Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([S-:17])#[N:16].[K+].BrBr>C(O)(=O)C>[NH2:16][C:15]1[S:17][C:13]2[CH:14]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of 4-benzylaniline (0.916 g, 5.00 mmol) and KSCN (0.97 g, 10.0 mmol, 2.0 eq) in 10 mL acetic acid was cooled at about 5° C., and was treated dropwise with a solution of bromine (0.258 mL, 5.00 mmol, 1.0 eq) in 2 mL acetic acid. The mixture was stirred at room temperature for about 1 hour. The precipitate was filtered off and washed with Et2O. The obtained solid was neutralized with saturated sodium carbonate solution, and a new precipitate was formed. It was filtered off, washed with water and MeOH, and dried under vacuum to give the desired compound 1.06 g (88%). LC/MS 241.2 (M+1); LC retention time 2.46 min.
Reaction SMILES: [C:1]([N:4]([C:8]1[CH:13]=[C:12]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]=23)[CH:11]=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[BH4-].[Na+].O.[CH2:32]([OH:34])[CH3:33]>>[C:1]([N:4]([C:8]1[CH:13]=[C:12]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:32](=[O:34])[CH3:33])[C:18]=23)[CH:11]=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)N(C(C)=O)c1cc(-c2c(-c3ccccc3)nn3cccnc23)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCCn2nc(-c3ccccc3)c(-c3ccnc(N(C(C)=O)C(C)=O)c3)c21
Yield: 46 %

Procedure:
To a mixture of N-acetyl-N-[4-(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl]acetamide (158 mg, 0.43 mmol, 1 eq) in 3 mL of ethanol is added sodium borohydride (35 mg, 0.94 mmol, 2.2 eq). The mixture is refluxed for 1 h. The mixture is then poured into water, extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 0:1) as eluent and 66 mg (46%) of N-acetyl-N-[4-(4-acetyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl]acetamide are obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Mg]Cl)(C)C.[CH3:14][C:15]([CH3:17])=[O:16]>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:15]([OH:16])([CH3:17])[CH3:14])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)=O
Reactant: Brc1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 3,5-dibromopyridine (Aldrich, Buchs, Switzerland, 4.6 mmol) in dry THF under Ar was added slowly a ˜2 M solution of isopropylmagnesium chloride in THF (2.76 ml). The RM was stirred for 2 h at it then was added acetone (6.9 mmol) and the RM was stirred for 2 h at rt. The RM was quenched with brine and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 70%). The fractions containing product were evaporated together to give the title compound as an oil. (HPLC: tR 1.82 min (Method A); M+H=216, 218 MS-ES)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Si:21]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 500-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of methyl trans-4-hydroxycyclohexane-1-carboxylate (16.6 g, 104.93 mmol, 1.00 equiv) and imidazole (14.28 g, 180.53 mmol, 1.72 equiv) in distilled DMF (25 mL). Tert-butyl(chloro)dimethylsilane (28.3 g, 187.76 mmol, 1.79 equiv) was added slowly and the resulting solution was stirred for 14 hrs at room temperature. After completion, the reaction was then quenched with water and extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10:1) to give the desired methyl trans-4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate (27.4 g, 96%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>Cl.O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg) in 3 mL of 4M HCl in dioxane and 1 mL of water was refluxed for 3 hours. After cooling to rt the mixture was diluted with water and sodium bicarbonate was added until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (70% ethyl acetate in hexane) to afford 9.1 mg of title compound as an off white solid. 1H NMR: (400 MHz, CDCl3) δ 8.97 (m, 1 H), 8.35 (m, 1 H), 8.16-8.13 (m, 2 H), 8.08-8.05 (m, 1 H), 7.93-7.91 (m, 1 H), 7.59-7.57 (m, 1 H), 7.25-7.23 (1 H), 2.63 (s, 3 H). MS: (M+H)/z=490.0.
Reaction SMILES: C[O:2][C:3](=O)[CH3:4].[CH:6]12[CH2:12]C([CH2:10][CH2:11]1)[CH:8]=[CH:7]2.C[O-].[Na+]>CO>[C:4]12([CH2:3][OH:2])[CH2:12][CH:6]([CH2:11][CH2:10]1)[CH:7]=[CH:8]2
Reactant: COC(C)=O
Reactant: C1=CC2CCC1C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCC12C=CC(CC1)C2

