Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][NH:35][N:36]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[N:36]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1ncc(-c2nn[nH]n2)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1nnc(-c2cnc(N)c(-c3cc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2)n1
Temperature: 80 °C

Procedure:
To the mixture of 1-(2-(2-amino-5-(2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (106 mg, 0.2 mmol, 1 eq) in anhydrous dimethylformamide (2 mL) under nitrogen atmosphere was added potassium carbonate (41.4 mg, 1.5 eq) and (2-bromoethoxy)-tert-butyldimethylsilane (0.06 mL, 1.3 eq). The resulting mixture was stirred and heated at 80° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure with silica gel. Gradient column chromatography (EtOAc-Hex from 1:100 to 3:1) gave 1-(2-(2-amino-5-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea as a fluffy white solid in the amount of 77 mg.
Reaction SMILES: [CH3:1][Li].[OH:3][C:4]1C=C2[C:7]([C:8]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[CH:9]C(=O)O2)=[CH:6][CH:5]=1.Cl.[CH3:26][CH2:27][O:28][CH2:29][CH3:30]>>[CH3:26][C:27]1([CH3:1])[CH:9]=[C:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:7]2[C:29](=[CH:30][C:4]([OH:3])=[CH:5][CH:6]=2)[O:28]1
Reactant: O=c1cc(-c2cccc3ccccc23)c2ccc(O)cc2o1
Reactant: [Li]C
Reactant: CCOCC
Agent: Cl
Product: CC1(C)C=C(c2cccc3ccccc23)c2ccc(O)cc2O1
Yield: 95 %

Procedure:
To a stirred solution of methyl-lithium in ether (60 ml, 2 M solution) at room temperature was added over 0.5 hours 7-hydroxy-4-(1-naphthyl)coumarin (7.5 g, 0.025 moles). The reaction mixture was refluxed for 2 hours, allowed to cool and decomposed by the addition of dilute hydrochloric acid. The organic layer was separated, the aqueous layer extracted with ether (2x) and the combined organic extracts washed with water and dried. Removal of solvent gave the required title chromene as an orange oil (7.22 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C.Cl[C:24]1[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:25]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:24]2[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[N:25]=2)[CH2:12][CH2:11]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: COc1ccccc1NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC1CCN(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 4-(2-methoxyphenylamino)-piperidine (0.8 g, 3.87 mmol) and triethylamine (1.3 g, 12.8 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.8 g, 3.61 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 2-(4-(2-methoxyphenylamino)-piperidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.2 g, 3.07 mmol, 85%) as white crystals.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([NH2:11])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:12]1(=O)[O:16][CH:15]=[CH:14][O:13]1.[C:18](=[O:21])([O-:20])[O-].[K+].[K+]>CCOCC>[C:12]([OH:16])(=[O:13])[C:18]([OH:20])=[O:21].[O:10]1[CH:15]=[CH:14][N:11]=[C:9]1[C:5]12[CH2:8][N:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=C([O-])[O-]
Reactant: O=c1occo1
Reactant: NC(=O)C12CCCN(CC1)C2
Agent: [K+]
Solvent: CCOCC
Product: O=C(O)C(=O)O
Product: c1coc(C23CCCN(CC2)C3)n1
Yield: 16 %

Procedure:
A stirred mixture of 1-azabicyclo[3.2.1]oct-5-ylcarboxamide (D20, 1.50 g, 0.0097 mole) and vinylene carbonate (1.2 g, 0.014 mole) in polyphosphoric acid (35 g) was heated at 120°-130° C. for 2h. The reaction mixture was allowed to cool, then treated with ice, before basifying with potassium carbonate solution. The aqueous was shaken well with ether, then the mixture filtered and the organic layer separated. The aqueous was again extracted with ether (2×80 ml) and all the ether extracts combined, dried (Na2SO4) and concentrated in vacuo to leave a yellow oil. This was chromatographed on a basic alumina column eluting with ethyl acetate and the material obtained converted to its oxalate salt and recrystallised from methanol/ether to give the title compound (E12) as a white solid (410 mg, 16%) m.p. 143°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(C)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and p-toluenesulfonyl chloride.
Reaction SMILES: O1[C:6]2[C@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3](=[O:25])[C:2]1=2.[ClH:26].C(=O)([O-])O.[Na+]>CC(C)=O>[Cl:26][C:2]1[C:3](=[O:25])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=1
Reactant: CCCCCCC=C[C@@H]1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCC=C[C@H]1C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 65 %

