Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](I)[CH:3]=1.[CH2:12](N(CC)CC)C.[C:19]([OH:25])(=[O:24])[CH2:20][CH2:21][C:22]#[CH:23].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1.CN(C)C=O>[CH3:12][O:24][C:19](=[O:25])[CH2:20][CH2:21][C:22]#[C:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1I
Reactant: CCN(CC)CC
Reactant: C#CCCC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC#Cc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
35.5 g (125 mM) of 4-chloro-2-iodo-1-nitrobenzene, 510 ml of triethylamine, 2.88 g (2.5 mM) of tetrakis(triphenylphosphine)palladium, 0.72 g of cuprous iodide and 50 ml of dimethylformamide (DMF) are mixed. 14 g (125 mM) of the methyl ester of 4-pentynoic acid are then added at room temperature, with stirring, and the reaction mixture is stirred for 24 hours at room temperature. 100 ml of toluene are added and the solvents are driven off under reduced pressure. The evaporation residue is taken up with 150 ml of ethyl acetate and 80 ml of N hydrochloric acid. The organic phase is separated off, washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The brown oil obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (9/1; v/v) as the eluent to give 21.5 g of the expected product in the form of a yellow solid (yield=65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
67 mL of 2-chloro-1,4-dimethylbenzene and 356 g of Potassium Permanganate were refluxed in 1.5 L of H2O for several hours and monitored for disappearance of starting material by TLC. The Potassium Permanganate was filtered and the reaction mixture was acidified and filtered to yield 2-chloroterephthalic acid. 46.8 g of 2-chloroterephthalic acid was treated with a saturated HCl gas solution in MeOH overnight at room temperature. The reaction mixture was concentrated, subjected to basic workup and dried to yield the dimethyl 2-chloroterephthalate. 20 g of dimethyl 2-chloroterephthalate was cooled to 0° C. in DCM and 87 mL of a 1 M in DCM solution of BBr3 was added dropwise over several hours. The reaction mixture was subsequently warmed to room temperature and stirred until complete. Following basic workup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash. 959 mg of 2-chloro-4-(methoxycarbonyl)benzoic acid was coupled to 750 mg of 4-chloro-3-(pyridin-2-yl)aniline via procedure G. 1 g of methyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was hydrolyzed via Procedure M to give 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to tert-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N4-tert-butyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 443.2 (M)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][CH2:60][CH2:61][N:62]1[CH2:66][CH2:65][CH2:64][C:63]1=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:60][CH2:61][N:62]([CH2:66][CH3:65])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCCC1=O
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(3-aminopropyl)pyrrolidin-2-one. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=7.07 Hz, 3 H) 1.17 (m, 2 H) 1.35-1.80 (m, 12 H) 2.32 (q, J=7.07 Hz, 2 H) 2.87 (br. d., 2 H) 3.33 (s, 3 H) 3.76 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.64 Hz, 2 H) 4.46 (m, 1 H) 7.47 (d, J=8.59 Hz, 1 H) 7.50 (s, 1 H) 8.14 (d, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). [M+H] calculated for C29H39F2N7O3, 572; found 572.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25].[OH:28][NH2:29].[OH-].[K+]>ClCCl>[OH:28][NH:29][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:24]([C:18]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[Cl:16])(=[O:26])=[O:25])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1Cl)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 2,4-dichlorobenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 415, exp (MH+) 415.3. 1H NMR (CD3OD, 400 MHz), 8.09 (d, 1H, J=8.4 Hz), 7.70 (d, 1H, J=2.0 Hz), 7.54 (dd, 1H, J1=8.4 Hz, J2=2.0 Hz), 7.46 (d, 1H, J=8.0 Hz), 7.33 (s, 1H), 7.14 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24](F)=[CH:23]2>C1COCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)=[CH:23]2
Reactant: Cc1cc(N)ccn1
Reactant: Fc1cc2cc(Br)ccc2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc3cc(Br)ccc3cn2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.2 %

