Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.F[C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[N:26][CH:27]=1.O>CC(N(C)C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:22]2[CH:27]=[N:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Add potassium tert-butoxide (4.84 g) to a solution of tert-butyl 4-hydroxy-1-piperidine-carboxylate (8.76 g) in dimethylacetamide (DMA, 39 mL) at 0° C. under nitrogen. Stir for 1 h and add drop wise a solution 5-fluoro-2-nitro-pyridine (5 g) in DMA (78 mL). Let the reaction stir at RT overnight. Add water and stand for 1 h. Filter, wash with water. Purify by silica gel column chromatography eluting with DCM/EA (0-15%) to afford 5.65 g of the title compound. MS (ES+): m/z=324 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26]>C(N(CC)CC)C>[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[CH:11]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 4.1 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 200 ml DMF and 1.8 g HOBtxH2O and 16.0 ml triethylamine is stirred for 0.5 h. Then it is added 6.6 g EDCxHCL and stirred for 0.5 h. After that 2.4 g (2-amino-phenyl)-carbamic acid tert-butyl ester are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate and evaporated. The title product is isolated by flash chromatography. By this method 3.7 g of a colorless solid is obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCCC2)cc1
Yield: 96.6 %

Procedure:
Add pyrrolidine (0.89 mL, 10.74 mmol) to a stirred solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) and triethylamine (1.5 mL, 10.74 mmol) in anhydrous THF (26 mL). Stir reaction overnight at room temperature. Partition the reaction mixture between EtOAc and water. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter, and concentrate in vacuo to obtain the desired intermediate (918 mg, 97%) suitable for use without further purification. MS (APCI+) m/z: 187 (M+H)+.
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>CO.Cl>[C:11]12([C:10]3=[C:5]([OH:4])[CH:6]=[CH:7][CH:8]=[C:9]3[O:15][CH2:14]1)[CH2:13][CH2:12]2
Reactant: COCOc1cccc2c1C1(CC1)CO2
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc2c1C1(CC1)CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 4-{[(methyloxy)methyl]oxy}spiro[1-benzofuran-3,1′-cyclopropane] (Reference Intermediate 213, 118 mg) in methanol (5 ml), HCl 2N in water (0.286 mL, 0.572 mmol) was added and the reaction mixture was stirred overnight at 50° C. Combined solvents were removed under reduced pressure and the residue was re-dissolved in toluen (10 ml) and the solvent was removed. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a white solid (70 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78][CH2:77]1>CN(C)C=O>[C:85]([O:84][C:82]([N:79]1[CH2:80][CH2:81][CH:76]([NH:75][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([CH3:31])[CH:24]=2)[CH2:77][CH2:78]1)=[O:83])([CH3:88])([CH3:86])[CH3:87]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0417 g (0.208 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0772 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-191) as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[C:15]1([CH2:21][C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 55.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.78 g, 4.1 mmol), phenylacetyl chloride (1.1 mL, 8.2 mmol), and triethylamine (1.8 mL, 13 mmol) in tetrahydrofuran (10 mL) provided 2-phenyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-acetamide (0.70 g). Mp 180-181° C.; Anal. Calcd. for C20H19NO2: C, 78.66; H, 6.27; N, 4.59; Found: C, 78.53; H, 6.13; N, 4.75.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([OH:17])(=O)[CH3:15]>>[OH:17][C:14]1[CH:15]=[CH:6][C:5]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:4][CH:9]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
The Schiffs base of Formula 19 (807 g, 4.098 m) , 4-nitrophenylacetic acid (Formula 20, 742 g, 4.098 m), and glacial acetic acid (3.5 liters) were charged into a 12 liter, 4 necked flask, fitted with a reflux condenser, a mechanical stirrer, and a long thermometer, and provided with an argon atmosphere. The mixture was heated to about 50° C., and stirred for about 7 days at that temperature, during when an orange solid formed in the reaction. After that period, the mixture was refluxed for about 2 hours, and the solution was concentrated to about 2500 ml by distilling off a quantity of the acetic acid. Cooling of the mixture gave an orange solid, which was then filtered, and dried. The product of Formula 21 was recrystallized from boiling acetonitrile to give bright yellow needles, which were filtered and dried in a vacuum oven at about 70° C. Yield: 693 g (70%), m.p. 208°-210° C.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.Cl.