Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:1].[CH3:28][N:8]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[N:15][C:11]=2[CH:10]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=2)[N:7]=1
Reactant: CC(Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C)c1ccccc1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: CC(Nc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(N)(=O)=O)cc4)n3)ccc2n1C)c1ccccc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(1-phenyl-ethyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (90 mg, 62%). 1H NMR (400 MHz, d6-DMSO) δ 9.13 (s, 1H), 7.71-7.75 (m, 3H), 7.42 (d, J=7.6 Hz, 2H), 7.26-7.30 (M, 2H), 7.16-7.19 (m, 4H), 7.11 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.79 (dd, J=8.4 and 2.0 Hz, 1H), 6.73 (s, 2H), 5.56 (d, J=6.0 Hz, 1H), 5.12 (m, 1H), 4.12 (s, 2H), 3.58 (s, 3H), 3.38 (s, 3H), 1.50 (d, J=7.2 Hz, 3H). MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[CH3:30].[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:43][C:40]4[CH:41]=[CH:42][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:28])[CH3:30])=[CH:38][CH:39]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NCCCCOc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NCCCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Product: Cl
Yield: 123.7 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (3.8 g) and 4-[4-(1-methylethyl)aminobutoxy]phenol (2.0 g), in 100 ml dimethylsulfoxide was reacted with sodium hydroxide (0.4 g) in 3 ml water under the conditions described in method A. The crude amine, extracted into ethyl acetate, was converted to the trihydrochloride salt by addition of excess hydrogen chloride in ethyl acetate to the dried extract. The crude salt was triturated with a small amount of hot methanol, then was crystallized from methanol-ethyl acetate to give 2.0 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[4-(1-methylethyl)aminobutoxy]phenoxy]ethyl]piperazine trihydrochloride, mp 220°-221°.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH:36]1C[CH2:39][CH:38]([OH:41])[CH2:37]1>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][N:35]4[CH2:36][CH2:37][CH:38]([OH:41])[CH2:39]4)=[CH:31][CH:32]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: NC1CCC(O)C1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCC(O)C4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 4 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 3-amino-cyclopentanol as starting materials, 8.7 mg (4%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.65 (s, 1 H), 3.60 (m, 2 H), 2.85-2.20 (m, 6 H); ES-MS m/z 515.99 [M+H]+, HPLC RT (min) 2.24.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=1)[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([NH:30][C:28](=[O:29])[C:27]1[CH:38]=[CH:39][N:40]=[C:25]([NH:24][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]([F:23])([F:22])[F:10])=[CH:14][CH:15]=2)[CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Yield: 6 %

Procedure:
Following the procedure as describe in preparation of Example 5, making variations as required to replace benzoyl chloride with 4-(trifluoromethoxy)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-trifluoromethoxybenzoylamino)isonicotinamide was obtained in 6% yield: mp 151-153° C.; 1H NMR (300 MHz, CDCl3) δ 8.83 (br s, 1H), 8.68 (s, 1H), 8.35 (d, J=5.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 2H), 7.58-7.54 (m, 1H), 7.38-7.28 (m, 7H), 6.75 (br s, 1H), 4.64 (d, J=5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 165.1, 164.5, 152.2, 151.8, 148.9, 144.2, 137.4, 132.0, 129.1, 128.8, 128.0, 127.8, 121.9, 120.8, 118.7, 118.5, 115.1, 110.5, 44.2; MS (ES+) m/z 416.4 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Reactant: Clc1cncc(Br)c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cncc(Cl)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=311.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 3-bromo-5-chloropyridine.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([O:28]CC)=[C:15](C(O)=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br.[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42].N1C(C)=CC=CC=1C>O1CCCC1>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([OH:28])=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOc1c(C(=O)O)cc(N=Nc2cccc(S(=O)(=O)Cl)c2)c2c(NS(C)(=O)=O)cccc12
Reactant: NCCCCCCBr
Agent: Br
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c(O)ccc(N=Nc3cccc(S(=O)(=O)NCCCCCCBr)c3)c12

