Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH3:20])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH3:20])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CNCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNCC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC)c(C)n(C)c5c4)c3s2)C1
Yield: 54.6 %

Procedure:
This material was prepared by the reaction of N-({1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl)-N-methylamine 46a (0.115 g, 0.41 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.090 g, 0.41 mmole) and Cs2CO3 (0.147 g, 0.41 mmole) in a manner as previously described for example 1 to give an off-white solid (0.110 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ8.54 (1H, s), 8.01 (1H, s), 7.83 (1H, m), 7.54 (2H, m), 7.02 (1H, s), 6.64 (1H, d, J=5.46 Hz), 3.93 (2H, m), 3.68 (3H, s), 3.54 (2H, m), 3.16 (2H, m), 2.99 (1H, m), 2.80 (3H, s), 2.79 (3H, s), 1.98 (2H, m), 1.65 (1H, m); HRMS (MH+): Calcd: 492.2064; Found: 492.2048.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2Cl)=[C:4]([F:24])[CH:3]=1.[CH3:25][O-:26].[Na+]>CO>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:26][CH3:25])=[C:4]([F:24])[CH:3]=1
Reactant: C[O-]
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Br
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Br)cc1F

Procedure:
using 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-chloro-4-trifluoromethyl-6(1H)-pyrimidinone and sodium methylate in methanol there is obtained 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 137° C.;
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:5][CH2:4][CH:3]([OH:6])[CH2:2][F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)CF
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CF)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-fluoropropane-1,2-diol (from Sigma, 0.750 g, 7.97 mmol) and triethylamine (1.39 mL, 9.96 mmol) in DCM (20 mL) was added p-toluenesulfonyl chloride (1.60 g, 8.37 mmol). The reaction was stirred at RT for 2 h. The mixture was concentrated to dryness and used in next step.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([O:9]C(=O)C)[C@@H:7]([CH2:13][O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:6][CH:5]1Cl)=[N+:2]=[N-:3].C[Si]([N:28]([Si](C)(C)C)[C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[N:30]=1)(C)C>ClCCCl>[N:1]([C@H:4]1[C@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]1[N:32]1[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][C:31]1=[O:35])=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Reactant: CC(=O)O[C@H]1[C@H](N=[N+]=[N-])C(Cl)O[C@@H]1COC(=O)c1ccccc1
Solvent: ClCCCl
Product: [N-]=[N+]=N[C@H]1[C@H](OC(=O)c2ccccc2)[C@@H](CO)O[C@@H]1n1ccc(N)nc1=O
Temperature: 62.5 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a stirred solution of 7.8 g. of 2-azido-2-deoxy-3-O-acetyl-5-O-benzoyl-D-arabinofuranosyl chloride in 300 ml, of 1,2-dichloroethane is added 6 g. of bis(trimethylsilyl) cytosine dissolved in 200 ml. of 1-2-dichloroethane. The solution is stirred at 60-65 degrees C. for 3 days, cooled to room temperature and washed successively with 100 ml. of a saturated NaHCO3 solution and 100 ml. of water. It is then dried and evaporated at reduced pressure at 45 degrees C., and the residue is dissolved in 50 ml. of chloroform. The chloroform solution is applied to a silica-gel column and the β and α anomers are eluted with an acetyl mixture of chloroform and 2-propanol (10:1). The β-anomer, 1-(2-azido-2-deoxy-3-O-acetyl-5-O-benzoyl-β-D-arabinofuranosyl) cytosine, is eluted from the column first, and is obtained after evaporation of the solvent in 37% yield. The α-anomer, 1-(2-azido-2-deoxy-3-O-benzoyl-α-D-arabinofuranosyl) cytosine, is obtained in 10% yield.
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].[ClH:20].O1CCOCC1>C(OCC)C>[Cl-:20].[C:1]([C:3]1([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7][NH2+:6][CH2:5][CH2:4]1)#[N:2].[ClH:20]
Reactant: CC(C)CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)CC1(C#N)CC[NH2+]CC1
Product: [Cl-]
Reaction time: 8 h

