Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([C:23]1[C:24]([CH3:30])=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)[N:11]=2>CS(C)=O>[NH2:29][C:26]1[N:25]=[C:24]([CH3:30])[C:23]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[C:8]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:9]3[CH2:31][CH:32]3[CH2:34][CH2:33]3)=[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:13]=2)=[CH:28][N:27]=1
Reactant: CN(C)CCN
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CS(C)=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(NCCN(C)C)n(CC3CC3)c2n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
N,N-Dimethylethylenediamine (110 mg, 1.3 mmol) and dimethyl sulfoxide (700 μl) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was concentrated, and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (64 mg, 52%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]CCCC.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:35]=1[CH:36]=[O:37]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:36]([OH:37])[C:35]1[C:38]([O:42][CH3:43])=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH3:32])(=[O:9])=[O:10]
Reactant: COc1cccc(OC)c1C=O
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2c(OC)cccc2OC)sc2ncccc12
Yield: 63.6 %

Procedure:
The title compcund was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.15 g, 0.35 mmoles) [Example 4(A)], THF (5 ml), n-BuLi (2.5 M, 0.16 ml, 0.41 mmoles) and 2,6-dimethoxybenzaldehyde (88 mg, 0.53 mmoles). Flash chromatography (50% EtOAc/hexanes) provided 0.13 g (62%) of the title compound as a pink oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[N:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][N:12]=1.O>CN(C=O)C>[I:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:16]=1
Reactant: Fc1cc(I)ccn1
Reactant: Oc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccnc(Oc2cncnc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 259 mg (26.9 mmol) pyrimidin-5-ol (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 min at rt. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80° C. Subsequently the mixture is poured into water and extracted with ethyl acetate (3×). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/ethyl acetate, gradient 0-60%) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](#[N:22])[CH:20]=[CH2:21].[CH2:23]([OH:26])CC>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:23](=[O:26])[N:16]([CH2:21][CH2:20][C:19]#[N:22])[N:15]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCO
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: C=CC#N
Product: N#CCCn1nc(-c2ccc(OCc3ccccc3)cc2)oc1=O
Yield: 88 %

Procedure:
To a solution of 100 mmoles of (4-benzyloxy benzoyl) hydrazine in 200 ml of 1-propanol, 100 mmoles of acrylonitrile are added and the mixture is heated for 24 hours at reflux. Then 50 mmoles of acrylonitrile are added and the heating is continued at reflux for 24 hours. After cooling, the product is filtered and crystallized in a water-ethanol mixture and 26 g (yield: 88%) of the expected product were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].C(OCC)(=O)C>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCCC(=O)NCC(=O)O
Yield: 79.5 %

Procedure:
Glycine (20 mmol) was reacted with nonanoyl chloride (22 ml) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 1 Part A. The crude crystalline product (4.25 g) was recrytallized from ethyl acetate (40-50 ml) to give the title compound (3.42 g, 79.5%), m.p. 106°-109° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[O:4][N:3]=1.Cl.C(O)C.CC(OC)(C)C>ClCCl>[CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[O:4][N:3]=1
Reactant: Cc1noc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CCO
Product: Cc1noc(C2CCCNC2)n1
Temperature: 40 °C
Yield: 114.4 %

Procedure:
tert-Butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 2a,b (0.81 g, 0.0030 mol) was dissolved in 5 mL dichloromethane. Hydrochloric acid in ethanol (2.5 M) (2.43 mL, 0.0060 mol) was added and the mixture was heated to 40° C. for 3 hours. 20 mL of MTBE was added and the product precipitated from solution. The solids were filtered and washed with 3×5 mL MTBE and dried under vacuum overnight to obtain 574 mg of a white solid in 94% yield. MS (ESI) m/z 168 [M+1]+. 1H NMR (DMSO-d6) δ 1.74-1.82 (m, 3H), 2.11-2.14 (d, 1H), 2.31 (s, 3H), 2.87 (t, 1H), 3.10-3.30 (m, 2H), 3.49-3.56 (m, 3H).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13](=[O:15])C)[CH:11]=2)[CH2:6][CH2:5]1.C([O-])(O)=[O:17].[Na+]>>[CH2:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([OH:15])=[O:17])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80 mmol, 6%) at 55° C. was added 1-(2,3-dihydro-1H-inden-6-yl)ethanone (120.0 g, 0.75 mol) and the mixture was stirred at 55° C. for 2 h. After cooling to room temperature, saturated NaHCO3 solution was added until the solution became clear. The produced precipitate was filtered, washed several times with water and dried to afford the desired product (120.0 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 2.07-2.17 (m, 2H), 2.96 (t, J=7.5 Hz, 4H), 7.30 (d, J=7.8, 1H), 7.91 (d, J=7.8, 1H), 7.96 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13](Cl)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13]([NH:16][C:17]3[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=3[C:22]([NH2:24])=[O:23])=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2cc(C(=O)Cl)oc12
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc2cccc(OCC)c2o1