Procedure:
A suspension of 4-[3-chlorosulfonylphenylazo]-1-ethoxycarboxy-5-methanesulfonamidonaphthalene (20.4 g), 6-bromohexylamine hydrobromide (14.4 g), 2,6-lutidine (600 ml) and tetrahydrofuran (30 ml) was reacted for one hour at 50°-55° C. The mixture was cooled and filtered; the filtrate was concentrated to an oil which was dissolved in a minimum amount of acetonitrile and chromatographed on silica gel using acetonitrile as the eluant. The orange colored eluate was concentrated and cooled to obtain the product; yield 7.3 g (32%), m.p. 163°-5° C.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:20][CH:9]2[CH2:10][O:11][C:12]3[C:17]([C:8]2([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:7][CH2:6]1)=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH:2]=C.[O:31]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:8]23[CH2:7][CH2:6][CH:5]([O:4][CH2:1][CH2:2][OH:31])[CH2:20][CH:9]2[CH2:10][O:11][C:12]2[C:17]3=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: O=[O+][O-]
Reactant: C=CCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCC(OCCO)CC1COc1c(F)ccc(F)c12
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 8-allyloxy-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene (1.55 g, 3.41 mmol) in 1:1 MeOH/CH2Cl2 (30 mL) at −78° C. was purged with O3 until a blue color persisted. The reaction mixture was then purged with nitrogen until the blue color dissipated, NaBH4 (0.39 g, 10.2 mmol) was added and the reaction mixture was warmed slowly to ambient temperature, After 18 h, the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was diluted with water and extracted with CH2Cl2 (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to afford the title compound (1.46 g, 93%): 1H NMR (CDCl3 400 MHz) δ 7.60 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.06 (m, 1H), 6.41 (m, 1H), 5.23 (dd, J=11.7, 3.7 Hz, 1H), 4.13 (d, J=11.7 Hz, 1H), 3.76 (t, J=5.1 Hz, 2H), 3.56-3.50 (m, 3H), 2.99 (m, 1H), 2.40-2.30 (m, 2H), 1.96-1.84 (m, 2H), 1.60 (br s, 1H), 1.54 (m, 1H), 1.16 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cc(Br)cc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A solution of 4-bromo-2,6-dimethyl-benzoic acid (4.04 g, 17.6 mmol) in acetone (50 mL), was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.43 g, 21 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography using 10% ethyl acetate in hexanes afforded 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.44 g, 80%). GC-MS: m/z 244 M+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([C:19]2[CH:18]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:15][C:14]=2[F:13])=[C:6]([F:8])[CH:7]=1
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2nc(C(=O)O)c(N)cc2F)c1
Yield: 28 %

Procedure:
Method 1 was followed using 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 3-amino-5-fluoro-6-(2-fluoro-5-propoxyphenyl)picolinic acid in 28% yield. LC/MS=309.1 (M+H), Rt=1.00 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Nc1c(F)c(N2CCNCC2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 96.1 %

Procedure:
To 1.57 g (5.00 mmol) of 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid in 20 ml of acetonitrile was added 1.7 g (20.0 mmol) of piperazine. The mixture was refluxed for four hours, cooled, filtered, and washed with acetonitrile to give 1.83 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12].[Cl-].[NH4+].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen stream, to a solution of 1-bromo-3-bromomethylbenzene (25 g) in tetrahydrofuran (200 ml) were sequentially added dropwise n-propylmagnesium bromide (60 ml, 2M solution in tetrahydrofuran) and lithium tetrachlorocuprate (5 ml, 0.1M solution in tetrahydrofuran) at −78° C. Then, this reaction mixture was stirred at 0° C. for 2 hours. Under ice-cooling, to this reaction mixture were sequentially added a saturated aqueous solution of ammonium chloride (100 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (200 ml). The resulting aqueous layer was again extracted with ethyl acetate (100 ml), the combined organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), and dried over anhydrous sodium sulfate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 100/1) to give the titled compound (8.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: c1ccc2ocnc2c1
Reactant: Oc1ccc2ncccc2c1
Product: c1cnc2ccc(OCC3CO3)cc2c1

