Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[C:6]([CH3:34])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=4)=[O:20])=[CH:14][C:13]=2[F:33])[C:9]=1[CH3:10].[OH-].[Na+]>O1CCOCC1>[CH2:31]([N:22]1[C:23]2[C:28](=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)[CH:29]=[C:21]1[C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[C:6]([CH3:34])=[N:7]2)=[C:13]([F:33])[CH:14]=1)=[O:20])[CH3:32]
Reactant: CCn1c(C(=O)Nc2ccc(Cn3nc(C)c(CC(=O)OC)c3C)c(F)c2)cc2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1c(C(=O)Nc2ccc(Cn3nc(C)c(CC(=O)O)c3C)c(F)c2)cc2cc(F)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 1-ethyl-5-fluoro-1H-indole-2-carboxylic acid (140 mg, 0.68 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.094 mL, 0.68 mmol) and a drop dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (177 mg, 0.61 mmol) and diisopropylethylamine (0.23 mL, 1.35 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (8.255 mg, 0.069 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo. The residue is purified by MPLC (dichloromethane/methanol 95:5) to yield 160 mg of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=481; Retention time HPLC: 0.93 min (method D)). b) To a solution of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (160 mg, 0.33 mmol) in dioxane (2 mL) is added an aqueous solution of NaOH (1 M, 0.66 mL) and the mixture is stirred at 60° C. for 1 hour. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with acetic acid (2 M). The precipitate is freeze dried, dissolved in methanol and a little dimethylformamide, and the product is precipitated with a little water, filtered and dried to yield 137 mg of the title compound (ESI mass spectrum: [M+H]+=467; Retention time HPLC: 0.89 min (method D)).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:18])[C@@H:10]([CH:11]=[C:12]([Br:14])[Br:13])[C@H:9]1[C:15](Cl)=[O:16].[O:19]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][OH:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:18])[C@@H:10]([CH:11]=[C:12]([Br:14])[Br:13])[C@H:9]1[C:15]([O:32][CH2:31][C:29]1[N:30]=[C:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:27][CH:28]=1)=[O:16]
Reactant: OCc1csc(Oc2ccccc2)n1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2csc(Oc3ccccc3)n2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
1.6 ml of pyridine was added dropwise at 0° C. to a solution of 1.7 g of (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylicacid chloride and 1 g of the product of Step B in 20 ml of benzene and the mixture was stirred for 2 hours at 20° C. and was poured into aqueous N hydrochloric acid solution. The decanted organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-ethyl acetate mixture to obtain 1.87 g of (2-phenoxy-4-thiazolyl)-methyl (1R,3R)2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylate melting at ≃50° C. and having a specific rotation of [α]D20 =-9°±1° (c=1% in benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:33])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-2-one was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12g) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 609.4 [(M+H)+]
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[CH3:29]>C(#N)C>[I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:28]([C:30]4[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH3:29])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C(C)Cl)cn1
Reactant: COc1cc(Cn2cnc3cc(I)cnc32)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(C)Oc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 49.3 %

