Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:33])[CH2:17][N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:11][C:10]=2[OH:34])=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(C)=O>[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:33])[CH2:17][N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:11][C:10]=2[O:34][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)CC(=O)OC)ccc(O)c2[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)CC(=O)OC)ccc(OCc3ccccc3)c2[nH]1

Procedure:
48.8 g of 4-[N-benzyl-N-(2-methoxycarbonyl-1-methylethyl)aminoacetyl]-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride, 41.4 g of potassium carbonate, and 25 ml of benzyl bromide are heated under reflux for 6 hours in 900 ml of acetone. After cooling, the reaction mixture is concentrated to dryness, the residue is taken up in ethyl acetate and saturated sodium bicarbonate solution, the organic phase is separated and extracted three times with saturated sodium bicarbonate solution. The organic phase is washed with water, dried, concentrated, and the residue is recrystallized from ethyl acetate/n-hexane, thus obtaining 42.5 g of 4-[N-benzyl-N-(2-methoxycarbonyl-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid ethyl ester, mp 120°-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1Nc1ccccc1

Procedure:
A mixture of 10 g. (0.038 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 7.1 g. (0.076 mole) of aniline in 200 ml. of ethanol was refluxed for 3 hours. Upon cooling a yellow solid precipitated from the solution. This was filtered off and rinsed with ethanol to give 4-anilino-2-phenyl-5-pyrimidine carboxylic acid ethyl ester, m.p. 98°-100° C. No further purification was done and the product was used directly in the next step.
Reaction SMILES: N1(/C=[C:7]2/[C:8](=[O:23])[C:9]3[C:18]([O:19][CH3:20])=[C:17]4[C:13]([O:14][CH:15]=[CH:16]4)=[C:12]([O:21][CH3:22])[C:10]=3[O:11]/2)CCCC1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:20][O:19][C:18]1[C:9]2[C:8](=[O:23])[CH2:7][O:11][C:10]=2[C:12]([O:21][CH3:22])=[C:13]2[O:14][CH:15]=[CH:16][C:17]=12
Reactant: COc1c2c(c(OC)c3occc13)O/C(=C\N1CCCC1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c2c(c(OC)c3occc13)OCC2=O

Procedure:
(Z)-2-[(1-pyrrolidinyl)methylene]-4,8-dimethoxybenzo[1,2-b:-5,4-b']difuran-3-(2H)-one (formula LXII). The title compound of Example 11 (6.5 g, 20 mmoles) and potassium carbonate are added to CH3CN (200 ml). To this solution is added pyrrolidine (1.42 g, 20 mmoles) and the resulting solution is stirred at room temperature for 18 hr. The CH3CN is removed in vacuo to leave a yellow solid which is washed with water, filtered, and dried to give 3.19 g (54% yield) of the above product having a melting point of 216°-217° C. Carbon:hydrogen:nitrogen analysis ratio is 64.86:5.55:4.42. Mass spectrum exhibits peaks at 315, 301, 300, 286, 285, 231, 230, and 217. NMR absorptions are observed at 7.5, 7.19, 6.91, 4.29, 4.12, 3.72, 1.99. Infrared absorptions are observed at 3140, 3100, 1675, 1625, 1600, 1585, 1545, 1495, 1340, 1270, 1235, 1125, and 1065 cm-1.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>C(#N)C>[N:11]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccccc1F
Agent: [Na]
Solvent: CC#N
Product: N#Cc1ccccc1-n1ccnc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
2-Fluorobenzonitrile (0.70 g, 5.78 mmol) was dissolved in acetonitrile (1 ml), and a sodium salt of imidazole (1.34 g, 14.8 mmol) was added thereto, followed by stirring at 100° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (the sample was eluted with an increasing concentration of chloroform from chloroform/hexane=1/2 to 100% chloroform) to give the title compound (0.96 g, 98%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][C:16]=2[O:18][CH3:19])[C:11](=O)[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][C:16]=2[O:18][CH3:19])[C:11]([Cl:25])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(Cc3ccccc3)n[nH]c(=O)c2c1
Product: COc1cc(OC)c2c(Cc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-benzyl-5,7-dimethoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[CH:2]1.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].CS[C:13]1[S:17][CH:16]=[CH:15][S+:14]=1>>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[S:14]1[CH:15]=[CH:16][S:17][C:13]1=[N+:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: C1=NCCS1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1csc(=[N+]2CCSC2)s1

