Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][O:23][C:17]=2[CH2:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[O:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1Cc2occc2CN1
Product: CC1Cc2occc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2ccc([C@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)c1
Yield: 41.6 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (200 mg, 0.51 mmol, prepared in example 17) and 3-acetamidophenylboronic acid (109 mg, 0.61 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with 2% methanol/methylene chloride to afford 85 mg (42%) of the title compound as a white solid when concentrated from ether.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:8]3[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=3[O:13][CH3:14])[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(C(C)C)cc1-c1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 18.7 %

Procedure:
5-Isopropyl-2-methoxybenzeneboronic acid (50.5 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (12 mg, 19%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:20]=2)[C:11]([O:13]C(C)(C)C)=[O:12])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]([OH:30])([C:22]([F:25])([F:23])[F:24])[C:26]([F:27])([F:28])[F:29])[CH:20]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)nc1
Temperature: 25 °C

Procedure:
To a 0° C. DCM (6.8 mL) solution of tert-butyl 3-(5-methylpyridin-2-yl)-5-[92,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (0.6 g, 1.38 mmol) from step C was added trifluoroacetic acid (6.9 mL). The mixture was warmed to rt over 2 h and concentrated to dryness to give a gummy solid. The crude title compound was used in step E without further purification. LC-MS (M+H)=380.1
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Cl[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: ClCc1cscn1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2cscn2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole: MS (ESI) m/z 324 (M+1)
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:22]/[C:18]1[NH:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc[nH]1
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 15.8 %

Procedure:
tert-Butyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (0.39 mmol, 37 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of tert-butyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate as a yellow solid. MS(ES): m/e 317 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([Br:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirring suspension of 7-benzyl-8-bromo-3-methylxanthine (10.06 g, 30.0 mmol) in anhydrous dimethylsulfoxide was added sodium hydride (864 mg, 36.0 mmol). After stirring at room temperature for 30 min, (R)-5-acetoxy-1-chlorohexane (5.9 g, 33.0 mmol) was added. After stirring at 70-75° C. for 12 hours, the mixture was cooled to room temperature, quenched with water (600 ml) and stirred at room temperature for 4 hours. The precipitate was filtered to provide (R)-1-(5-Acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (12.31 g, 86% yield) as a beige powder.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][S:6][CH:7]=1.[NH2:8][CH2:9][CH2:10][SH:11]>>[NH2:8][CH2:9][CH2:10][S:11][CH2:2][C:3]1[N:4]=[N:5][S:6][CH:7]=1
Reactant: NCCS
Reactant: OCc1csnn1
Product: NCCSCc1csnn1

Procedure:
Reacting 4-hydroxymethyl-1,2,3-thiadiazole with cysteamine by the procedure of Example 1 gives 4-[(2-aminoethyl)thiomethyl]-1,2,3-thiadiazole. From this compound by the procedures of Examples 1,2 and 3, the following products are prepared:
Reaction SMILES: C(OC(=O)C[O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11](C2C=CC=CC=2)[CH:10]=1)(C)(C)C.C(N(C(C)C)CC)(C)C.[F:36][C:37]([F:50])([F:49])[S:38]([O:41]S(C(F)(F)F)(=O)=O)(=[O:40])=[O:39]>ClCCl.O>[O:19]=[C:14]1[C:13]2[CH:12]=[C:11]([O:41][S:38]([C:37]([F:50])([F:49])[F:36])(=[O:39])=[O:40])[CH:10]=[C:9]([O:8][S:38]([C:37]([F:50])([F:49])[F:36])(=[O:40])=[O:39])[C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)COc1cc(-c2ccccc2)cc2c1CCCC2=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)cc21
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 69.2 %

Procedure:
To a suspension of 5,7-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (XXV, prepared as described in Scheme 3 above, 320 mg, 1.79 mmol) in dichloromethane (25 mL) was added diisopropylethylamine (925 mg, 7.16 mmol) at −5 to 0° C. To the resulting solution was then added trifluoromethanesulfonic anhydride (1.06 g, 3.76 mmol) dropwise over 5 minutes at this temperature. The resulting brown solution was stirred for 45 minutes at ˜0-5° C. and then warmed to room temperature and stirred for another 15 minutes. The reaction mixture was then diluted with dichloromethane (50 mL) and water (70 mL). The aqueous layer was separated and extracted with dichloromethane (25 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in dichloromethane (10 mL) and diluted with hexanes (50 mL). The brown solution was stored in the refrigerator for 15 h. The resulting solids were collected by filtration and washed with hexanes. After drying in the air, trifluoro-methanesulfonic acid 8-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (0.548 g, 69%) was obtained as a light brown solid: EI(+)-HRMS m/e calcd. for C12H8F6O7S2 (M+) 442.9616, obsd. 442.9618.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[O:6][C:7]3([C:32]4[N:33]([CH:34]=[CH:35][CH:36]=4)[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26]C(C)(C)[O:24]2)=[C:17]([O:30][CH3:31])[CH:16]=1)=[O:14])[CH2:9][CH2:8]3.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[O:6][C:7]3([C:32]4[N:33]([CH:34]=[CH:35][CH:36]=4)[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([OH:24])[CH2:27][OH:26])=[C:17]([O:30][CH3:31])[CH:16]=1)=[O:14])[CH2:9][CH2:8]3
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccc(Cl)cc2-n2cccc23)ccc1OC[C@@H]1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccc(Cl)cc2-n2cccc23)ccc1OC[C@@H](O)CO
Temperature: 80 °C

