Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[S:17]([C:20]3[CH:25]=[CH:24][C:23](C=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl.[OH:39][NH2:40].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[S:17]([C:20]3[CH:21]=[CH:22][C:23](=[N:40][OH:39])[CH2:24][CH:25]=3)(=[O:19])=[O:18])[CH2:12][CH2:13]2)=[O:7])=[CH:36][CH:37]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)C1=CCC(=NO)C=C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
N-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-4-formyl-N-(2-methoxyphenyl)benzenesulfonamide (63 mg, 0.12 mmol) and hydroxyamine hydrochloride (9.5 mg, 0.132 mmol) were dissolved in ethanol (2 ml) to which were subsequently added anhydrous sodium carbonate (14 mg, 0.132 mmol) and water (1 ml). After 1.5 hours of stirring at room temperature, ethanol was removed by evaporation, and the resulting residue was mixed with water (10 ml) to collect crystals by filtration. The thus collected crystals were washed with water and hexane, dissolved in methylene chloride (50 ml) and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation to obtain 65 mg (100%) of the title compound in the form of colorless powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=2)[N:23]=[C:22]([C:31]([O:33][CH3:34])=[O:32])[CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([C:31]([O:33][CH3:34])=[O:32])[CH:21]=[C:20]2[N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]([C:4]2[NH:5][C:6]([CH3:9])=[C:7]([Cl:8])[C:3]=2[Cl:2])=[O:11])[CH2:14][CH2:15]1
Reactant: COC(=O)c1cc(Cl)c2cc(Cl)ccc2n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2cc(Cl)ccc2n1
Yield: 35.5 %

Procedure:
A solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 59 mg, 0.21 mmol), methyl 4,6-dichloroquinoline-2-carboxylate (F R Alexandre, et. al., Tetrahedron 2003, 59: 1413; 57 mg 0.22 mmol) and diisopropylethylamine (0.10 ml) in DMF (2.0 ml) was heated in a microwave reactor to 180° C. for 30 minutes. The reaction was diluted with 50 ml of EtOAc, then extracted with 25 ml of 1 N NaOH, 2×25 ml of water, dried over anhydrous MgSO4 and concentrated in vacuo. The crude solid was flash chromatographed through neutral silica gel using EtOAc as the eluent to give 37 mg of the title compound; crystallization from MeOH gave a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:10]CCCO1.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[ClH:1].[O:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][C:5]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[O:10])[CH2:22][CH2:23]2)=[N:25]1
Reactant: Fc1ccc(C2(CCCCl)OCCCO2)cc1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Product: Cl
Product: O=C(CCCN1CCN(c2noc3ccccc23)CC1)c1ccc(F)cc1
Yield: 25 %

Procedure:
Reaction of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane with 3-(1-piperazinyl)-1,2-benzisoxazole according to the procedure of Example 12 and conversion of the free base to the hydrochloride salt affords a 25% yield of 4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride, m.p. 260°-262°, from methanol (25% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25](Br)[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:33][Sn](C)(C)C>CN(C)C=O.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:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([CH3:33])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C)c3C[C@H]2O)C1
Temperature: 110 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
According to Scheme 13: A mixture of 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.05 g, 0.10 mmol), tetramethyltin (101 mg, 0.566 mmol) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) in N,N-dimethylformamide (2 ml) was stirred at 110° C. for 18 h. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 23 mg of 3-[5-acetyl-1-((1R,2R)-6-fluoro-2-hydroxy-4-methyl-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (19a).
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][N:25]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Agent: Cl
Product: O=C1CCCN1CC(=NOCc1ccccc1)c1cccnc1
Yield: 30.8 %

Procedure:
0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20 and 0.35 g (2.21 mmol) of benzyloxyamine hydrochloride salt were treated as described in Example 22 to obtain 0.14 g (31% yield) of 1-(2-benzyloxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (1.02:1).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[C:18](OC)([CH3:20])[CH3:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:12]([O:11][C:9]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2][O:1][C:18]([CH3:20])([CH3:19])[O:15][CH2:14]1)=[O:10])[CH3:13]
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Yield: 91 %