Procedure:
To a stirred mixture of 4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol (1.32 g, 3.46 mmol) and potassium carbonate (1.30 g, 9.41 mmol) in acetonitrile (25 mL) was added 5-(1-chloroethyl)-2-methoxypyridine (0.72 g, 4.20 mmol). The mixture was heated at 100° C. After 6.5 h, an additional quantity 5-(1-chloroethyl)-2-methoxypyridine (0.300 g, 1.75 mmol) was added, and heating was continued. After 22 h, the mixture was allowed to cool to room temperature and was partitioned between water and 1:5 ethyl acetate/diethyl ether. The phases were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (40 g SiO2 column, 0-10% 0.01 M ammonia in methanol/dichlormethane elute) afforded 0.88 g (49%) of 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an impure solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:5]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2cnccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C=Nc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosgene (20 ml, 20% in toluene from Fluka) in CH2Cl2 (300 mL) at 0° C. was treated with DMAP (10 g) in CH2Cl2 (100 mL) slowly. After complete addition, the mixture was treated with 5-aminoisoquinoline (5 g) in CH2Cl2 (100 mL) dropwise. The mixture was allowed to warm to room temperature and then stirred overnight. The solvent was removed under reduced pressure. The solid residue was extracted with diethyl ether (400 mL). The diethyl ether was filtered to provide the title compound in diethyl ether as a pale yellow solution. The diethyl ether solution was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9][CH3:10].[Br:11]Br.[Cl-].[Al+3].[Cl-].[Cl-].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].C(OCC)C.ClCCl>[Br:11][C:6]1[CH:7]=[C:2]([F:1])[C:3]([S:9][CH3:10])=[C:4]([F:8])[CH:5]=1
Reactant: CSc1c(F)cccc1F
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCOCC
Product: CSc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
Combine 1,3-difluoro-2-methylsulfanyl-benzene (4.3 g, 27 mmol), iron (300 mg, 5.4 mmol), bromine (1.4 mL, 27 mmol), aluminium chloride (400 mg, 3.0 mmol) and dichloromethane (100 mL), at 0° C. Stir the reaction mixture at room temperature for 2 hours. Add saturated sodium thiosulfate solution (20 mL) and diethyl ether (100 mL). Separate the layers and wash the organic layer with brine (20 mL). Dry with MgSO4, filter and concentrate in vacuo. Chromatograph the residue on a column eluting the material with diethyl ether in hexane (0 to 5%) to give 1.1 g of 5-bromo-1,3-difluoro-2-methylsulfanyl-benzene (17%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.C([N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([CH:19]2[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:30])=[CH:24][CH:25]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccccn1)C1CCNCC1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 ml of anhydrous tetrahydrofuran (THF) at -65° C. was added 88 ml (0.22 mole) of a commercial solution of 2.5M n-butyllithium in hexane at such a rate that the temperature did not exceed -60° C. The dark solution was stirred at -65° C. for 1 hr and then treated dropwise with a solution of 24.9 g (0.1 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 ml of THF at such a rate that the temperature did not exceed -60° C. The mixture was stirred for 1 hr at -65° C. and overnight at ambient temperature. The dark mixture was poured into 2 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with a 500-ml portion of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 500 ml of a 4% sodium hydroxide solution, 250 ml of water, and 250 ml brine.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.O>ClCCl>[C:15]([O:19][C:20]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([O:3][CH3:2])=[O:14])=[CH:13][CH:12]=1)=[O:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Yield: 99 %