Procedure:
A dry 40 mL scintillation vial equipped with a screw cap with a teflon insert was cooled under nitrogen, equipped with a stir bar and charged with 2-methylpyridine-4-amine (263 mg, 3.32 mmol) and anhydrous THF (27 mL) and maintained under a N2 atmosphere. LiHMDS was added as a solid (0.925 g, 5.53 mmol). The reaction mixture was stirred at RT under nitrogen for 5 min. To the mixture was added 6-bromo-3-fluoro isoquinoline (500 mg, 2.21 mmol), the vial was flushed with N2, tightly capped and placed in a pre-heated oil bath at 85° C. After 4 h at 85° C., additional 2-methylpyridine-4-amine (96 mg, total: 359 mg, 3.32 mmol) and LiHMDSi (185 mg, total: 1.11 g, 6.64 mmol) were added, and the reaction was heated an additional 2 h at 85° C. The reaction was cooled, and the THF was removed in vacuo. The crude reaction mixture was partitioned between water and DCM containing 10% MeOH. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was absorbed onto Celite® and purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 10% MeOH) to afford 196 mg (28%) of 6-bromo-N-(2-methylpyridin-4-yl)isoquinolin-3-amine (94) as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:28])[N:17]([CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)[CH3:18])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:28])[N:17]([CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH:26]=[O:27])[CH2:22][CH2:21]1)[CH3:18])([CH3:12])([CH3:14])[CH3:13]
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
0.45 ml of oxalyl chloride in 5.0 ml of dichloromethane were cooled to −78° C.; then, 0.41 g of dimethylsulfoxide in 2.0 ml of dichloromethane were slowly added and the reaction mixture stirred at −78° C. for 10 minutes. Then, 0.680 g (2.64 mmol) trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester dissolved in 5.0 ml of dichloromethane were added and the reaction mixture stirred at −78° C. for 10 minutes. Subsequently, 1.84 ml of triethylamine were added at the same temperature, the reaction mixture stirred 30 minutes at −78° C., warmed to room temperature and stirred for 1 hour. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 4:1 v/v mixture of dichloromethane and ether as the eluent giving 0.615 g (91.1%) trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester as colorless amorphous solid, MS: 273 (MNH4+).
Reaction SMILES: CO[C:3]1[CH:14]=[CH:13][C:6]2N[C:8](=O)[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25](=[O:27])[N:24]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][N:37]=[C:36]([C:40](O)=[O:41])[CH:35]=4)[CH2:30][CH2:29]3)[CH2:23][CH2:22][C:21]=2[CH:43]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]1[C@@H:6]2[C@H:5]([CH2:4][CH2:3][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:40]([C:36]1[N:37]=[CH:38][N:39]=[C:34]([N:31]2[CH2:32][CH2:33][CH:28]([N:24]3[CH2:23][CH2:22][C:21]4[CH:43]=[C:17]([O:16][CH3:15])[CH:18]=[CH:19][C:20]=4[NH:26][C:25]3=[O:27])[CH2:29][CH2:30]2)[CH:35]=1)=[O:41]
Reactant: COc1ccc2c(c1)CCNC(=O)N2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: 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
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC[C@H]5CCCC[C@@H]5C4)ncn3)CC1)C(=O)N2

Procedure:
Analogously to decahydroisoquinoline-2-carbonyl)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one the following compounds were prepared from 4.0 mg (10 μmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 3.6 mg (11 μmol) TBTU, 12 μmol of the corresponding amine and 3.9 μL DIPEA in 350 μL DMF:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([S:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.C[Si](Cl)(C)C.[CH:26]([NH2:28])=[O:27]>C1(C)C=CC=CC=1.CC#N>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:20])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[NH:28][CH:26]=[O:27])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: NC=O
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(Cl)c2F)cc1
Temperature: 50 °C