Procedure:
16 mg (46 microliters) of (4R)-2,3-epoxy-4-(1-octenyl)-5-(6-methoxylcarbonylhexylidene)cyclopentenone was dissolved in 1 ml of acetone. To the solution was added 0.1 ml of concentrated hydrochloric acid, and then the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried product was concentrated and subjected to silica gel column chromatography (silica gel, 5 g; eluent, hexane:ethyl acetate=15:1→6:1) to give 11 mg (yield 65%) of (4S)-2-chloro-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.C(O)C>O>[NH2:9][C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]=1[OH:26]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C

Procedure:
Sodium dithionite (174.11 g, 1.0 moles) in water (400 ml) was dropwise added to the nitrophenol ((a), 93.0 g, 0.38 mole) in refluxing ethanol. The resulting solution was refluxed for further 3 hours, then cooled at room temperature and filtered. The obtained solution was concentrated at a final volume of 100 ml. Water (100 ml) was added and the separated amine ((b), 72.0 g, 88%) was recoverd as brown powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1O>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: Oc1c(F)cccc1Cl
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2c(F)cccc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 2-chloro-6-fluorophenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:34]([CH3:44])=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[Br:45]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:45][CH2:44][C:34]1[C:35]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:37]2[C:32]([CH:33]=1)=[CH:31][C:30]([C:2]([OH:1])([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=1)[CH:3]([CH3:5])[CH3:4])=[CH:39][CH:38]=2
Reactant: COC(=O)c1cc2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2cc1CBr
Yield: 99.5 %

Procedure:
Methyl 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-3-methyl-2-naphthoate (5.93 g) was suspended in carbon tetrachloride (150 ml) and N-bromosuccinimide (2.01 g) and 2,2′-azobisisobutyronitrile (0.17 g) were added. The reaction mixture was heated under reflux for 4 hrs. and the solvent was concentrated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a crude title compound (6.70 g) as a brown amorphous solid.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.[OH-].[Na+].O.O=[CH:21][C:22]([OH:24])=[O:23].[Br:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([F:35])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH:21]([N:13]2[CH2:12][CH2:11][C:9]3([O:8][CH2:7][C:6](=[O:16])[N:5]([CH:2]4[CH2:4][CH2:3]4)[CH2:10]3)[CH2:15][CH2:14]2)[C:22]([OH:24])=[O:23])=[C:28]([F:35])[CH:27]=1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: O=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A suspension of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (4.05 mmol) in dichloromethane (10 mL) was treated with 1N aq sodium hydroxide (5.00 mmol) at room temperature. After one hour the organic layer of the reaction had turned from cloudy to clear. The aqueous layer was removed via pipet. To the remaining organic solution was added 2-oxoacetic acid monohydrate (4.05 mmol) and (4-bromo-2-fluorophenyl)boronic acid (4.05 mmol) at room temperature. The reaction was allowed to stir at room temperature for three days, after which the solution was concentrated to dryness under a stream of nitrogen. The resulting crude material was diluted with acetonitrile (10 mL) and transferred to a microwave reactor vial. The reaction vessel was sealed and the mixture irradiated in a Biotage Initiator Microwave at 80° C. for 30 min and then at 100° C. for 30 min. The reaction was concentrated to dryness in vacuo. The resulting crude material was purified by reverse phase HPLC (10-40% acetonitrile/water w/0.1% NH4OH) to afford the title compound as a white solid (853 mg, 45%). MS(ES)+ m/e 441.0/443.1 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][S:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[S:19][CH3:18])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CSc1ccccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CSc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-(methylthio)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][SH:12])[CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][S:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:2]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: SCCCNCc1cccnc1
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCCN1Cc1cccnc1
Yield: 48.4 %