Procedure:
Under ice cooling, terephthalic acid monomethylester chloride (1.1 g, 5.0 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No. 1-1, 1.1 g, 5.0 mmol) and triethylamine (30 mL) in dichloromethane (15 mL), and then the mixture was stirred at room temperature for 4 hours. Water (50 mL) was added thereto, and the whole was extracted with ethyl acetate (40 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with a mixed solvent (hexane (10 mL) and ethyl acetate (5 mL)), and the whole was dried under reduced pressure to give 1.8 g of the title reference compound as a white solid. (Yield 99%)
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH:4]=[O:5])[O:7][C:8]=2[CH:14]=1
Reactant: COc1ccc2cc(C(=O)N(C)OC)oc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)oc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
An ice-cooled solution of 4.0 g (0.017 mole) of N,6-dimethoxy-N-methyl-2-benzofurancarboxamide in 100 ml of tetrahydrofuran was treated cautiously over 15 minutes (under a nitrogen atmosphere) with 0.65 g (0.017 mole) of lithium aluminum hydride. The mixture was stirred for 1 hour, then quenched by the careful addition of 100 ml of saturated aqueous sodium bisulfate solution. The reaction mixture was extracted with ether (3X 75 ml), and the combined extracts were washed with cold 2% aqueous hydrochloric acid (2X 100 ml), followed by brine (lX 100 ml). The organic layer was dried (anhydrous magnesium sulfate) and evaporated. The residue was chromatographed (silica gel, dichloromethane elution) to yield 2.2 g (74% yield) of the analytically pure aidehyde, mp 75°-77° .
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([F:14])[CH:8]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:17]=[O:19])=[C:9]([F:14])[CH:8]=1
Reactant: COC(=O)COc1ccc(N)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, (4-amino-3-fluoro-phenoxy)-acetic acid methyl ester hydrochloride (Kori, Masakuni; Mild, Takashi; Nishimoto, Tomoyuki; Tozawa, Ryuichi. PCT Int. Appl. (2001), WO 2001098282 A1) was reacted with triphosgene in the presence of Et3N (3.5 eq.) in CH2Cl2 under reflux conditions for 14 h to give the title compound as brown solid. MS: m/e=243.1 [M+NH4+].
Reaction SMILES: [O:1]([C@@H:12]1[C@@H:29]([OH:30])[C@@H:28]([OH:31])[C@@H:27]([CH2:32][OH:33])[O:26][C@H:13]1[O:14][C@H:15]1[C@H:21]([OH:22])[C@@H:20]([CH2:23][OH:24])[O:19][CH:17]([OH:18])[C@@H:16]1[NH2:25])[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O.CC1OC(OP(OP(OCC2OC(N3C4NC(N)=NC(=O)C=4N=C3)C(O)C2O)(O)=O)(O)=O)C(O)C(O)C1O>>[O:14]([C@H:15]1[C@H:21]([OH:22])[C@@H:20]([CH2:23][OH:24])[O:19][CH:17]([OH:18])[C@@H:16]1[NH2:25])[C@@H:13]1[O:26][C@H:27]([CH2:32][OH:33])[C@H:28]([OH:31])[C@H:29]([OH:30])[C@H:12]1[OH:1]
Reactant: C[C@@H]1O[C@@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](CO)OC(O)[C@@H]3N)O[C@H](CO)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CC1OC(OP(=O)(O)OP(=O)(O)OCC2OC(n3cnc4c(=O)nc(N)[nH]c43)C(O)C2O)C(O)C(O)C1O
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Synthesis of Fucα1-2Galβ1-3GlcNH2 βSEt. Galβ1-3GlcNH2 βSEt is prepared as described above and used directly or after isolation as acceptor for a α1-2-fucosyltransferase (e.g. EC 2.4.1.69) reaction with a suitable glycosyl donor such as GDP-Fuc.
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.C(N(CC)CC)C.[CH3:34][CH:35]([NH2:37])[CH3:36]>CN1CCCC1=O.CO>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]4[C:2]([NH:37][CH:35]([CH3:36])[CH3:34])=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccc1
Reactant: CC(C)N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1noc(C)c1-c1ccc2nc(NC(C)C)n3c2c1OCC3c1ccccc1
Temperature: 120 °C
Yield: 28.8 %

Procedure:
To 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (9.1 mg, 0.025 mmol) in N-methylpyrrolidinone (0.40 mL), triethylamine (10 μL, 0.075 mmol) and 2-propanamine (21.2 μL, 0.25 mmol) were added and the mixture was heated at 120° C. overnight. The mixture was diluted with MeOH and purified by preparative LCMS (pH 10) to give the desired compound (2.8 mg, 29%). 1H NMR (500 MHz, DMSO-d6): δ 7.29 (3H, m); 6.92 (3H, m); 6.78 (1H, m); 6.55 (1H, m); 5.80 (1H, s); 4.68 (1H, m); 4.45 (1H, m); 4.00 (1H, m); 2.20 (3H, s); 2.02 (3H, s); 1.20 (3H, m); 1.09 (3H, m). LCMS calc. for C23H25N4O2 (M+H)+: m/z=389.2. found: 389.2.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[F:15][C:16]([F:23])([F:22])[C:17](=O)[CH2:18][C:19]#[N:20]>CCO>[NH2:20][C:19]1[N:1]([C:3]2[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=[C:17]([C:16]([F:23])([F:22])[F:15])[CH:18]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: CCOC(=O)Cc1cccc(NN)c1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Yield: 57 %

Procedure:
A mixture of ethyl (3-hydrazinophenyl)acetate (8.77 g, 0.028 mol, available from Example A5) and 4,4,4-trifluoro-3-oxo-butyronitrile (5.75 g, 0.042 mol) in EtOH (200 mL) was heated at reflux overnight. The mixture was concentrated and the residue purified by column chromatography to yield ethyl 2-(3-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetate (5 g, 57% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-d6): 7.50-7.43 (m, 3H), 7.30-7.33 (m, 1H), 5.81 (s, 1H), 5.75 (s, 2H), 4.09 (q, J=7.2 Hz, 1H), 3.76 (s, 2H), 3.38 (s, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: [C:1]1([S:7]([NH:10][NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCOC(C)=O>[C:1]1([S:7]([NH:10][NH:11][C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NNS(=O)(=O)c1ccccc1)c1ccc(NCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 17.7 %