Procedure:
From 7-ethoxybenzofuran-2-carbonyl chloride (4.124 g, 20 mmol), 1 (1.82 g, 10 mmol), DMAP (32.5 mg, 0.27 mmol) and Et3N (2.02 g, 20 mmol) in anhydrous CH2Cl2 (65 mL) using the same procedure as for 3 the title compound was obtained as?a white solid; mp: 219-221° C.; 1H NMR (DMSO-d6) δ 0.86 (t, J=7 Hz, 3 H), 1.43 (t, J=7 Hz, 3 H), 1.56 (sxt, J=7 Hz, 2 H), 2.42 (t, J=7 Hz, 2 H), 3.91 (s, 3 H), 4.28 (q, J=7 Hz,2 H), 7.10 (d, J=6 Hz, 1 H), 7.26 (t, J=6 Hz, 1 H), 7.35 (d, J=6 Hz, 1 H), 7.50 (s, br. 1 H), 7.71 (s, 1 H), 7.76 (s, br. 1 H); MS (m/z): 371 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[OH-].[Na+].O>[C:14]1([S:20]([O:1][C:2]2[CH:13]=[CH:12][C:5]3[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=3[CH:3]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1csc2ccc(O)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 96.5 %

Procedure:
5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11) (M. Martin-Smith et al. J. Chem. Soc (C),1899-1905 (1967) 8.63 g (44.4 mmol)) was dissolved in aqueous tetrahydrofuran (water content, 20%; 160 ml) and 1 N sodium hydroxide (44 ml). To the solution were added dropwise 0.56 N sodium hydroxide (87 ml) and benzenesulfonyl chloride (6.2 ml, 48.4 mmol) simultaneously with stirring under ice-cooling while maintaining the pH at 11-12. After the completion of the reaction, the mixture was diluted with water, basified, and washed with toluene. The aqueous layer was made slightly acidic by adding concentrated hydrochloric acid with stirring, and the deposited crystals were filtered, washed with water and dried to provide 14.33 g of 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (12).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[OH:32])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: Nc1ccccc1O
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(Nc5ccccc5O)sc4c3)c2cc1OC
Temperature: 110 °C
Yield: 16.3 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (70 mg, 0.17 mmol) from Example 2 and 2-aminophenol (95 mg, 0.87 mmol) in anhydrous DMA (300 μL) at rt was added DIEA (90 μL, 0.52 mmol). The mixture was stirred and heated in a sealed tube at 110° C. for 96 h. After cooling to rt, the mixture was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)phenol (12 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.77 (br s, 1H), 8.14-8.26 (m, 2H), 7.75 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.24-7.29 (m, 1H), 7.16-7.22 (m, 2H), 6.79-6.92 (m, 3H), 5.46 (s, 2H), 3.76 (s, 6H). LCMS (ESI) m/z 461 (M+H)+.
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].S(OC)(OC)(=O)=O.S(OS(OC)(=O)=O)(OC)(=O)=O.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:1]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)(=[O:4])=[O:2])=[CH:26][CH:25]=1
Reactant: Clc1ccccc1
Reactant: O=S(=O)=O
Agent: COS(=O)(=O)OS(=O)(=O)OC
Solvent: COS(=O)(=O)OC
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
When the components are passed once through the reactor at a rate giving a residence time of from 1 to 3 minutes, the conversion rate is 57%. This can be increased to 91% conversion by continuously pumping the effluent reaction mixture back to the fixed bed of the reactor to give an average residence time of approximately 15 minutes. No advantage is gained, we have found, by first converting sulfur trioxide and dimethyl sulfate to reactive dimethyl pyrosulfate and then reacting the latter with chlorobenzene. Precipitating the product in chlorobenzene instead of aqueous sulfuric acid gives bis(4-chlorophenyl) sulfone having a purity of >99.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].C([Li])CCC.[C:15](=[O:17])=[O:16].O>C1COCC1.CCCCCC>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:7]=1[CH3:8])[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: Cc1c(Br)cncc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cncc1C(=O)O
Reaction time: 0.25 h