Procedure:
subjecting norbornene methyl acetate (IIIB) to trans-esterification reaction in the presence of methanol and sodium methoxide at a temperature of from about 40° C. to about 50° C. to form norbornene methanol (IB):
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([S:11]([OH:14])(=[O:13])=[O:12])[C:8]2[C:3](=[CH:4][C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:6][C:7]=2[NH2:15])[CH:2]=1.[OH-].[Na+:21]>O.C(O)C>[Na+:21].[Na+:21].[NH2:15][C:7]1[CH:6]=[C:5]([S:16]([O-:19])(=[O:18])=[O:17])[CH:4]=[C:3]2[C:8]=1[C:9]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:10][CH:1]=[CH:2]2
Reactant: Nc1cc(S(=O)(=O)O)cc2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(S(=O)(=O)[O-])cc2cccc(S(=O)(=O)[O-])c12
Yield: 87 %

Procedure:
To a solution of 25.0 g of 1-naphthylamine-3,8-disulfonic acid in 100 ml of water is added 20 ml of 5N sodium hydroxide with stirring. The mixture is warmed on a steambath and diluted with absolute ethyl alcohol to yield a crystalline precipitate. The solid is collected at room temperature and is washed with 75% aqueous ethyl alcohol, ethyl alcohol and ether. The product is dried in vacuo at 110° C. overnight to yield 22.8 g of (87%) 8-amino-1,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2].[Cl:20]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[C:11]([Cl:20])=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccn1Cc1ccccc1[N+](=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)n1Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.5 g of methyl 1-(2-nitrobenzyl)pyrrole-2-carboxylate in 50 mL of dry tetrahydrofuran is added 1.54 g of N-chlorosuccinimide. The reaction is allowed to stir at room temperature for 48 hours. To the reaction mixture is added sodium sulfite, the reaction is stirred for an additional 1 hour, filtered and evaporated to dryness. The residue is extracted into 200 mL of ether, the extract is dried over anhydrous magnesium sulfate and evaporated to dryness to yield methyl 1-(2-nitrobenzyl)-5-chloropyrrole-2-carboxylate which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13].[C:36]1([N:42]2[C:46]([S:47]Cl)=[N:45][N:44]=[N:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:47][C:46]2[N:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:43]=[N:44][N:45]=2)=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13]
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: ClSc1nnnn1-c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(Sc3nnnn3-c3ccccc3)c3ccccc3c2O)c(C(C)(C)CC)c1
Yield: 77.7 %

Procedure:
To a solution of 47.6 g of 1-hydroxy-N-[4-(2,4-di-t-amylphenoxy)-butyl]-2-naphthamide in 500 ml of carbon tetrachloride, was added a solution of 21 g of 1-phenyl-5-tetrazolylsulfur chloride (prepared according to Org. Synth. Coll., vol. II, page 445) in 200 ml of carbon tetrachloride. The mixture was refluxed overnight and concentrated in vacuo. The solid was recrystallized from 500 ml of acetonitrile, yielding 50 g of 1-hydroxy-4-(1-phenyl-5-tetrazolylthio)-N-[4-(2,4-di-t-amylphenoxy)-butyl]-2-naphthamide of formula ##STR10## which melted at 147°-148° C. (Synthesis as described in U.S. Pat. No. 3,701,783).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH:20]5[CH2:22][CH2:21]5)[CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:28])[CH:16]([CH:20]5[CH2:21][CH2:22]5)[CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C4CC4)C3)c(F)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 210 mg of 1-cyclopropyl-7-(3-cyclopropyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.24 ml of 37% formaldehyde and 0.30 ml of 90% formic acid was heated at 100° C. for 4 hours, then allowed to cool and the excess reagents removed under reduced pressure. Water was added and the pH adjusted to 7 with 1N sodium hydroxide. The mixture was then extracted several times with chloroform:methanol (95:5), the extracts combined, dried, filtered and evaporated. The resulting oil was triturated with ether, giving 170 mg of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:39][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccco3)nn12
Reactant: NC1CCCC1
Solvent: CCOC(C)=O
Product: c1coc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (200 mg, 0.53 mmol) was dissolved in 5 mL of cyclopentylamine. The solution was heated at 100° C. overnight, then cooled to room temperature. Ethyl acetate was added to dilute the reaction mixture, the organic phase was washed with water and brine and dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (1:4 ethyl acetate:hexanes) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine (206 mg, 91%) as a yellow solid. 1H NMR (CDCl3): δ 8.20 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.32 (t, 1H), 6.92 (d, 1H), 6.59 (m, 2H), 6.05 (m, 2H), 5.11 (d, 1H), 4.43 (m, 1H), 4.04 (m, 1H), 2.14 (m, 4H), 1.87–1.56 (m, 12H). MS m/z 429 (M+1).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>C1(C)C=CC=CC=1.CS(O)(=O)=O>[C:10]([O:12][CH2:5][CH2:4][C:3]#[C:2][CH3:1])(=[O:11])/[CH:9]=[CH:8]\[C:7]([O:6][CH2:1][CH2:2][C:3]#[C:4][CH3:5])=[O:13]
Reactant: O=C1C=CC(=O)O1
Reactant: CC#CCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC#CCCOC(=O)/C=C\C(=O)OCCC#CC