Procedure:
In a round bottom flask was placed tert-butyl 4-cyano-4-isobutylpiperidine-1-carboxylate (2, 17 g, 63.8 mmol) and diethyl ether (200 mL). To the flask was added HCl in dioxane (4M, 2.327 g, 63.8 mmol) and the solution stirred overnight. A fine white solid formed in suspension and was filtered with a medium frit to give 4-cyano-4-isobutylpiperidinium chloride (3) as an HCl salt in quantitative yield after washing with diethyl ether (3×50 ml). MS 167 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH:5][CH2:6][CH2:7]Cl.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].[I-].[Na+]>C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:6][CH2:7][NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: CC(C)(C)N
Reactant: ClCCNc1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)NCCNc1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 159.4 %

Procedure:
15.0 g of 2-(3,4-dichloroanilino)ethylchloride, 19.2 g of tert.butylamine and approximately 1 g of sodium iodide were stirred for 26 hours at 90° C. After having been left to stand the weekend over at room temperature, the product was taken up in diethyl ether, washed with successively 2 N sodium hydroxide solution and sodium bicarbonate solution and dried. After evaporating the solvent, 15.85 g of product were obtained, which were purified by column chromatography and then converted into the HCl salt with an alcoholic HCl solution. Melting point 206°-207° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[C:12]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]>C1CCCCC1>[C:12]([N:16]([CH2:8][CH2:9][CH2:10][Cl:11])[C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: ClCCCBr
Reactant: CC(C)(C)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: CC(C)(C)N(CCCCl)C(C)(C)C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20° C. di-t-butyl amine (289 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50 wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 234 g (51% yield) of the title compound is isolated as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].NC(N)=O.C1C=CC2O[C:25](=O)[NH:24][C:22]=2C=1>>[OH:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:7]=1[NH:8][C:9]([N:24]([CH3:25])[CH3:22])=[O:11]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Agent: NC(N)=O
Product: CN(C)C(=O)Nc1ccc([N+](=O)[O-])cc1O

Procedure:
6-Nitrobenzoxazolinone was converted into the urea as described above for benzoxazolinone, using 267 g of the nitro analogue.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([Cl:42])=[O:30])=[CH:27][CH:26]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)Cl)cc1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of compound 10 (0.215 g; 0.487 mmol) and anhydrous DMF (120 uL) in 8 mL of methylene chloride, oxalyl chloride (0.18 g; 5 mmol) was added dropwise at room temperature and the reaction mixture was stirred for 2 h. Then it was concentrated and the oxalyl chloride carefully removed by distillation to yield compound L (0.217 g; 97%). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([Cl:16])[CH:4]=[N:3]1.Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:21]2.C(N(CC)C(C)C)(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:30][CH2:29][C@H:28]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[C:18]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]=3[Cl:16])[CH:19]=2)[C:23]1=[O:27])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)NC[C@H](c1ccccc1)N1Cc2cc(Br)ccc2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@@H](CN)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A mixture of 1-methyl-4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69.5 mg, 0.334 mmol), bis(tri-t-butylphosphine)palladium (14 mg, 0.028 mmol), tert-butyl [(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate (120.0 mg, 0.2782 mmol) and N,N-diisopropylethylamine (145 μL, 0.835 mmol) in 1,4-dioxane (1000 μL) and water (50 μL) was microwaved at 110° C. for 15 minutes. After filtering and concentration, the residue was purified by prep.—HPLC (pH=10). To the purified intermediate was added methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL). The solution was stirred at room temperature for 1 h. After concentration, the residue was neutralized with TEA (0.5 mL) then concentrated. Purification by prep.—HPLC (pH=10) afforded 25.6 mg (25% yield) of the desired product as white solid. LC-MS found: 367.1 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OCC)(=O)C>CN(C)C=O>[N+:17]([C:14]1[CH:15]=[CH:16][C:8]2[C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[O:11][C:10](=[O:12])[C:9]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1cccnc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1oc2ncccc2c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2-(2-Hydroxypyridin-3-yl)-5-nitrobenzoic acid (Reference Compound No. 1-3-(3), 50 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL), then N,N-diisopropylethylamine (141 μL, 0.81 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol) were added thereto, and then the reaction mixture was stirred at room temperature overnight. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with water (30 mL) and saturated brine (30 mL) successively. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Chloroform was added to the obtained residue, and then filtered to give the titled reference compound (35 mg) as a pale yellow solid. (Yield 71%)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14](O)[CH2:13][NH:12][C:11]1=[O:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][NH:12][C:11]1=[O:16]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)NCC1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCn1cc[nH]c1=O
Reaction time: 16 h
Yield: 90 %