Procedure:
Diethyl 2,2-bis(hydroxymethyl)malonate (20 g, 90.82 mmol), acetone (20 ml), 2,2-dimethoxypropane (20 ml), and concentrated sulfuric acid (0.2 ml) were stirred at 25° C. for 2 days. The reaction was slowly poured into saturated aqueous sodium carbonate. The organic supernatant was separated and concentrated in vacuo. The residue was then dissolved in ether, rinsed with saturated aqueous sodium carbonate and brine, and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (21.4 g, 91%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.27 (t, J=7.1 Hz, 6H, 2×CH3), 1.42 (s, 6H, 2×CH3), 4.24 (q, J=7.1 Hz, 4H, 2×OCH2), 4.29 (s, 4H, 2×OCH2).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].N1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:15]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=2)[CH2:16][CH2:17][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccnc(CCl)c1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: COC(=O)c1ccnc(CN2CCCC2)c1
Reaction time: 0.08 h

Procedure:
A solution of product of stage (iii) (1.6 g) in dry dichloromethane (50 ml) at -50° was treated with triethylamine (1.07 ml) and the mixture was stirred for 5 min. A pre-cooled solution of pyrrolidine (1.28 ml) in dry dichloromethane (30 ml) was added at -60° and the mixture was stirred at -60° to 0° for 1 h and at ambient temperature for 72 h. The mixture was poured into aqueous sodium carbonate (1M; 50 ml) and the product was extracted with dichloromethane (50 ml). The organic solution was dried and evaporated leaving an oily residue (1.7 g) which was purified by flash chromatography eluting with dichloromethane/methanol/ammonia 200:10:1 to give the title compound as an oil (0.3 g).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:18]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:29]=[C:28]([CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH:18]=3)[S:13][C:6]=12)[NH2:30]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)cn4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)cn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 1.1 %

Procedure:
To a solution of nitro compound 169 (400 mg, 0.88 mmol) in EtOH/H2O (8 mL/4 mL) at 100° C. (bath) was added iron powder (420 mg, 7.48 mmol) and NH4Cl (41 mg, 0.76 mmol) and the reaction mixture was stirred vigorously at reflux temperature for an hour. The mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was collected and concentrated to give the title compound 170 (4.20 mg, 88% purity) as a yellow solid. MS (m/z): 424.0 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:28])=[C:7]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][CH:24]=[CH2:25])=[C:17]([CH3:26])[CH:16]=2)=[O:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C(OCC)C>C1COCC1>[CH2:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14]2[O:11][C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]=3[CH3:28])=[N:12][N:13]=2)=[CH:16][C:17]=1[CH3:26])[CH:24]=[CH2:25]
Reactant: C=CCOc1c(C)cc(C(=O)NNC(=O)c2scc(CC(C)C)c2C)cc1C
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOc1c(C)cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc1C
Yield: 118.3 %

Procedure:
A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N′-(4-isobutyl-3-methyl-thiophene-2-carbonyl)-hydrazide (160 mg, 0.4 mmol) and (methoxycarbonyl-sulfamoyl)triethylammonium hydroxide (350 mg, 1.27 mmol) in dry THF (5 mL) is heated at 110° C. in a microwave oven for 6 min. The mixture is poured into diethyl ether (10 mL) and washed with 1M aq. HCl (10 mL). The aq. phase is re-extracted with ether (10 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to give 181 mg of crude 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazole; LC-MS: tR=1.23 min, [M+1]+=383.35.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C
Temperature: 65 °C
Yield: 56 %