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:15])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.0 g (3.22 mmol) Boc-D-Phe(4-NO2)—OH (Iris Biotech) and 0.84 g (3.22 mmol) H-Phe(4-NO2)—OMe.HCl (Aldrich) were suspended in 25 ml of DMF and stirred on the ice bath. After addition of 1.66 g (3.22 mmol) of PyBOP and 1.67 ml (9.66 mmol) of DIPEA (pH 7-8), the mixture was stirred at 0° C. for 2.5 h. The solvent was removed in vacuo and the yellow oil was taken up in 5% KHSO4 soln./EtOAc. The organic phase was washed 3× with 5% KHSO4 soln., 1× with sat. NaCl soln., 3× with sat. NaHCO3 soln. and 3× with sat. NaCl soln. The organic phase was dried with MgSO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Cl[C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14].C(OC(CCCCCC(=O)C(OC)=O)=O)(C)(C)C>[Zn]>[C:7]([O:6][C:4]([CH2:3][CH2:2][C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: COC(=O)C(=O)Cl
Agent: COC(=O)C(=O)CCCCCC(=O)OC(C)(C)C
Agent: [Zn]
Product: COC(=O)C(=O)CCC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
3-Bromopropanoic acid, tert-butyl ester (2.2 g, 10.6 mmol), activated zinc (1.25 g in 25 ml of THF) and methyl chlorooxoacetate (1.4 ml, 11.4 mmol) were reacted by the same procedure as described in Example 1 for the preparation of methyl 7-tert-butyoxycarbonyl-2-oxoheptanoate to give the crude title material (1.65 g) as a colorless liquid which is used directly in next step.
Reaction SMILES: O1CCOCC1.[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([O:29][CH2:30][C:31]#[N:32])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:34])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([Sn]([N:48]=[N+:49]=[N-:50])(CCCC)CCCC)CCC.[OH-].[Na+]>CCOCC>[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([O:29][CH2:30][C:31]4[NH:50][N:49]=[N:48][N:32]=4)=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1c(OCc2nnn[nH]2)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 25 °C

Procedure:
To a 5 ml 1,4-dioxane solution of 300 mg of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile was added 0.8 ml of tributyltin azide, followed by heating under reflux for 2 days. After cooling to room temperature, aqueous 1M sodium hydroxide solution and ether were added, followed by layer separation operation. To the aqueous layer was added 1 M hydrochloric acid, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. By adding ether to the resulting residue and collecting the insoluble materials by filtration, 70 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(1H-tetrazol-5-ylmethoxy)quinolin-4(1H)-one was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 15 g of Piperazine-1-carboxylic acid tert-butyl ester in 200 ml of DCM, 18 g of triethylamine was added and the mixture was cooled to 0° C. Then, 12.1 g of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 16 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1 M aqueous hydrochloric acid followed by saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 21.9 g.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[C:15]4[C:16](=[O:38])[N:17]([CH3:37])[C:18]([CH:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30]C)=[O:29])=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=5)[C:14]=4[CH:13]=[CH:12]3)[CH:7]=[CH:6][C:5]=12.[Li+].[OH-].Cl>O1CCCC1.CO>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[C:15]4[C:16](=[O:38])[N:17]([CH3:37])[C:18]([CH:27]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[C:28]([OH:30])=[O:29])=[C:19]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)[C:14]=4[CH:13]=[CH:12]3)[CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc4nonc4c3)c2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc3nonc3c2)cc1
Temperature: 70 °C

Procedure:
A mixture of the crude methyl 2-(1-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate in Tetrahydrofuran (THF) (1 mL) and Methanol (1 mL) was treated with 2M LiOH (1 mL, 2.000 mmol) and then heated to 70° C. for one hour. The mixture was cooled to 0° C., adjusted to pH <2 with 1N HCl and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min.) to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.77-7.85 (m, 1H) 7.52-7.59 (m, 1H) 7.41-7.49 (m, 2H) 7.36-7.41 (m, 1H) 7.29-7.34 (m, 2H) 7.05-7.13 (m, 1H) 6.09-6.19 (m, 1H) 5.87-6.02 (m, 2H) 5.46-5.52 (m, 1H) 3.66 (s, 3H) 2.45 (s, 3H) 1.00 (s, 9H); LCMS (m/z) ES+=501 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)=[O:5])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH2:37]>ClCCl.O>[C:41]([O:40][C:38]([NH:36][NH:37][C:12](=[O:14])[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)c1cnn(CC(=O)O)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnn(CC(=O)NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of the compound (9.4 g) obtained in Example 115b, N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (18.1 g) and 1-hydroxybenzotriazole (6.5 g) in dichloromethane (100 mL) was cooled to −20° C., and a solution of tert-butyl hydrazinecarboxylate (9.5 g) in dichloromethane (20 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether/ethyl acetate/triethylamine=10/1/0.001) to give ethyl 1-{2-[2-(tert-butoxycarbonyl)hydrazino]-2-oxoethyl}-1H-pyrazole-4-carboxylate (9.2 g) as a colorless solid. The solid was dissolved in ethyl acetate (50 mL), and hydrogen chloride-ethyl acetate (50 mL) was added. The mixture was stirred at room temperature for 1 hr, and the precipitate was collected by filtration to give the title compound (6.0 g) as a colorless solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:30][C@H:31]1[CH2:36][O:35][CH2:34][CH2:33][NH:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][C@@H:31]4[CH3:30])=[O:22])[CH:17]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:15]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Reactant: C[C@H]1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1C(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[4-(Cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylic acid (95 mg) was dissolved in DMF (3 mL) and (3S)-3-methylmorpholine added. DIPEA (0.125 mL) and HATU (137 mg) were added and the reactions stirred at RT for 3 h before being concentrated in vacuo and partitioned between DCM (25 mL) and water (25 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to dryness to give the desired material as a solid (88 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)([CH3:10])[CH3:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([O:16][CH3:17])[CH:3]=1.O=S(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(Cl)c(C(C)(C)O)cc1NC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=C(C)c1cc(NC(C)=O)c(OC)cc1Cl
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of N-(4-chloro-5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)acetamide (3.2 g, 12.4 mmol) in DCM (20 mL) at −5° C., SOCl2 (3.7 g, 37.25 mmol) was added dropwise. The mixture was warmed to RT, and then stirred at reflux for 2 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=3:1) to afford the desired product (1.9 g, 64% yield).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:18]1[CH:19]=[CH:20][C:21]([CH:23]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:30])[CH2:27][CH2:28]2)=[CH:22][C:17]=1[Cl:16])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)CCC(c2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.2 ml of triflic anhydride are added at 5° C. to 9.7 g of 2-chloro-4-(4,4-dimethylcyclohexyl)phenol (compound IX.1) in 60 ml of pyridine, and the reaction mixture is left at 0° C. for 30 mintues and then stirred at room temperature for 12 hours. The reaction mixture is hydrolysed and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is taken up in toluene and the solvents are then evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 100/0 to 99/1 (v/v). 15 g of the compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]Br.O>ClC1C=CC=CC=1>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: O=C(O)C(Br)c1ccc(Cl)cc1
Temperature: 105 °C
Yield: 95 %

Procedure:
In a stirred reactor with reflux condenser (connected to a caustic scrubber) 171 g 4-chlorophenyl acetic acid are pre-charged in 750 g chlorobenzene and 41 g phosphortrichloride (0.3 Mol) are added. The mixture is heated to 100-110° C. and 280 g bromine (1.75 mole) are added within 1 hour through a dropping funnel. The reaction mixture is stirred for another 3-4 hour at 110-115° C. until the conversion of the 4-chlorophenyl acetic acid is complete (control by LC). The reaction mixture is cooled to 50° C. and 100 ml water is added. Excess bromine is destroyed by addition of NaHSO3 solution. The reaction mixture is adjusted to pH 1 with aqueous NaOH solution and then the organic product phase is separated from the aqueous phase. The chlorobenzene phase contains 237 g bromo-(4-chloro-phenyl)acetic acid by LC analysis (yield=95% of theory based on 4-chlorophenylacetic acid). The “bromoacid” bromo-(4-chloro-phenyl)acetic acid can be isolated partly by concentration to a 50% solution and crystallisation/filtration at 0° C. About 200 g of bromo-(4-chloro-phenyl)acetic acid can be isolated in a crystallised form. Melting point=92-93° C. 1H-NMR (CDCl3) δ (ppm): 5.3 (s, 1H); 7.4 (4H, Ar); 9.7 (1H, OH)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:15]2[CH:16]=[C:12]([N+:9]([O-:11])=[O:10])[N:13]=[CH:14]2)[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(-n2cnc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 21 h
Yield: 34.2 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 4-nitroimidazole (1.24 g) and potassium carbonate (1.65 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 21 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 1-(4-methylpyridin-2-yl)-4-nitroimidazole (698 mg).