Procedure:
[2-(5-Hydroxy-2-oxo-imidazolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (7.85 g, 32 mmol) was suspended in DCM (250 mL) and a solution of TFA (100 mL) in DCM (250 mL) was added over 10 min to the stirred suspension, which dissolved. The solution was stirred for 16 h, concentrated, and azeotroped with MeCN. The resulting TFA salt of the product was dissolved in MeOH (10 mL) and purified on 50 g of SCX resin, washing with MeOH and eluting off with 2 M NH3 in MeOH. Concentration gave the product as a pale yellow oil (3.66 g, 90%). MS (M+H)+ 128.
Reaction SMILES: C[N:2]1[CH:9]=[CH:8][C:6](=[O:7])[N:5](C)[C:3]1=O.[O-]CC.[Na+].[NH:15]1[C:19](N)=[CH:18]C=N1>C(O)C>[N:15]1[N:2]2[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]2=[CH:18][CH:19]=1
Reactant: Nc1ccn[nH]1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccn2nccc2[nH]1
Temperature: 60 °C
Yield: 58 %

Procedure:
1,3-Dimethyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 mL of a 21% solution in ethanol) were added to a solution of 1H-pyrazol-5-amine (1.7 g, 20.4 mmol) in ethanol (50 mL). The resulting mixture was heated to 60° C. for 2 h and was then cooled to room temperature. The pale brown solid was isolated by filtration to give pyrazolo[1,5-a]pyrimidin-5(4H)-one (1.6 g, 58%). Retention time (min)=0.820, method [3], MS(ESI) 136.1 (M+H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[C:25](O)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]
Reactant: O=Cc1ccc(O)cc1
Reactant: C/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/C(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 111.9 %

Procedure:
17.8 g of N,N'-dicyclohexylcarbodiimide were added while stirring within 5 minutes to a solution of 7.0 g of 4-hydroxybenzaldehyde, 7.4 g of (E)-but-2-enoic acid and 0.1 g of 4-(dimethylamino)pyridine in 50 ml of dichloromethane. The reaction mixture was stirred overnight, then filtered. The filtrate was washed with saturated sodium bicarbonate solution and with water and concentrated. Chomatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 3:7) and two-fold recrystallization of the fractions which were pure according to thin-layer chromatography gave 12.2 g of 4-[(E)-but-2-enoyloxy]benzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[O:22]=[S:21]1(=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30](=[O:31])[N:20]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: COc1cccc2c1OC(CN)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(CNCCCCN1C(=O)c3ccccc3S1(=O)=O)CC2
Yield: 21.5 %

Procedure:
5.3 g (0.027 mol) 2-aminomethyl-8-methoxychroman from example 93g, 9.5 g (0.03 mol) N-(4-bromobutyl)saccharin, 3.05 g (0.03 mol) triethylamine and 80 ml dimethylformamide were heated to 50° C. for 4h. Work-up as described in example 93h furnished 16.6 g crude product, which was filtered through 175 g silica with toluene/ethyl acetate. This gave 3.4 g dialkylation product and 7.1 g monoalkylation product. Rechromatography of the monoalkylation product on 230 g silica with toluene/methanol (10:1) gave 2.5 g pure 2-(N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-8-methoxy-chroman.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(O)C>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH:16][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c([C@H]3C[C@@H]3CN)cccn2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2c([C@H]3C[C@@H]3CNC(=O)C3CC3)cccn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a suspension of 1-[(1S,2S)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added cyclopropanecarbonyl chloride (372 μL, 4.10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Ethanol was added to the reaction solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (646 mg, yield 88%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][Br:13].C(OCC)C>O1CCCC1>[Br-:13].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][N:4]1[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]1
Reactant: COc1ccc(CBr)cc1OC
Reactant: Cn1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(Cn2cc[n+](C)c2)cc1OC
Product: [Br-]
Yield: 93.7 %

