)O)cnc21
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(C)=O)cnc21
Product: CCn1nc(N(C)C2CCOCC2)c2cc(C(=O)NNC(C)=O)cnc21

Procedure:
Intermediate 53 was prepared from Intermediate 52 using an analogous method to that for Intermediate 4. LCMS showed MH+=361; TRET=1.91 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][CH:43]([C:46]([O:48]CC)=[O:47])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2].[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[C:22]([N:40]3[CH2:41][CH2:42][CH:43]([C:46]([OH:48])=[O:47])[CH2:44][CH2:45]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cnc(N[C@H]3C[C@@H](CC)N(C(=O)OCC)c4ccc(OC)nc43)nc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCC(C(=O)O)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 50 °C
Yield: 89.1 %

Procedure:
To a solution of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpiperidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (245 mg) in ethanol (2 ml) is added aqueous 2N-potassium hydroxide solution (0.332 ml) and the mixture is heated under reflux at 50° C. for 1 hour. The reaction solution is diluted with ethyl acetate and acidified with 1N-hydrochloric acid. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform to chloroform:methanol=90:10) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypiperidin-1-yl) pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (210 mg). MS (m/z): 711 [M+H]+.
Reaction SMILES: [Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](O[P+](N(CC)CC)(N(CC)CC)N(CC)CC)[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1>C(C(C)=O)C(C)C>[Br:1][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:11]([F:14])([F:13])[F:12]
Reactant: CCN(CC)[P+](OC(c1ccc(OC)cc1)C(F)(F)F)(N(CC)CC)N(CC)CC
Reactant: [Br-]
Solvent: CC(=O)CC(C)C
Product: COc1ccc(C(Br)C(F)(F)F)cc1
Yield: 82.5 %

Procedure:
In a round-bottom flask equipped with reflux condenser, 53.2 g (0.1 mol) [1-(4-methoxyphenyl)-2,2,2-trifluoroethoxy]tris(diethylamino)phosphonium bromide (product from Example 5) were refluxed in 80 ml of methyl isobutyl ketone for 10 minutes. The subsequent distillation gave 22.2 g (83% of yield) of 1-(1-bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (b.p. 108° to 110° C./8 mbar).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]([F:25])([F:24])[C:11]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([F:16])[C:12]([F:15])([F:14])[F:13]>C(#N)C>[Cl:1][C:22]1[CH:23]=[C:17]([C:11]([F:16])([C:12]([F:15])([F:14])[F:13])[C:10]([Br:9])([F:24])[F:25])[CH:18]=[CH:19][C:20]=1[NH2:21]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1Cl

Procedure:
18.24 g (0.14 mol) of N-chlorosuccinimide were added at 60° C. to a mixture of 40.0 g (0.12 mol) of 4-(1-bromo-1,1,2,3,3,3-hexafluoro-2-propyl)aniline from Example 6 and 125 ml of acetonitrile, and the resulting mixture was heated to reflux for 3 hours. Subsequently, the solvent was for the most part distilled off, the residue was washed with 100 ml of 1N NaOH solution, the organic phase was dried over sodium sulphate and finally the remaining solvent was removed under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCOc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCOc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 53.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-ethoxyphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.89 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-ethoxyphenyl)urea (0.93 g) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1.[Na].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].[I-].[Na+]>O1CCCC1>[CH3:14][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[O:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1cc(CCCCCCCBr)on1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCOc2ccc([N+](=O)[O-])cc2)on1
Temperature: 80 °C