Procedure:
(R)-(8-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-methoxyphenyl)methanone (41 mg, 0.076 mmol) and 4-methylbenzenesulfonic acid hydrate (2.9 mg, 0.015 mmol) were dissolved in MeOH (760 μL) and H2O (76 μL) was added. The reaction mixture was heated at 80° C. for 45 min. The mixture was filtered and the residue was purified by reverse phase HPLC using 5 mM HCl/H2O and MeOH to yield (S)-(8-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)methanone. ESI-MS m/z calc. 498.2, found 499.3 (M+1)+; Retention time: 4.72 minutes (15 min run).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH3:26]>CCCCCCC.CCOC(C)=O>[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH2:25][CH3:26]
Reactant: CCCOC1CCNCC1
Reactant: O=C1CSc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCOC1CCN(CCCN2C(=O)CSc3ccccc32)CC1
Yield: 79.5 %

Procedure:
4-(3-Chloropropyl)-4H-benzo[1,4]thiazin-3-one (81MF07) (0.18 g, 0.74 mmol), K2CO3 (0.20 g, 14.8 mmol), NaI (0.22 g, 14.8 mmol) and 4-propoxypiperidine (0.12 g, 0.81 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (81MF07KS) (0.205 g, 79%). 1H NMR (CDCl3) δ 7.33 (d, J=7.6 Hz, 2H), 7.21 (d, J=3.2 Hz, 2H), 7.00-6.96 (m, 1H), 4.03 (t, J=7.2 Hz, 2H), 3.38-3.34 (m, 4H), 3.26-3.21 (m, 1H), 2.69 (t, J=5.6 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H), 2.04 (t, J=9.8 Hz, 2H), 1.86-1.76 (m, 4H), 1.58-1.51 (m, 4H), 0.90 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 165.2, 139.7, 128.5, 127.2, 124.1, 123.4, 118.1, 75.2, 69.7, 55.4, 51.5, 43.2, 31.8, 31.7, 25.3, 23.4, 10.8.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(OCCO)C>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc2ccsc2c1NCc1ccc(Cl)cc1Cl
Yield: 75.9 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), 2,4-dichlorobenzylamine (217.6 mg, 0.17 mL, 1.24 mmol), N,N-diisopropylethylamine in 5 mL of 2-ethoxyethanol is heated at reflux for 4 hours. After cooling the mixture is concentrated in vacuo and the residue is treated with a saturated aqueous sodium bicarbonate solution for 1 hour. The precipitate is collected by filtration, washed with water, dried in vacuo, and then purified by flash column chromatography eluting with a gradient of 2% methanol in dichloromethane to 4% methanol in dichloromethane to provide 261.2 mg of 7-[(2,4-dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 215–216° C.; 1H NMR (DMSO-d6) δ 4.95 (d, J=5 Hz, 2H), 7.28 (d, J=6 Hz, 1H), 7.40 (dd, J=6, 2 Hz, 1H), 7.46 (dd, J=4, 2 Hz, 1H), 7.69 (d, J=2 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.16 (m, 1H) 8.47 (d, J=6 Hz, 1H); MS 334.0, 335.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[N:25][OH:26])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)C(Cc1ccc(Cl)cc1)N1CCCC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one (200 mg, 0.79 mmol, from Step B) dissolved in ethanol (2 mL), was added pyridine (63 mg, 0.79 mmol), and hydroxylamine hydrochloride (78 mg, 1.12 mmol). The mixture was refluxed for 24 h when LC/MS indicated disappearance of all starting material. The mixture was cooled to room temperature, concentrated under reduced pressure, treated with 33% aqueous potassium carbonated, and extracted with chloroform 5 times. The organic layers were combined and filtered over glass wool and dried over potassium carbonate. The filtrate obtained after passing through sintered glass was concentrated to give the oxime, homogeneous by TLC, Rf=0.3 in 95:5 CH2Cl2:MeOH. LC/MS m/e=267 (M+1). 500 MHz 1H NMR (CDCl3) δ 1.73 (m, 4H), 1.76 (s, 3H), 2.40 (m, 2H), 2.60 (m, 2H), 2.72 (dd, J=2.7, 10.8 Hz, 1H), 2.94 (dd, J=4.3,8.8 Hz, 1H), 3.03 (dd, J=4.4, 13.3 Hz, 1H), 3.8 (s, 1H), 6.96 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(F)cc1O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (500 mg, 3.18 mmol) and tin (II) chloride (1.76 g, 9.2 mmol) in ethanol (10 mL) was heated at 80° C. under argon. After 30 min, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of 5% aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave the title compound(335 mg, 83%). 1H NMR (CD3OD/CDCl3): δ6.6 (m, 1H), 6.38 (dd, 1H, J=8.3 Hz and J=2.8 Hz), 6.29 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][N:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: COc1cnc2ccc(=O)[nH]c2n1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc2ccc(=O)n(CC3OCCO3)c2n1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.30 g of 3-methoxypyrido(2,3-b)pyrazin-6(5H)-one in 6 mL of N,N-dimethylformamide, 0.35 g of potassium carbonate was added, and the mixture was stirred at 65 to 75° C. for 10 minutes. Thereto was added 0.21 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 95 to 100° C. for 1 hour 30 minutes. Thereto were further added 0.05 mL of 2-bromomethyl-1,3-dioxolan and 120 mg of potassium carbonate, and the mixture was stirred at 95 to 100° C. for 2 hours 15 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were then added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=2:1 to obtain 0.13 g of 5-(1,3-dioxolan-2-ylmethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH2:8]([O:10][CH:11](OCC)OCC)[CH3:9].C(OC(=O)C)(=O)C.C(O)(=O)C>C(O)C>[CH2:8]([O:10][CH:11]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(C)=O
Reaction time: 2.5 h