Procedure:
In a 25 ml one-necked flask, 0.35 g (4.26 mmol) of 1-methylimidazole is dissolved in 10 ml of tetrahydrofuran and then 1.18 g (5.12 mmol) of 3,4-dimethoxybenzyl bromide are added. After heating under reflux overnight, 50 ml of diethyl ether are added. The precipitate formed is drained and then washed with diethyl ether. 1.25 g (94%) of 3-(3,4-dimethoxybenzyl)-1-methylimidazolium bromide are thus obtained in the form of a light beige powder, used as it is in the next step, whose characteristic is the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:22]([C:19]1[CH:18]=[N:17][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:21][N:20]=1)=[O:23])([CH3:39])[CH3:35]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cnc(OCc2c(-c3ccc(F)cc3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 5-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (96 mg, 0.29 mmol) and TBTU (103 mg, 0.32 mmol) in DMF (1.5 mL) was added DIPEA (250 μL, 1.46 mmol). Then isopropylamine (27 μL, 0.32 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (53 mg, 49%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=371.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=1[OH:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].[CH3:24]CCCCCC>S(=O)(=O)(O)O>[C:17]([O:16][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:24])=[CH:7][C:2]=1[CH3:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCc1ccc(O)c(C)c1
Reactant: CCCCCCC
Agent: O=S(=O)(O)O
Product: CCCCCCCCCc1ccc(OC(C)=O)c(C)c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
4-Octyl-2-cresol (6a) (245.51 g, 1.116 mol) was treated with acetic anhydride (149.3 g, 1.45 mol) in the presence of a few drops of concentrated sulfuric acid at 110° C. for 1.5 h. After cooling to ambient temperature, the reaction mixture was transferred into a 4-I separatory funnel with aid of heptane (400 mL). The resulting organic phase was washed with aqueous sodium bicarbonate solution and water until the pH became 6 or so. The heptane phase was dried over sodium sulfate and concentrated to obtain 4-nonyl-2-methylphenyl acetate (285.5 g) in 97.6% yield.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:21]=[N+:22]=[N-:23].[Na+].O>C1(C)C=CC=CC=1>[NH:21]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[N:2][N:23]=[N:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
1.16 g (10 mmol) of methyl 4-cyanobenzoate, 2.06 g (15 mmol) of triethylamine hydrochloride and 0.98 g (15 mmol) of sodium azide in toluene (20 ml) was allowed to react at 100° C. for 16 hours, and after cooling to room temperature, water (20 ml) was added, and the reaction solution was allowed to separate. Concentrated hydrochloric acid was added to the aqueous layer, and the precipitated colorless solid was collected by filtration through a Kiriyama funnel and dried under reduced pressure to obtain methyl 4-(1H-tetrazol-5-yl)benzoate (1.96 g, yield 96%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]=[CH:5][N:6]([CH3:12])[C:7]=2[NH:8][C:9](=[S:11])[N:10]=1.Cl[CH2:14][C:15]([NH2:17])=[O:16].C(=O)([O-])O.[Na+]>O>[C:15]([CH2:14][S:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH3:12])=[C:2]([CH3:1])[N:10]=1)(=[O:16])[NH2:17]
Reactant: Cc1nc(=S)[nH]c2c1ncn2C
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nc(SCC(N)=O)nc2c1ncn2C
Yield: 67.5 %

Procedure:
6,9-Dimethylpurine-2-(3H)-thione (0.45 g), chloroacetamide (0.3 g), sodium hydrogen carbonate (0.25 g), and water (10 ml) were heated under reflux for 1 hr. Refrigeration gave a solid which recrystallised from water to give the carbamoylmethylthiopurine (0.40 g), m.p. 163°-164° (Found: C, 45.3; H, 4.9; N, 29.2. C9H11N5OS requires C, 45.6; H, 4.7; N, 29.5%).