Procedure:
A mixture of N-(3-pyridylmethyl)3-aminopropanethiol (1.8 g), 1-nitro-2,2-bis(methylthio)ethylene (1.7 g) and ethanol (40 ml) was heated under reflux for 5 hours under a nitrogen stream. After the reaction, about 2/3 by volume of ethanol was distilled off under reduced pressure. Ether was added little by little to the reaction mixture to precipitate crystals. The crystals were collected by filtration, and washed with a mixture of ethanol and there to give the desired 3-(3-pyridylmethyl)2-nitromethylenetetrahydro-2H-1,3-thiazine (1.2 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[CH:3]=1.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].CN(C)[CH:17]=[O:18]>C(OCC)C>[CH2:10]([C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH:17]=[O:18])[CH2:11][CH2:12][CH3:13]
Reactant: CN(C)C=O
Reactant: [Li]CCCC
Reactant: Fc1cc(Br)cc(Br)c1
Solvent: CCOCC
Product: CCCCc1cc(F)cc(C=O)c1
Yield: 43 %

Procedure:
Dissolve 1,3-Dibromo-5-fluoro-benzene (12.00 g, 0.05 mmol) in diethyl ether (470 mL) and cool to −78 C. Slowly add 1.6 M n-butyllithium in hexanes (29.5 mL, 49.6 mmol) and stir at −78 for one hour. Add dimethylformamide (3.45 g, 0.05 mmol) dropwise and warm to room temperature overnight. Quench with saturated aqueous ammonium chloride solution. Separate the layers and extract the organic layer (1×300 mL) with diethyl ether. Combine the organic layers and wash (1×150 mL) with water, (1×100 μL) with saturated aqueous sodium chloride and dry over magnesium sulfate. Purify using medium pressure chromatography (silica gel, 0-10% diethyl ether:hexanes) to give the desired product (4.15 g, 43%) as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=O.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:6]2[CH2:10][CH2:9][CH2:8][C:7]=2[NH:16][N:15]=1
Reactant: COC(OC)C(=O)C1CCCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(OC)c1n[nH]c2c1CCC2

Procedure:
5.7 g (30.6 mmol) of 2-(2,2-dimethoxyacetyl)cyclopentanone is dissolved in 50 mL of ethanol and after the addition of 6 g (96 mmol) of hydrazine hydrate (80%) refluxed for 2.5 hours. The ethanol is distilled off, the residue is combined with water and extracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The crude product is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate 1:2. Yield: 3.1 g (56%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>N1C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:13][NH2:14])=[CH:3][CH:4]=1
Reactant: NN
Reactant: FC(F)(F)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(C(F)(F)F)cc1
Temperature: 180 °C
Yield: 20 %