Procedure:
1.0 g of thiazoline and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from ethanol, whereby 2.3 g (yield: 79.3%) of 3-(1,3-dithiol-2-ylidene)thiazolidinium perchlorate (Compound No. 36) was obtained as crystals having a melting point of from 179° to 180° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:14]=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][OH:36]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: OCCI
Reactant: O=c1oc2cc(N3CCNCC3)ccc2cc1-c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(N3CCN(CCO)CC3)ccc2cc1-c1nc2ccccc2s1
Yield: 26 %

Procedure:
240 mg crude 3-benzothiazol-2-yl-7-piperazin-1-yl-chromen-2-one in 10 mL DMF are stirred for 72 h at room temperature in the presence of 858 mg (at least 4 eq.) cesium carbonate and 0.103 mL (at least 2 eq.) 2-iodoethanol. The reaction mixture is extracted with ethyl acetate and a saturated solution of sodium carbonate and washed with brine. The combined organic phases are dried with sodium sulphate and evaporated. The residue is column chromatographed (silica gel, dichloromethane/methanol 95:5+1% conc. NH4OH) to yield 70 mg (26%) desired product as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=2[CH:21]=1>>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: N#CCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4cccc(CC#N)c4)n3)cc21

Procedure:
{3-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-acetonitrile was prepared from [3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (from Example 358a) in an analogous manner to Example 1d. (120° C., 20 min) Title compound was isolated as a white foam: 99 mg (69%) HPLC purity 90%, LCMS: 447.25 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.39-7.30 (m, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=8.0 Hz, 2H), 3.77 (s, 2H), 3.90-3.50 (bm, 2H), 2.71-2.60 (m, 2H), 2.34-2.23 (m, 2H), 2.05-2.12 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29](=O)[CH2:30]Br)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:30]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: N#Cc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Yield: 37 %

Procedure:
4-[4-(4-Cyano-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (100 mg, 37%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-cyanophenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.44-8.47 (m, 2H), 8.27 (d, J=8.5 Hz, 2H), 7.94-8.00 (m, 4H), 7.63-7.68 (m, 1H), 7.47-7.52 (m, 1H), 7.28 (dd, J=7.6, 1.4 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H).
Reaction SMILES: Cl.CO.[C:4]([Cl:7])(=O)C.CO.[NH:10]1[CH2:18][C@H:16]([OH:17])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13]>C(OCC)C>[ClH:7].[CH3:4][O:13][C:12](=[O:14])[C@@H:11]1[CH2:15][C@@H:16]([OH:17])[CH2:18][NH:10]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of hydrogen chloride-methanol prepared from acetyl chloride (19 ml, 270 mmol) and methanol (170 ml) was added L-hydroxyproline (25 g, 190 mmol), and the reaction mixture refluxed for 7 hours with stirring, cooled to room temperature. The mixture was stirred at 5° C. for 1 hour after addition of diethyl ether (340 ml). The resulting precipitate was collected by filtration, washed with a solution of diethyl ether-methanol (2:1, 50 ml), and dried under nitrogen for 4 hours to afford the title compound (30.64 g, 89% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.ClC(OCC)=O.[BH4-].[Li+]>C1COCC1.[Cl-].[Na+].O>[F:15][C:14]([F:16])([F:17])[CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(F)(F)F)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(F)(F)F
Temperature: 23 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To an ice-cooled solution of (S)-2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (1.0 g, 3.89 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.813 mL, 4.67 mmol) in THF (15 mL) was added dropwise ethyl chloroformate (0.409 mL, 4.28 mmol). The cooling bath was removed and the mixture was stirred at 23° C. for 2 h. The mixture was filtered to remove the white precipitate, and the filtrate was treated with a 2 M THF solution of lithium borohydride (1.944 mL, 3.89 mmol) resulting in vigorous gas evolution. The mixture was stirred at room temperature for 2 h. Brine (25 mL) was added. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried (MgSO4), filtered, then concentrated under vacuum. The residue was purified by silica gel flash chromatography to give (S)-tert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (0.80 g) as a white solid. This solid was treated with 4 M HCl in dioxane (10 mL) for 60 min then concentrated to give the HCl salt of the title compound (0.54 g) as a white solid. 1H NMR (400 MHz, CD3OD) δ 2.55-2.79 (m, 2H), 3.42 (bs, 1H), 3.54 (dd, J=11.6, 5.6 Hz, 1H), 3.66 (dd, J=11.6, 3.9 Hz, 1H), 3.53 (bs, 1H), 8.27 (bs, 3H).
Reaction SMILES: C(ON=O)CC(C)C.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1N.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccccc1
Reactant: Nc1ccccc1Br
Agent: CC(C)CCON=O
Product: Brc1ccccc1-c1ccccc1