Procedure:
Under argon, a solution of 3,5-dibromo-4-methylpyridine (intermediate 10.1, 2.51 g, 10 mmol) in anhydrous THF (100 ml) is reacted at a temperature of −100° C. with a solution of n-butyllithium in hexane (1.6N, 6.5 ml). The reaction mixture is stirred for 15 min and then dry ice is added. The temperature is kept for 15 min at −85° C., for 1 h 30 min at −78° C. and for 2 h at room temperature. Water is added. The solvents are evaporated under vacuum and the residue is purified, eluting on diol grafted silica with MeOH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:23])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.51 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot methanol, filtered while hot, and cooled to room temperature. The resulting solid was collected by filtration and dried under high vacuum at room temperature to give 3.00 g (54%) of title compound, mp>250° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]([NH2:9])=[S:8].Cl[CH2:11][C:12](=O)/[C:13](=[N:17]/[O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])/[C:14]([OH:16])=[O:15].Cl>O>[NH2:6][C:7]1[S:8][CH:11]=[C:12](/[C:13](=[N:17]/[O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])/[C:14]([OH:16])=[O:15])[N:9]=1
Reactant: NC(N)=S
Reactant: COC(=O)CO/N=C(\C(=O)O)C(=O)CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 12 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
Sodium acetate (120 gm) is added to water (400 ml) and thiourea (41.6 gm) at 25-30° C., cooled to 12° C. and then (Z)-4-chloro-2-[[(methoxycarbonyl)methoxy]imino]acetoacetic acid (100 gm) Is added at 12° C. The contents are stirred for 3 hours at 25-30° C., cooled to 5° C., pH is adjusted to 3.0 with conc. hydrochloric acid at 5-0° C. Then the reaction mass is cooled to 0° C. and stirred for 1 hour at 0-5° C. The resulting solid is filtered, washed two times with chilled water (each time 100 ml) and dried at 100-105° C. to give 95 gm of (Z)-2-(2-aminothiazol-4-yl)-(methoxycarbonyl)methoxyimino acetic acid (High Performance Liquid Chromatographic (HPLC) purity: 99.5%). B) 2,2′-Dithiobis(benzothiazole) (117.75 gm) and acetonitrile (580 ml) are added to (Z)-2-(2-aminothiazol-4-yl)-(methoxycarbonyl)methoxyimino acetic acid (75 gm) at 25-30° C. and then distilled off 50 ml of acetonitrile under vacuum at 45-50° C. The contents are cooled to 25° C. under N2 atmosphere, flushed with 20 ml of acetonitrile and cooled to 13° C. Triethylamine (30 gm) is added to the contents at 13° C., stirred for 30 minutes at 13° C. under N2 atmosphere and then cooled to 0° C. Triphenylphosphine (96 gm) is added to the reaction mass at 0° C., stirred for 1 hour at 0-2° C. and cooled to −10° C. Then the reaction mass is stirred for 4 to 5 hours at −10° C., filtered the mass and washed with chilled methanol. Methanol (470 ml) is added to the reaction mass at 25° C., cooled to −5° C. under N2 atmosphere, the wet cake is added for 5 minutes at −5° C. and stirred for 1 hour at −5° C. Filtered the mass, washed with methanol (100 ml) and dried to yield 93.75 gm of 2-mercapto-1,3-benzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-(methoxycarbonyl)-methoxyimino acetate (HPLC purity 98.2%).
Reaction SMILES: [Mg].F[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:11]12[CH2:10][C:14](=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]2=1
Reactant: C1=CCC=C1
Reactant: Fc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: C1=C2CC(=C1)c1ccccc12
Reaction time: 1 h
Yield: 40 %