Procedure:
15 g of 3-pentyn-1-ol was reacted with 8.35 g of maleic anhydride in 25 ml of toluene and in the presence of one drop of methanesulfonic acid. 11.5 g of DPTNM was isolated from the reaction mixture (bp=134-140° C./full vacuum GC purity=98.8%). 1H NMR data: 1.77 (t, J=3 Hz, CH3), 2.52 (m, CH2CC), 4.22 (t, J=7 Hz, CH2 --O), 6.22 (s, maleate olefin CHs).
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>C(Cl)Cl>[CH2:14]([NH:16][C:17]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=1)=[O:18])[CH3:15]
Reactant: CCN=C=O
Reactant: Cc1nn(-c2cccnc2)cc1N
Solvent: ClCCl
Product: CCNC(=O)Nc1cn(-c2cccnc2)nc1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To a solution of 3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.1 g, 0.574 mmol) in DCM (5.74 ml) was added ethyl isocyanate (0.041 g, 0.574 mmol) and the reaction mixture was stirred at ambient temperature for 40 minutes. The reaction mixture had turned from a clear solution to a suspension with white solid material. The reaction mixture was concentrated and purified using silica gel chromatography (0-20% MeOH/DCM) to yield the title compound as a white solid (0.135 g, 95%): mp 197-200° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.3 Hz, 1H), 8.48-8.37 (m, 1H), 8.32 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.52 (br s, 1H), 7.41-7.25 (m, 1H), 5.79 (br s, 1H), 3.33-3.23 (m, 2H), 2.29 (d, J=2.9 Hz, 3H), 1.16 (dd, J=8.7, 5.7 Hz, 3H); ESIMS m/z 246 ([M+H]+), 244 ([M−H]−).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](C)N
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
L-alanine methyl ester hydrochloride (15.0 g, 107 mmol) was dissolved in N,N′-dimethylformamide (150 mL), added potassium carbonate (32.5 g, 235 mmol) and benzyl bromide (18.4 g, 107 mmol) and the mixture was stirred at 80° C. overnight. Then, the mixture was reverted to room temperature, the reaction solution was filtered through a pad of celite, extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (12.7 g, 61%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:18][C:19]([OH:21])=[O:20])[C:15]([OH:17])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:16][C:15](=[O:17])[C@H:14]([CH2:18][C:19]([OH:21])=[O:20])[CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Reaction time: 18 h
Yield: 99 %

Procedure:
(S)-2-((7-Bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinic acid (95 mg, 0.266 mmol) was suspended in toluene (15 mL). p-Toluenesulfonic acid monohydrate (3.5 mg, 0.018 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 18 hours. Mixture was concentrated to dryness. Title compound was obtained as tan solid in 99% yield. LCMS (M−H)−=339.0, 337.0.
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[C:11]([NH2:14])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:15](O)(=[O:17])[CH3:16]>>[CH2:1]([N:5]1[C:12]([NH2:13])=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Product: CCCCn1c(N)c(NC(C)=O)c(=O)[nH]c1=O