Procedure:
Compound 79 was prepared in the manner of compound 6 substituting 6-hydroxy-quinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].CC([NH:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])=O.O>COCCO>[CH2:2]([S:4][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([CH:14]=1)[NH2:8])[CH3:3]
Reactant: CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCS
Agent: [Na]
Solvent: COCCO
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
Sodium (2.76 g.) was added to dry 2-methoxyethanol (75 ml.) and the solution was cooled to 0°-5° C. Ethanethiol (8.72 g.) in 2-methoxyethanol (10 ml.) was added during 5 minutes and the subsequent solution was stirred at 0°-5° C. for 10 minutes and then added in portions to a solution of 5-chloro-2-nitro acetanilide (21.5 g.) in boiling 2-methoxyethanol (150 ml.) during 10 minutes. After 3 hours the mixture was cooled and poured into water (1 l.). The mixture was stirred and cooled to 10° C. The solid which formed was collected by filtration, washed with water, and recrystallized from ethanol to give 5-ethylthio-2-nitroaniline (16.4 g.), m.p. 75°-6° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:19][CH3:20])(OC)(=O)=O>C(#N)C.C(=O)(O)[O-].[Na+].O>[CH2:11]([O:10][C:8]([C:7]1[C:2]([Cl:1])=[CH:3][C:20](=[O:19])[N:5]([CH3:4])[CH:6]=1)=[O:9])[CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(C)c(=O)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
Ethyl 4,6-dichloronicotinate [prepared according to the literature procedure of J. Chem. Soc. 5163 (1963)] (3.19 g, 14.5 mmol) and dimethyl sulfate (6.0 mL, 63 mmol) were combined in a thick-walled glass tube with a Teflon cap. The tube was sealed and heated in a 120° C. sand bath. After 5 h, the reaction was cooled to ambient temperature and diluted with acetonitrile (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The reaction mixture was stirred vigorously overnight (ca. 18 h). This mixture was further diluted with water and extracted with dichloromethane (3×). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.65 g, 85% yield) as an oil that solidified upon standing.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>N1C=CC=CC=1>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: COC(=O)c1ccc2c(O)n[nH]c2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1nc(O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
Methyl 3-hydroxy-1H-indazole-6-carboxylate (1.6 g, 8.3 mmol) was suspended in pyridine (10 mL). Ethyl chloroformate (1.0 mL, 10 mmol) was added slowly and the reaction was allowed to stir at room temperature for 2 hours. The reaction was poured into water (65 mL) and cooled in a refrigerator for 4 hours. The resulting brown precipitate was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (1.35 g, 61%) as a beige solid. +ESI (M+H) 265.0; 1H NMR (400 MHz, CDCl3, δ): 8.80 (d, J=6.0 Hz, 1H), 8.01 (dd, J=8.2, 1.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 4.60 (q, J=7.0 Hz, 2H), 3.98 (s, 3H), 1.57 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1>[CH2:1]([Sn:5]1([CH2:6][CH2:7][CH2:8][CH3:9])[O:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCO
Reactant: CCCC[Sn](=O)CCCC
Solvent: c1ccccc1
Product: CCCC[Sn]1(CCCC)OCCO1
Reaction time: 4 h
Yield: 94.2 %

Procedure:
24.98 g (0.1 mol) of dibutyltin oxide and 6.21 g (0.1 mol) of ethylene glycol were introduced into a 500 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 250 ml of benzene was added, and the mixture was dehydrated by azeotropic distillation at 93° C. and stirred for 4 hours during which it became an uniform solution. Then, the solution was filtered while it was hot. The benzene was distilled off under reduced pressure, and the resulting white solids were dried at 60° C. for 3 hours in vaccuo to give 1,1-dibutylstanna-2,5-dioxacyclopentane, 27.6 g (94.2% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16](N)[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:22]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:1][C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([OH:22])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1ncnc2c1nc(N)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Nc1nc2c(O)ncnc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 37 °C
Reaction time: 72 h

Procedure:
In a round-bottom flask 2 g (7.5 mmol) of 8-amino-2′-deoxyadenosine (Long R. A. et al ref. 36 and Example 2) were dissolved with 150 ml of 0.1 M aqueous sodium phosphate buffer (pH 7.5). Adenosine deaminase (150 mg of crude powder from calf intestinal mucosa) was added. The resulting solution was stirred at 37° C. for 72 hrs. A precipitate was formed that was the desired product. Completion of the reaction was checked by TLC (ethanol/dichloromethane 1:4). It was observed the disappearance of the starting material to produce a more polar compound. The precipitate was filtered yielding 1.8 g (6.7 mmol, 89% yield) of 8-amino-2′-deoxyinosine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]([CH3:30])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[N:17][CH:18]=1.O.NN.ClCCl>C(O)C>[NH2:3][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]([CH3:30])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[N:17][CH:18]=1
Reactant: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccccc21
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile (200 mg, 0.51 mmol) in ethanol (15 mL) is added hydrazine hydrate (327 mg, 10.2 mmol). The mixture is stirred at room temperature overnight. The reaction mixture is poured into dichloromethane (100 mL) and extracted with 1M HCl in water. The combined aqueous phase is basified with 5M NaOH in water and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo to give 2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile, which is used in the next step without further purification. MS (ESI) m/z 263.27 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][C:42]([CH3:44])=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][C:11]=4[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:40]4[N:41]=[C:42]([CH3:44])[N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.5 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 28%).
Reaction SMILES: [OH:1]CC(C1N=C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)SC=1)C(O)=O.[CH:32]1([N:38]=[C:39]=[N:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1>[CH:41]1([NH:40][C:39]([NH:38][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:1])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C(CO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
In 20 ml of anhydrous tetrahydrofuran were dissolved 430 mg (1 millimole) of 3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionic acid, 510 mg (1 millimole) of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3 -cephem-4-carboxylic acid benzhydryl ester, and after adding thereto 206 mg (1 millimole) of N,N'-dicyclohexylcarbodiimide, the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then 40 ml of ethyl acetate was added to the residue. Insoluble N,N'-dicyclohexylurea formed was filtered off and the filtrate was washed with a diluted aqueous acid solution and an aqueous solution of sodium hydrogencarbonate and dried by anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then, the residue was treated with ether to form a powder, which was recovered by filtration, and washed with water to provide 720 mg of 7β-[3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3 -cephem-4-carboxylic acid benzhydryl ester.