Procedure:
4Aminobenzoic acid 2-(phenylsulfonyl)hydrazide (100 mg, 0.34 mmol) was dissolved in THF (3.4 mL), treated with acetic acid (20 μL, 0.34 mmol) and benzaldehyde (23 μL, 0.34 mmol), and stirred for 5 minutes. Sodium triacetoxyborohydride (87 mg, 0.41 mmol) was added, and the reaction was stirred overnight. The reaction was diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 3:2 hexanes/EtOAc to give 23 mg (18%) of the desired product. MS: 382.0 (M+1 for C20H19N3O3S1); mp 214-215° C.; TLC (SiO2) Rf=0.43 (1:1 hexane/EtOAc); HPLC (C18 column, 1:1 CH3CN/H2O+0.1% TFA) 99.04%, RT=8.309 min. HRMS (calc) 382.1225 (found) 382.1222; IR (KBr, cm−1): 3404, 3355, 3107, 1657, 1607, 1159. 1H NMR (DMSO-d6) δ 4.25 (d, 2H, J=5.6 Hz), 6.47 (d, 2H, J=8.3 Hz), 6.86-6.88 (m, 1H), 7.26-7.28 (m, 4H), 7.37-7.40 (m, 2H), 7.42-7.45 (m, 2H), 7.52-7.56 (m, 1H), 7.74 (d, 2H, J=7.8 Hz), 9.58 (s, 1H) 9.68 (s, 1H, 10.13 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:8][C:5]1[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)(=[O:20])=[O:19]
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccccc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 2-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOCC>C1COCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: N#CCCN1CCC(C2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 3-(4-cyclohexylpiperidin-1-yl)propionitrile (5.11 g, 23.3 mmol, 1.0 equiv) in anhydrous THF (15 mL) under argon was added a solution of BH3 in THF (1.0M, 82 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6N, 55 mL) was added and stirring was continued for 2 hours at 55°-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 58 mL, 2.5 equiv). The solvents were removed, ether (40 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×20 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2 Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.63 g (88%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Cl[CH2:16][CH2:17][C:18](Cl)=[O:19].CCN(C(C)C)C(C)C>C1COCC1>[F:2][C:3]([F:13])([F:14])[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:17][C:18](=[O:19])[NH:12]2)=[CH:9][CH:10]=1
Reactant: O=C(Cl)CCCl
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(c2ccc(OC(F)(F)F)cc2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.9 %

Procedure:
The compound was prepared according to Rees and Tsoi Chem. Commun. 2000, 415. A suspension of (4-trifluoromethoxyphenyl)-hydrazine hydrochloride (300 mg, 1.32 mmol, 1.00 eq), 3-chloropropionyl chloride (167 mg, 1.32 mmol, 1.00 eq), and PS-DIEA (1.30 grams (g), 5.28 mmol, 4.00 eq) in THF (20 mL) was stirred at ambient temperature for 12 h. The solution was then filtered, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (120 mg, 37%).
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:18][C:19]([OH:21])=O)[N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:18][C:19]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([F:30])=[C:23]([Cl:22])[CH:24]=3)=[O:21])[N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: Cn1c(CC(=O)O)nc(N2CCOC(CF)C2)cc1=O
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Na]
Product: Cn1c(CC(=O)Nc2ccc(F)c(Cl)c2)nc(N2CCOC(CF)C2)cc1=O

Procedure:
The product is prepared by following the procedure described in step 3b of example 1b, but using 250 mg of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid and 237 mg of 3-chloro-4-fluoroaniline. 97 mg of 2-[4-(2-fluoromethylmorpholin-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(3-chloro-4-fluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([NH2:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2,4-dichloro benzonitrile and a) phenyl magnesium bromide b) NaBH4 in MeOH in analogy to known methods.9