Procedure:
59.4 g (0.3 mole) of 1-butyl-5,6-diaminouracil are refluxed for 2 hours with stirring in 240 ml of acetic acid in a reactor equipped with a condenser. The acetic acid is evaporated and the residue is taken up in a little ethanol which is then evaporated. This operation is repeated until a semi-crystalline residue is obtained. The semi-crystalline residue thus obtained is then triturated until solidification is complete. The solid is filtered and washed with ether, giving 72 g of fine, faintly yellow crystals.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:23][CH2:24][O:25][CH3:26])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(I)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reactant: COCCBr
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)ccc(OC)c21

Procedure:
The title compound is prepared starting from 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole and (2-bromoethyl)-methyl ether using the same reaction conditions as described in Example 1. The title compound is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[CH:15][C:9]=2[S:10][C:11]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[CH:15][C:9]=2[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(C(=O)O)sc2ccsc12
Agent: [Cu]
Agent: O=C=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCCCCc1csc2ccsc12
Temperature: 260 °C
Yield: 207.2 %

Procedure:
A mixture of compound 62 (14.6 g, 0.054 mol), copper powder (2.00 g), and quinoline (80 mL) was heated at about 260° C. in a Woods metal bath. When no further bubbles of CO2 were detected (about 2 hours), the mixture was allowed to cool to room temperature, and hexane (200 mL) was added. The mixture was washed repeatedly with HCL (1-2 M in water) to remove the quinoline. The organic layer was dried over MgSO4 and concentrated by evaporation. The residue was purified by column chromatography (SiO2/hexanes) to yield compound 58 (25.1 g, 90.3%). GC/MS: 224 g/mol (M). 1H NMR (CD2Cl2) δ 7.36 (m, 1H), 7.25 (m, 1H), 7.01 (m, 1H), 2.73 (t, 2H), 1.69 (m, 2H), 1.34 (m, 6H), 0.89 (t, 3H), 13C NMR: 140.39, 139.13, 135.39, 127.01, 122.19, 120.26, 32.01, 30.29, 29.43, 23.01, 14.24.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11](OC)=[O:12])[CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.C([Mg]Cl)(C)C.[NH4+].[Cl-]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([NH:30][CH:27]2[CH2:29][CH2:28]2)=[O:12])[CH:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(N3CCN(C)CC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Cl)nc(N2CCN(C)CC2)c1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 3-[5-chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 107b) in tetrahydrofuran (6 mL) under nitrogen was added cyclopropylamine (0.15 mL) followed by iso-propylmagnesium chloride (2M in tetrahydrofuran, 0.8 mL), portionwise. After 1 h, sat. aqueous NH4Cl was added and the mixture extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (35 mg).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:13]([O:17][CH3:18])([O:15][CH3:16])=[O:14])([F:12])[CH3:11])=[CH:6][CH:5]=1.[Li+].[OH-].Cl>O1CCOCC1>[CH3:16][O:15][P:13]([C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=1)([F:12])[CH3:11])([O:17][CH3:18])=[O:14]
Reactant: COC(=O)c1ccc(C(C)(F)P(=O)(OC)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COP(=O)(OC)C(C)(F)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[1-(Dimethoxy-phosphoryl)-1-fluoro-ethyl]-benzoic acid methyl ester (0.56 g, 1.93 mmol) was made 0.25 M in dioxane and to this stirring solution was added 3 M aqueous LiOH (0.14 g, 5.79 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was neutralized with 1N aq HCl and concentrated in vacuo. The residue was carried forward without further purification: MS: cal'd 277 (MH+), exp 277 (MH+)
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][CH3:18])[C:7]=2[C:6](=[O:19])[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1.[C-:26]#[N:27].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH2:17]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([F:16])=[CH:13][C:14]=2[C:15]2[C:3]([CH2:2][C:26]#[N:27])=[N:4][N:5]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6](=[O:19])[C:7]1=2)[CH3:18]
Reactant: [C-]#N
Reactant: CCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 93.3 %

Procedure:
A two-phase mixture of 7.2 g (18 mmol) of 1-(bromomethyl)-5-ethyl-8-fluoro-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 3.53 g (72 mmol) of sodium cyanide and of 0.58 g (1.8 mmol) of tetrabutylammonium bromide in 300 ml of dichloromethane and 150 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. 5.8 g (16.8 mmol) of compound are isolated, which compound is used as is in the following stage.