Procedure:
A solution of 8.8 mL of isoamylnitrite in 120 mL of benzene at 45° C. was treated dropwise over 30 minutes with a solution of 7.5 g of 2-bromoaniline in 30 mL of benzene. After the addition was complete, the mixture was heated at reflux for 90 minutes then cooled and concentrated under vacuum. The product was purified by preparative high presssure liquid chromatography on silica, eluting with hexanes. 1H NMR (200 MHz,CDCl3): 7.23 (m,2H), 7.35 (m,1H), 7.44 (s,5H), 7.70 (d,8 Hz,1H).
Reaction SMILES: N1C=CC=CC=1.[Cr](O)(O)(=O)=O.[OH:12][CH:13]1[CH2:17][CH2:16][CH:15](/[CH:18]=[CH:19]/[C:20]([OH:27])([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:14]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[OH:27][C:20]([CH3:26])([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C@@H:15]1[CH2:16][CH2:17][C:13](=[O:12])[C@H:14]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCCCC(C)(O)/C=C/C1CCC(O)C1CCCCCCC(=O)OC
Agent: O=[Cr](=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(C)(O)C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC
Reaction time: 0.33 h

Procedure:
To a solution of dry pyridine (5.85 ml) in methylene chloride (135 ml, purified by shaking with H2SO4, and dried over CaO, and distilled) is added chromic acid (4 g) at 15° C. The mixture is stirred for 20 min. To this mixture is added a solution of the compound of formula 1 in which R2 is methyl, methyl trans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]heptanoate, described in Example 92, in methylene chloride (50 ml). The mixture is stirred for 1 hour. The reaction mixture is filtered and the collected slurry on the filter pad is washed with more methylene chloride. The organic phase of the filtrate and washing are combined and washed with water, dried (Na2SO4) and the solvent concentrated, to yield the crude product. Chromatography of the product on a silica gel column affords the title compound, identical to the product of the same name described in Example 91.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[S:12].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]3=[S:12])[C@H:2]([CH3:1])[C@@H:6]2[OH:7])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=S
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=S)[C@H](C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 12 h

Procedure:
To a stirred solution of 2′-deoxy-2′-methylthiouridine (1.09 g, 4 mmol) in dry pyridine (10 mL) was added 4,4′-dimethoxytritylchloride (1.69 g, 5 mmol) and 4-dimethylaminopyridine (50 mg) at room temperature. The solution was stirred for 12 hours and the reaction mixture quenched by adding MeOH (1 mL). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and saturated aqueous NaCl (2×50 mL), and dried with MgSO4. The solution was concentrated under reduced pressure and the residue purified by silica gel (30 g) column chromatography. Elution with CH2Cl2—MeOH-triethylamine (89:1:1) furnished the title compound as a homogenous material. Pooling and concentrating the appropriate fractions furnished the 5′-O—DMT nucleoside as a foam (1.5 g, 66.5%).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(F)C=2)(=O)=O)N)=CC=CC=1)=O)CC1C=CC=CC=1>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=2)(=[O:35])=[O:34])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccc1)S(=O)(=O)c1cccc(F)c1
Product: O=C(NCCc1ccccc1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(F)c1