Procedure:
253 g (2.5 moles) of acetylacetone, 1,110 g (7.5 moles) of orthoformic acidtriethyl ester and 8 g of acetic anhydride are heated to ebullition in a flask with vigorous stirring. During the reaction, about 23 g of acetic acid is added and the ethanol formed is distilled off. After 2 to 3 hours the reaction is completed. The unreacted orthoformic acid triethyl ester is distilled out at reduced pressure (5 to 1 Torr) through the top of the column and fed back to the next batch. Following this, 355 g of ethoxymethylene acetylacetone is evaporated, separated from the residue through a simple distillation bridge at 0.1 to 0.3 Torr. The yield, referred to acetylacetone, was 91% of theory.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:15])OCC.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:11]([NH:10][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=1)=[O:15]
Reactant: CCOC(=O)Nc1nc2c(s1)CCCC2
Reactant: CNCC=O
Product: CN(CC=O)C(=O)Nc1nc2c(s1)CCCC2
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Ethyl N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate (13.6 grams; 0.06 mol) and the dimethyl acetal of 2-methylaminoacetaldehyde (20 mol.) were charged into a glass reaction vessel equipped with a stirrer, reflux condenser and gas addition tube. The reaction mixture was blanketed with nitrogen gas and heated at 120° C. for a period of 24 hours. Since starting material remained, the mixture was heated for an additional 48 hours and then for an additional 18 hours. After this time the reaction mixture was distilled to remove excess starting material. The residue was purified by chromatography using ethyl acetate as the eluant on silica gel adsorbant yielding the desired product, dimethyl acetal of 2-[1-methyl-3-(4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde; (8.9; melting point 89°-92° C.). The structure of the product was verified by infrared and NMR spectroscopy.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.8 %

Procedure:
A solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) and triethylamine (2.77 mL, 20 mmol) in CH2Cl2 (20 mL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (1.15 mL, 15 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (1.53 g, brown oil, 100% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][N:23]4[CH:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.FC1C(F)=CC(C2C=CC(OCC3C=CC=C4C=3C=CN4)=CC=2)=C(OC)C=1.C(OC(=O)/C=C/C)C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:24]4[C:25]=3[CH:21]=[CH:22][N:23]4[CH:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[CH:13][CH:14]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(C)CC(=O)O)c3c2)cc1
Agent: C/C=C/C(=O)OCC
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(C)CC(=O)O)cc1

Procedure:
3-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acid was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acid from starting materials 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and (E)-but-2-enoic acid ethyl ester to yield the product as a clear to opaque oil/film (6 mg, 13%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])=[C:16]([F:25])[CH:15]=2)[CH2:10]1)C(=O)[O-])(C)C.O1CCOCC1>Cl>[CH3:24][C:21]([C:17]1[C:16]([F:25])=[CH:15][C:14]([O:13][C@H:11]2[CH2:10][C@H:9]([NH2:5])[CH2:12]2)=[CH:19][C:18]=1[F:20])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1c(F)cc(O[C@H]2C[C@H](N(C(=O)[O-])C(C)(C)C)C2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1c(F)cc(O[C@H]2C[C@H](N)C2)cc1F
Yield: 77.1 %

Procedure:
1,1-dimethylethyl(trans-3-{[4-(1,1-dimethylethyl)-3,5-difluorophenyl]oxy}cyclobutyl)carbamate (257 mg, 0.723 mmol) was stirred in 4M HCl in dioxane (5 mL, 20 mmol) overnight and then concentrated in vacuo and loaded onto an SCX cartridge (10 g) and eluted with MeOH (3 column volumes) and then flushed with ammonia in MeOH. Concentration of the product containing fractions in vacuo gave the title compound (142.3 mg).