Procedure:
Intermediate 16.2 is prepared in analogy to a published literature procedure (Chem. Lett. 1988, 9, 1531-1534). A mixture of 3-chloro-2-fluorobenzaldehyde (2.00 g, 12.6 mmol), p-toluenesulfinic acid (2.96 g, 18.9 mmol), TMSCl (1.75 mL, 13.9 mmol) and formamide (1.25 mL, 31.5 mmol) in toluene (7 mL) and CH3CN (7 mL) is heated at 50° C. for 5h. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless powder; HPLC: AtRet=4.21 min; 1HNMR(CDCl3) 8.18 (s, 1H), 7.72 (d, 2H), 7.50-7.45 (m, 1H), 7.40-7.30 (m, 3H), 7.20-7.10 (m, 1H), 7.00 (d, 1H), 6.60 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1

Procedure:
At 0° C., 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 27, 0.30 g, 0.58 mmol) is added to methanol saturated with hydrogen chloride gas (7 mL) with stirring. The reaction mixture is allowed to reach rt and stirred there for 30 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (6 mL) and ammonium carbonate (0.548 g, 3.48 mmol) is added. After stirring at rt for 48 h, the reaction mixture is concentrated and the residue obtained is purified by preparative HPLC to afford 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (br, 4H), 8.62 (m, 2H), 8.53 (s, 1H), 8.32 (s, 1H), 8.0 (d, 1H), 7.83 (m, 4H), 7.64 (d, 1H), 7.43 (m, 5H), 6.96 (d, 1H), 5.6 (br, 1H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 533.1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:25])[CH2:10][N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH3:7][O:8][C:9](=[O:25])[CH:10]([NH2:11])[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(N)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Dry tetrahydrofuran (250 ml) was cooled to −78° C. Potassium tert-butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino) acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was stirred 30 min at −78° C. Benzoyl chloride (6.59 g; 56.72 mmol) was added dropwise and the reaction mixture was stirred 30 min at −78° C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. The reaction mixture was heated to room temperature and 2/3 of the solvent was removed in vacuo. Water (700 ml) was added and the reaction mixture was washed with diethyl ether (400 ml). The aqueous phase was evaporated in vacuo and the residue was dissolved in methanol and evaporated (2×150 ml). Methanol (80 ml) was added. The mixture was filtrated and the filtrate was evaporated in vacuo. The residue was recrystallised from tetrahydrofuran/diethyl ether to afford 8.86 g of 2-amino-3-oxo-3-phenylpropionic acid methylester as a hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:6][NH:5][C:4](=[O:7])[N:3]=1.C(O[CH:12]1[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[CH2:13]1)(=O)C.C(=O)(O)[O-].[Na+].C[O-].[Na+]>ClC(Cl)C.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]([C@H:12]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[CH2:13]2)[C:4](=[O:7])[N:3]=1
Reactant: Nc1nc(=O)[nH]s1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2C[C@H](O)[C@@H](CO)O2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
5-Amino-1,2,4-thiadiazol-3-one (1, 2.0 g, 0.017 mole) was silylated as described in example II, and dissolved in dry dichloroethane (100 ml). 1,3,5-Tri-O-acetyl-2-deoxy-D-ribofuranose [M. J. Robins and R. K. Robins, J. Amer. Chem. Soc., 87, 4934 (1965); 4.4 g, 0.017 mole] in dichloroethane (25 ml) was added followed by stannic chloride (2.1 ml). The reaction mixture was protected from moisture and stirred at ambient temperature overnight, before it was poured into 250 ml of cold, saturated aqueous sodium bicarbonate solution containing 200 ml of chloroform keeping the mixture basic at all times. The organic layer was separated and washed with water (2 × 100 ml) before it was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and the residual gum was chromatographed on silica gel column (4 × 70 ml) using chloroform:methanol (95:5, v/v) as the solvent. The band carrying the products was collected and evaporated to dryness, leaving 0.4 g of gummy blocked anomeric nucleosides (5) which was dissolved in anhydrous methanol (25 ml). The methanolic solution was treated with 1N sodium methoxide in methanol till the pH of the solution was 8.5 and stirred at ambient temperature for 2 hr. The sodium ions were removed by stirring the reaction mixture with Amberlite IRC-50 (H+) resin (5 g, dry weight) for 15 min before the neutral solution, free from resin, was evaporated to dryness. The residual gum was subjected to preparative tlc (silica gel) using ethyl acetate:water:n-propanol(4:2:1, v/v, upper phase) as the developer. The bands carrying the homogeneous products were eluted with the same solvent system and evaporated to dryness. The residue was crystallized from water to yield 80 mg of 5-amino-2-(2-deoxy-α-D-ribofuranosyl)-1,2,4-thiadiazol-3-one (11), m.p. > 150° (dec.) 1H nmr (Me2SO-d6) multiplet of four centered at δ6.1 and other protons.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH2:9])[CH2:11]2)[CH:3]=1
Reactant: Cc1cccc(Br)c1
Reactant: Nc1cccnc1
Product: Cc1cccc(N2C=CC=C(N)C2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.6 %