Procedure:
A mixture of 4-chlorobenzotrifluoride (1.08 g), hydrazine hydrate (1.8 g, 6 molar equivalents) and pyridine (5 ml) was heated in an autoclave (purged with argon) for 6 hours at 180° C. The mixture was cooled, the excess hydrazine decanted and the organic phase evaporated in vacuo. The residue was crystallised from petroleum ether to give the title compound in 20% yield. It was shown that 20% of the starting material had been consumed, thus indicating that the reaction had occurred with high selectivity.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:6](OC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+].O.ClCCl>CO>[OH:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: COC(=O)C(CN1CCN(C)CC1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)NC(CO)CN1CCN(C)CC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
A solution under inert atmosphere of 3.27 g of methyl (acetylamino)-3-(4-methyl-piperazin-1-yl)propanoate in 100 mL of anhydrous methanol is cooled at a temperature of about 10° C., then 0.76 g of sodium borohydride are added using a spatula. The reaction medium is stirred for 5 hours at a temperature of about 20° C., then are added again 0.26 g of sodium borohydride and the stirring is carried out for 38 hours. Then, 5 mL of water is dropped into the reaction mass which is heated and concentated under reduced pressure (2 kPa) at a temperature of about 30° C. The obtained residue is taken up with dichloromethane and the insoluble matter is removed by filtration. The filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. The residue is purified by chromatography under argon pressure (60 kPa), on a column of silica gel (particle size 40–63 μm; diameter 5 cm; height 19 cm), eluting with successive mixtures of 20% dichloromethane/methanol/aqueous ammonia (98/2/0, 95/5/0.1, 90/10/0.2, 80/20/0.25, 50/50/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.92 g of N-[2-hydroxy-1-(4-methyl-piperazin-1-ylmethyl)ethyl]acetamide are obtained in the form of a yellow-colored liquid. [Infrared spectrum CH2Cl2 3621; 3429; 3352; 2944; 2803; 1657; 1513; 1460; 1284; 1050; 1011 and 816 cm−1].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH3:49][N:50]([CH:67]([C:75](=[O:78])[NH:76][CH3:77])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:51](=[O:66])[CH:52]([NH:64][CH3:65])[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[N:64]([CH3:65])[C@@H:52]([C:51](=[O:66])[N:50]([C@@H:67]([C:75](=[O:78])[NH:76][CH3:77])[CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH3:49])[CH2:53][C:54]2[CH:63]=[CH:62][C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:55]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
To a suspension of 4-tert-butoxycarbonylamino cyclohexanecarboxylic acid (115 mg, 0.47) in 5 ml of dichloromethane was added 1-hydroxy-7-azabenzotriazole (64 mg, 0.47 mmol) in 0.5 ml N,N-dimethylformamide. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.52) was added and the solution was stirred for 20 min. Diisopropylethylamine (120 mg, 0.94 mmol) and N-methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide (191 mg, 0.47 mmol) in 5 ml of dichloromethane was added and the mixture was alloved to stand overnight at room temperature. The mixture was washed with water (5 ml), sodium bicarbonate (5 ml) water (2×5 ml) and brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (20 g) with ethyl acetate as eleuent to give 242 mg of (4-[N-Methyl-N-{(1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphtyl)ethyl}-carbamoyl]cyclohexyl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:29])([F:28])[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1.[H-].[Na+].O>CN(C=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:27][C:25]3[S:26][C:22]([C:21]([F:29])([F:28])[F:20])=[N:23][N:24]=3)[C:3]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2s1
Reactant: Nc1nnc(C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc(Nc2ncnc3sc(Cc4c(Cl)cccc4Cl)nc23)s1
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (83 mg, 0.3 mmol) and 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamine (63 mg, 0.4 mmol) in DMF (1 mL) was added NaH (60% dispersion in oil; 20 mg, 0.5 mmol) at rt. After 12 h, the reaction mixture was poured into H2O (5 mL) and the resulting solid was collected by vacuum filtration and washed with 1:1 (IPA-H2O) to afford the title compound as a yellow solid (48 mg, 41%). MS (ESI): mass calcd. for C15H7Cl2F3N6S2, 462.0; m/z. found, 462.9 [M+H]+. 1H NMR ((CD3)2SO): 8.45 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.46-7.41 (m, 1H), 4.72 (s, 2H).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH2:22][OH:23]>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:23][CH2:22][C:21]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:20]=1[F:19])=[O:3]
Reactant: OCc1cc(F)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(F)ccc1F
Product: Cl

Procedure:
2,5-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,5-difluorobenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.247 g, 77% overall); (Found: C, 52.5; H, 6.1; N, 8.7%. C14H18F2N2O2.HCl requires C, 52.4; H, 6.0; N, 8.7%); δH (400 MHz, DMSO-d6), 9.98 (2H, br),7.29 (3H, m), 5.15 (2H, s), 4.31 (2H, m), 3.15 (2H, d, J 12.8 Hz), 3.06 (2H, dd, J 5 and 13 Hz), and 1.31 (6H, d, J 7.2 Hz).