Procedure:
To a solution of ethyl 2-chloro-4-methyl-1,3-thiazole-5-carboxylate (X-1) (0.25 g, 1.22 mmol) and phenol (0.15 g, 1.61 mmol) in acetone (3 mL) was added K2CO3 (0.25 g, 1.81 mmol). The mixture was heated for 18 h at 65° C. Additional K2CO3 (0.25 g) was added and the mixture was continued to heat at 70° C. for 24 h. Upon cooling, water was added (10 mL). The mixture was extracted with Et2O. The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a white solid (0.18 g, 56%). 1H NMR (CDCl3) δ 7.44 (m, 2H), 7.33-7.27 (m, 3H), 4.26 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH3:31])=CC=1C(O)=O.N1CCCC1>>[CH3:31][NH:30][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CNS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 45 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-methylsulfamoyl-benzoic acid and pyrrolidine and obtained in 45% yield. MS (m/e): 283.1 (MH−, 100%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[O:23][C:24]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:25]=5[N:26]=4)=[CH:17][CH:16]=3)[C:7]=12.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH:33]3[CH2:38][CH2:37][CH2:36][N:35]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:34]3)[N:13]=[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]4[O:23][C:24]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:25]=5[N:26]=4)=[CH:19][CH:20]=3)[C:7]=12
Reactant: CN(C)CC(=O)O
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCNC5)c5ncnc(N)c45)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)CN(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
A mixture of N2-{4-[4-amino-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine acetate (0.04 g, 0.000078 mol), dimethylglycine (0.01 g, 0.000097 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.019 g, 0.000097 mol), N,N-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.011 g, 0.000078 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic solvent was washed with brine. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-[3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-2-(dimethylamino) 1-ethanone acetate (0.015 g, 0.00003 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.27 (d, 1H), 7.94 (d, 2H), 7.67 (d, 2H), 7.11 (s, 1H), 6.51 (s, 1H), 4.81-1.91 (br, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 1.91 (s, 3H). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.7 min.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:4]([C:22]1[CH:21]=[CH:20][C:19]([O:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:18][CH:23]=1)([CH3:13])([CH3:5])[CH3:3]
Reactant: Oc1ccccc1F
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 70.3 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 2-fluorophenol (63 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, and washed with H2O. The precipitate was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 79 (23 mg, 40% yield) as a tan solid. LC-MS (M+H=307, obsd.=307). 1H NMR (400 MHz, d6-DMSO): δ 11.99 (s, 1H), 8.74 (dd, 1H), 8.50 (dd, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 7.49 (m, 1H), 7.33 (m, 4H), 7.18 (dd, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[C:22](=[O:30])[N:23]([CH3:29])[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:18]=[C:17](Br)[CH:16]=1)[CH3:7])[CH3:2].[C:47]1(B(O)O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:18]=[C:19]([C:21]2[C:22](=[O:30])[N:23]([CH3:29])[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:20]=1)[CH3:7])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(Br)cc(-c2cn(C)c(=O)n(C)c2=O)c1
Product: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(-c2ccccc2)cc(-c2cn(C)c(=O)n(C)c2=O)c1
Yield: 28.6 %