Procedure:
Following the general procedure using 3-bromotoluene (121 μL, 1.00 mmol) and 3-aminopyridine (113 mg, 1.20 mmol), the reaction was stirred for 20 h at rt. Column chromatography on silica gel (eluting with 40% EtOAc/hexanes) afforded the product as an off-white solid (180 mg, 98%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].[C:13]1([C:19]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=3)=[N:23][N:22]=[N:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>>[CH2:1]([C:3]1[N:12]([CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[N:20]([C:19]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:21]=[N:22][N:23]=3)=[CH:36][CH:35]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH2:1]([C:3]1[N:12]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[NH:20][N:21]=[N:22][N:23]=3)=[CH:32][CH:33]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nc2nccc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 154.5 %

Procedure:
2-Ethyl-7-methyl-3 (2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Part A of Example 7, from 2-ethyl-7-methylimidazo[4,5-b]pyridine (0.5 g, 3.11 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.82 g, 3.26 mmol) and NaH (3.12 mmol). The crude product (1.9 g, foam) was purified by flash chromatography on silica-gel using EtOAc-hexanees (1:1.5) to give the desired product as a white solid (0.95 g, 47.5 %). 1H NMR (300 MHz, CDCl3): 8.2 (d, 1H, J=5 Hz), 7.9 (d, 1H, J=8 Hz), 6.80-7.55 (m, 23H), 5.4 (s, 2H), 2.58-2.85 (m, 5H), 1.25 (t, 3H, J=7.8 Hz).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)#[N:25]>CN(C)C=O>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[O:34])=[CH:30][CH:31]=1)#[N:25]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: Nc1ccccc1N
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Nc1ccccc1NC(=O)Nc1ccc(C#N)cc1)c1ccccc1
Reaction time: 8 h

Procedure:
1.16 g (10.8 mmol) 1,2-phenylene diamine was dissolved in 10 ml dimethyl formamide, 2.1 g (15 mmol) potassium carbonate and 1.47 ml (10.8 mmol) 1-bromo-1-phenylethane were added with stirring. After 8 hours (h) at rt, most of the starting materials were consumed. Potassium bromide was filtered off, the solvent removed, the mixture redissolved in 20 ml THF and then 1,15 g (8 mmol) 4-cyanophenylisocyanate were slowly added and stirred for another 50 h at rt. The mixture was worked up by filtration, evaporated to dryness, dissolved in ethyl acetate and washed with diluted HCl, sodium carbonate solution and brine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].C1COCC1.[CH:14]1([CH2:20][Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]([OH:8])[CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]CC1CCCCC1
Reactant: Cc1ncsc1C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ncsc1C(O)CC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A 3-neck, 100 mL round-bottom flask was charged with the product from Example 22D (412.6 mg, 3.5 mmol) and anhydrous THF (15 mL) under N2 atmosphere. The reaction was cooled to −10° C. Cyclohexylmethylmagnesium bromide (7 mL, of a 1.0M solution in ether, 7 mmol) was added dropwise. The reaction was stirred for 1 hour, warmed to room temperature, and stirred for an additional 3 hours. The reaction was quenched with 10 mL THF/1M HCl (1:1). The aqueous and organic layers were separated. The pH ofthe aqueous layer was adjusted to 3 with 1M HCl. The aqueous layer was extracted with EtOAc (3×10 mL). All organic layers were combined and washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by silica gel column (1:1 EtOAc/hexanes) to provide 425.2 mg (58%) of the title compound as an orange oil.