Procedure:
From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 3-fluorophenylsulfonyl chloride, according to the general working procedure 221 mg of 2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained;
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([OH:30])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)(OC)[O:19]C)[CH2:11][C@H:10]2[O:31][CH3:32])=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.Cl.N>O>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([OH:30])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])[CH2:11][C@H:10]2[O:31][CH3:32])=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC(O)C(OC)(OC)c2ccc(F)cc2)C[C@H]1OC
Agent: Cl
Agent: N
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC(O)C(=O)c2ccc(F)cc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 2.88 parts of cis-4-amino-5-chloro-N-[1-[4-(4-fluorophenyl)-3-hydroxy-4,4-dimethoxybutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, 30 parts of concentrate hydrochloric acid and 25 parts of water was stirred for 18 hours at room temperature. 100 Parts of water were added and the whole was alkalized with ammonia. The precipitated product was filtered off and taken up in trichloromethane. The organic phase was separated, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in benzene. Upon the addition of petroleum ether, the product was precipitated. It was filtered off and dried, yielding 0.47 parts (16%) of cis-4-amino-5-chloro-N-[1-[4-(4-fluorophenyl)-3-hydroxy-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 146.4° C. (compound 238).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:36][CH2:35][CH2:34][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: NCCN1CCCCC1
Product: O=C(NCCN1CCCCC1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-(piperidin-1-yl)ethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 20.4 mg of 257. MS (Q1) 491.8 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][C@@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:10]
Reactant: C[C@H](N)C(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)c1ncc2c(-c3ccccc3)noc2c1O)C(=O)O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.1 g, 0.35 mmol) was dissolved in 10 mL of DMF. L-Alanine (0.627 g, 7.04 mmol) and sodium ethoxide (0.36 g, 5.28 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 2. The resulting suspension was filtered and the solid dried under vacuum to give 91 mg of the title compound. MS: (+) m/z 328.00 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[C:3]=1[NH2:15].[C:16](OC)(=[O:20])[C:17]([CH3:19])=O>CCCCO>[Cl:1][C:2]1[C:3]2[N:15]=[C:17]([CH3:19])[C:16](=[O:20])[N:8]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)=O
Reactant: CC[C@H](COC)Nc1nccc(Cl)c1N
Solvent: CCCCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(Cl)ccnc21
Temperature: 60 °C
Yield: 133.1 %

Procedure:
(R)-4-Chloro-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.24 g, 1.04 mmol) was dissolved in n-BuOH, followed by methyl pyruvate (1.07 g, 10.4 mmol) and the reaction was heated at 60° C. for 5 h, before heating at reflux overnight. The reaction was concentrated in vacuo and purified by column chromatography (20% EtOAc/hex) to yield 0.39 g, 100% of (R)-8-chloro-4-(1-methoxymethylpropyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one: MS (AP) m/z 281.74 [(M+H)+, 100].
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]1([OH:22])[CH:21]=[C:19]([CH3:20])[CH:18]=[C:16]([OH:17])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:20][C:19]1[CH:21]=[C:14]([OH:22])[CH:15]=[C:16]([O:17][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:18]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1cc(O)cc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
2-(Chloromethyl)-quinoline hydrochloride (1.28 g, 6.0 mmol), orcinol (568 mg, 4.0 mmol), K2CO3 (1.68 g, 12.0 mmol) and a catalytic amount of tetrabutylammonium iodide (˜10 mg) are dissolved/suspended in anhyd. DMF (10 mL) and heated at 50° C. overnight. The reaction is cooled to r.t. and partitioned between water (100 mL) and ethyl ether (100 mL). The pH of the aqueous layer is adjusted to ˜5 and further extracted with ethyl ether (100 mL). The organic fractions are pooled and washed with brine (2×100 mL), dried over MgSO4, filtered and preadsorbed onto silica gel. The crude preadsorbed material is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. This product (approx. 80% purity, remainder is 2-methylquinoline) is used without further purification. MS (ESI) 266 (M+H)+.