Procedure:
A similar procedure as described in Example 1, step 2 was used, starting from 4-[3-{6-[3-bromo-5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-phenoxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (27 mg, 0.04 mmol) and phenylboronic acid (23 mg, 0.19 mmol) to obtain 4-[3-{6-[5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-biphenyl-3-yloxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (8 mg, 30%) as a light yellow oil: ES(+)-LRMS m/e calculated for C41H50N2O8 (M+H)+ 699.6, found 699.4.
Reaction SMILES: C[O-].[Na+].CC1C=CC(S(O[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:17]#[N:18])(=O)=O)=CC=1.Cl.[NH2:24][CH:25](C(OCC)=O)[C:26]([O:28][CH2:29]C)=[O:27]>CO>[NH2:18][C:17]1[CH:16]=[C:15]([C:19]([CH3:20])([CH3:21])[CH3:22])[NH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)C(C)(C)C)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred sodium methoxide solution (15% by weight, 80 mL total) was added drop-wise a solution of 1-cyano-3,3-dimethylbut-1-en-2-yl 4-methylbenzenesulfonate (10.0 g, 36 mmol) and diethyl aminomalonate hydrochloride salt (9.0 g, 43 mmol) in methanol (50 mL). After the addition was completed, the reaction was stirred at room temperature for 2 hours, the solvent was removed under vacuum and the crude product was dissolved in water and extracted with ethyl acetate. The combined organic layers was washed with brine, dried and the solvent removed under vacuum. The crude product was purified by column chromatography (silicagel, dichloromethane:methanol 95:5) to afford 2.4 g of the desired methyl 3-amino-5-tert-butyl-1H-pyrrole-2-carboxylate used as such in the next step.
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][CH2:8][N:9]([CH:14]1[CH2:19][CH2:18][CH:17]([N:20](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][CH2:15]1)[S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]>CCO.CO.[OH-].[OH-].[Pd+2]>[C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][CH2:8][N:9]([CH:14]1[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]1)[S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCN(C1CCC(N)CC1)S(C)(=O)=O
Yield: 98 %

Procedure:
N-[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-N-(4-dibenzylamino-cyclohexyl)-methanesulfonamide (3.282 g, 6.18 mmol) and Pd(OH)2 (0.40 g) were combined in EtOH/MeOH under Ar, and treated with H2 (45 psi) at RT for 1 day. The reaction mixture was then filtered, the solid washed with EtOH, the filtrates combined, and solvent removed in vacuo to yield N-[2-(t-butyl-dimethyl-silanyloxy)-ethyl]-N-(4-amino-cyclohexyl)-methanesulfonamide (2.123 g).
Reaction SMILES: C1[S:5][C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[N:3]C=1CSCCC(NS(N)(=O)=O)=N.NCCC1N=CNC=1.[H][H].C(CCSCC1N=C(NC(N)=N)SC=1)#N.NN=CNC(N)=S.[Cl:53][CH:54](Cl)[C:55](=[O:57])[CH3:56]>CC(C)=O>[ClH:53].[Cl:53][CH2:54][C:55]1([OH:57])[CH2:56][S:5][C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[N:3]1
Reactant: CC(=O)C(Cl)Cl
Reactant: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Reactant: [H][H]
Agent: N#CCCSCc1csc(NC(=N)N)n1
Agent: NCCc1c[nH]cn1
Agent: NN=CNC(N)=S
Solvent: CC(C)=O
Product: Cl
Product: N=C(N)NC1=NC(O)(CCl)CS1

Procedure:
Famotidine is a well-known histamine H2-receptor antagonist and gastric acid secretion inhibitor. A key intermediate for the preparation of this compound is N-[4-(cyanoethylthiomethyl)-2-thiazolyl]guanidine (also known as N-[4-[[(2-cyanoethyl)-thio]methyl]-2-thiazoyl]guanidine). To prepare this intermediate U.S. Pat. Nos. 4,562,261 and 4,609,737 describe a route based on N-[4-(chloromethyl)-4,5-dihydro-4-hydroxy-2-thiazolyl]-guanidine hydrochloride as the starting material. The synthesis involves preparing this starting material by portionwise addition of (aminoiminomethyl)thiourea to dichloroacetone in acetone at temperatures of about -5° to -7° C. and stirring the resultant mixture for 5 days at below 0° C. The resultant N-[4-(chloromethyl)-4,5-dihydro-4-hydroxy-2-thiazolyl]-guanidine hydrochloride is isolated, purified and converted to N-[4-[[(2-aminoiminomethyl)thio]methyl]-2-thiazoyl]guanidine) dihydrochloride by reaction with thiourea. Without isolating this intermediate, the reaction mixture is cooled below 10° C. and to the solution are added 3-chloropropionitrile and isopropyl alcohol, followed by dropwise addition of aqueous NaOH whereby crystals of N-[4-(cyanoethylthiomethyl)-2-thiazolyl]guanidine are formed.