Procedure:
A mixture of 3.0 g (0.0115 mole) of 5-(7-bromoheptyl)-3-methylisoxazole and 1.85 g (0.0115 mole) of the sodium salt of 4-nitrophenol in 50 ml of dry tetrahydrofuran containing a few crystals of sodium iodide was heated at 80° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue triturated with 100 ml of methylene dichloride and 40 ml of water. The organic phase was dried and concentrated, and the residue crystallized from ether to give 3.5 g of 3-methyl-5-[7-(4-nitrophenoxy)heptyl]isoxazole, colorless solid, m.p. 58° C.; MIC vs. polio-2 virus in vitro=1.5 μg/ml.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-trifluoromethyl-benzene following the procedure of Example 478: MS (ESI) m/z 552.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:17]=1.[CH3:31]C(O)=O.C=O.[BH3-]C#N.[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:31])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=1
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrahydro-2H-pyran-4-yl)amino)benzamide (300 mg, 0.73 mmol) in MeOH (6 mL) was added AcOH (0.05 mL) and HCHO (548 mg, 7.3 mmol, 40% w/w). The mixture was stirred at 20° C. for 2 h. NaBH3CN (276 mg, 4.38 mmol) was added and the resulting mixture was stirred at 20° C. for 16 h. The reaction solution was concentrated, the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (105 mg, Yield 33.9%). 1H NMR (CD3OD, 400 MHz): δ 7.37-7.29 (m, 1H), 7.23-7.17 (m, 1H), 7.17-6.97 (m, 6H), 4.18-4.08 (m, 1H), 4.07-3.90 (m, 3H), 3.80-3.68 (m, 2H), 3.62-3.51 (m, 3H), 3.51-3.43 (m, 1H), 2.99-2.79 (m, 7H), 2.75-2.58 (m, 2H), 1.94-1.79 (m, 2H), 1.72-1.59 (m, 2H). LCMS (m/z): 424.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5][N:4]=1.FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: COc1cc(B(O)O)ccn1
Product: COc1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)ccn1
Yield: 100 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 100% yield, starting from 2-methoxypyridine-4-boronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, 1 H), 7.23-7.34 (m, 8 H), 7.09-7.23 (m, 3 H), 6.96 (dd, 1 H), 6.80 (dd, 1 H), 6.70-6.78 (m, 2 H), 4.31-4.37 (m, 1 H), 4.03-4.10 (m, 1 H), 3.91 (s, 3 H), 3.62-3.73 (m, 4 H), 2.90-3.07 (m, 2 H), 2.43-2.49 (m, 1 H); MS (ESI) m/z 437[M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11]([NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:36][NH2:37]>C(O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11](=[N:36][NH2:37])[NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)c1cc(C(=S)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(C(=NN)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-piperidin-1-yl-thiobenzamide (unpurified product of the previous step: F67-03), ethanol (5 mL), hydrazine monohydrate (0.5 mL) was placed in a test tube and heated for 1.5 hours under reflux. After completing the reaction, the reaction mixture was concentrated under reduced pressure while adding toluene several times. The residue thus obtained was subjected to the next step without purification.
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:4]2=1)[CH3:2].C1C(=O)N([Br:30])C(=O)C1>C1COCC1>[Br:30][C:20]1[C:19]([NH2:22])=[CH:18][C:5]2[O:6][CH2:7][CH2:8][CH:9]3[CH2:10][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:16][CH2:17][C:3]3([CH2:1][CH3:2])[C:4]=2[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC12CCC3(CC1CCOc1cc(N)ccc12)OCCO3
Solvent: C1CCOC1
Product: CCC12CCC3(CC1CCOc1cc(N)c(Br)cc12)OCCO3
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
A solution of rac-(7aR,11aS)-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (86, R2=Ethyl) (11.2 g, 37.0 mmol) in THF (370 mL) was cooled to about −10° C. in a salt/ice bath and was then treated with NBS (6.59 g, 37.0 mmol) with stirring for about 5 min. The reaction was quenched by addition of sat. aq. NaHCO3 (250 mL), and the mixture was diluted with EtOAc (350 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (350 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (220 g, eluted with 0% to 40% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (87, R2=Ethyl) (13.6 g, 96%) containing about 20% of a minor regioisomer. The material was used directly in Step #4 without further purification. LC/MS, method 3, 2.49 min, MS m/z 382, 384 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: OCCN1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(CCO)CC3)ncc2c1=O
Yield: 68 %

Procedure:
5.6 g. of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine, 5.2 g. of 1-β-hydroxyethyl piperazine and 50 cm3 of toluene are heated under reflux for 2 hours. After cooling, the solution is filtered to remove the hydrochloride which has precipitated, and the organic solution is diluted with its own volume of chloroform, is washed with water and dried (MgSO4). After evaporation, the residue is recrystallised from 40 cm3 of a mixture of isopropanol (1 volume) and isopropyl ether (2 volumes). 5.14 g. (68%) of 2-(4'-β-hydroxyethyl-piperazino)-5-oxo-6-carbethoxy-8-ethylpyrido(2,3-d)pyrimidine are obtained; melting point 172° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:40].N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)(=[O:38])[NH2:40]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)ccc21
Reactant: [NH4+]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 208 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (549 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (304 mg) and WSC.HCl (288 mg) were dissolved in DMF (5 ml), diisopropylethylamine (517 μl) was added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ncnc2c1ncn2CCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCn1cnc2c(N)ncnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A mixture of 9-(3-chloropropyl)adenine (1.9 g, 9 mM) and sodium azide (1.75 g, 27 mM) in DMF was stirred at 80° C. for 24 hours, cooled to room temperature, and filtered. The solid was washed with CH2Cl2. The solvent was removed from the combined filtrates and the residue was taken up in water with sonication. The aqueous layer was extracted with CH2Cl2 (3×60 mL). After removing solvent, the crude product was recrystallized from ethanol to give 9-(3-azidopropyl)adenine as a white crystalline solid in 81% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([F:22])=[C:14]([Cl:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture solution of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol), 3-chloro-4-fluoro-benzaldehyde (16.1 g, 100 mmol) and p-toluenesulfonic acid (384 mg, 2.0 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-chloro-4-fluoro-benzylidene)-amino]-benzoic acid ethyl ester (30.8 g, quant.) as a pale-white solid: MS calcd. for C16H13ClFNO2 306.74, obsd. (ESI+) [(M+H)+] 306.1.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH:20]=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH:20]=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=CCON([C@H]1CN[C@H](C(=O)OC)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of (2S,5R)-1-tert-butyl 2-methyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-methyl-5,6-dihydropyridine-1,2(2H)-dicarboxylate (Intermediate 27, 2.06 g, 4.03 mmol) in DCM (20 mL) at room temperature was added zinc bromide (0.648 mL, 12.08 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the desired product (1.650 g, 100%) as a light yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:4][C:5]([Cl:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[Cl:12][C:5]1[C:6]2[C:11]([C:2]3[NH:1][S:24](=[O:26])(=[O:25])[N:23]([CH3:22])[CH:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[C:3]=3[CH:4]=1)=[N:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1c(C(=O)c2ccc(F)cc2)cc(Cl)c2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cc2)c2cc(Cl)c3cccnc3c2NS1(=O)=O
Yield: 44.4 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-5-chloro-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 400 (105 mg, 0.34 mmol), N-methylsulfamoyl chloride 213 (135 mg, 1.0 mmol) and NaBH4 (14 mg, 0.34 mmol) in pyridine (4 ml) gave the title compound (57 mg, 44%) after purification by preparative HPLC (acidic conditions 1).