Procedure:
10 g of magnesium turnings which are covered with approximately 75 cm3 of anhydrous tetrahydrofuran are placed in a round flask fitted with a condenser, a thermometer, a nitrogen inlet, a dropping funnel, and protected from atmospheric moisture by a calcium chloride tube. 25 cm3 of a solution, prepared beforehand, of 65 g of ortho-fluorobromobenzene and 26 g of cyclopentadiene in 200 cm3 of anhydrous tetrahydrofuran are then added. The formation of the organomagnesium compound is initiated by heating the reaction mixture locally with a hairdryer, and the solvent is then kept at boiling point by dropwise addition of the remaining solution. The whole addition is completed in approximately 1 hour. The mixture is then filtered at ambient temperature and the solution is concentrated under reduced pressure. The solution is taken up again in ether and the ether phase is washed with ammonium chloride, separated by gravity and dried over magnesium sulphate; the solvent is then removed by evaporation under vacuum. The residue is then distilled and benzonorbornadiene, whose boiling point is 82°-83° C. at a pressure of 16 millibars, is obtained in a yield of 40%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: COC(=O)CCBr
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCC(=O)OC)OCC
Reaction time: 8 h
Yield: 26.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (8.72 ml, 60 mmol) was reacted with methyl 3-bromopropionate (3.27 ml, 30 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.75 g, 27%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]/[C:4]#[N:5].C[O:8][C:9](=O)[C:10]#[CH:11].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CN(C=O)C>[CH3:6][C:2]1[NH:1][C:9](=[O:8])[CH:10]=[CH:11][C:3]=1[C:4]#[N:5]
Reactant: C#CC(=O)OC
Reactant: C/C(N)=C\C#N
Solvent: CN(C)C=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1[nH]c(=O)ccc1C#N
Temperature: 230 °C

Procedure:
A solution of (E)-3-amino-but-2-enenitrile (100 g) and propynoic acid methyl ester in DMF (200 ml) was stirred at 25° C. for 2 h and refluxed for additional 1 h. Dowtherm (100 ml) was added and the temperature was raised to 230° C. DMF and MeOH were distilled off. The reaction mixture was cooled down, EtOAc (200 ml) was added and the resulting crystals were filtered off and washed with EtOAc and ether affording the title compound (44.8 g, FP>250° C.).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[C:15](OC(=O)C)(=O)C.[ClH:22].O1CCOCC1>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6](=[O:5])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 5.04 mmol) in DCM (15 mL) is added acetic anhydride (0.52 mL, 5.55 mmol) and the reaction stirred at about 25° C. for 72 hours. The reaction is concentrated, and the residue dissolved in DCM (15 mL) and treated with 4M HCl in 1,4-dioxane (5.04 mL, 20.2 mmol). The reaction is stirred overnight, and the solid filtered to afford the title compound (O).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][C:8]2([S:11]([O-])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1.[Na+].P(Cl)(Cl)([Cl:19])=O>>[CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][C:8]2([S:11]([Cl:19])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)OC[C@H](CC2(S(=O)(=O)[O-])CC2)O1
Agent: [Na+]
Product: CC1(C)OC[C@H](CC2(S(=O)(=O)Cl)CC2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium (S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate (1 eq) and phosphoryl trichloride (POCl3, 0.7 mL/mmol) is heated at 80° C. for 1 hour. The reaction mixture is cooled to room temperature, poured onto ice, stirred for 30 minutes and extracted with chloroform (2×). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: N#Cc1c(N)cccc1OC[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N

Procedure:
Prepared as in Example 2a from (R)-benzyl 2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example 92c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]([NH2:16])=[O:34])=[N:13][CH:14]=1
Reactant: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)cccc21
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(1-methyl-1H-indol-4-ylamino)pyrazine-2-carbonitrile (18 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 380.5 (M+H); UV 221.2, 273.8, 322.5 nm; t 0.518 min.