Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:34](=[O:35])[N:6]2[CH:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:8]([CH2:16][O:17][C:18](=[O:20])[CH3:19])(OS(C)(=O)=O)[CH2:9][S:10][C@:5]12[S:36][CH3:37])=[N+:2]=[N-:3].CCN(CC)CC>C(Cl)Cl>[N:1]([CH:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:9][S:10][C@:5]12[S:36][CH3:37])=[N+:2]=[N-:3]
Reactant: CS[C@]12SCC(COC(C)=O)(OS(C)(=O)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Yield: 96.3 %

Procedure:
A solution of p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-methylsulfonyloxy-cepham-4-carboxylate (211 mg., 0.366 mMol) and Et3N (102 μ1., 0.732 mMol) in anhydrous CH2Cl2 (2 ml.) is stirred at room temperature for 35 mins. The solution is washed with H2O (2x), 10% HCl, H2O, and brine, dried with MgSO4, filtered, and evaporated in vacuo to yield p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethylceph-3-em-4-carboxylate (169 mg.) as an oil: ir (neat) 4.72, 5.59, 5.75, 6.55, and 7.40μ; nmr (CDCl3) 2.08 (s, 3, COCH3, 2.18 (s, 3, SCH3), 3.43, 3.95 (ABq, 2, J=19Hz, SCH2), 4.77 (s, 1, H7) 4.83, 5.17 (ABq, 2, J=14Hz, CH2OAc), 5.38 (s, 2, CH2Ar), and 7.57, 8.23 (ABq, 4, J=8.5Hz, ArH); mass spectrum m/e 479 (M+), 451, 436, 404, 392, 271, 260, 216, 200, and 136.
Reaction SMILES: [CH3:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]1=[O:10].[CH3:17]O>S(=O)(=O)(O)O>[CH3:17][O:8][C:7]([C:5]1[O:6][C:2]([CH3:1])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:10])[CH:4]=1)=[O:9]
Reactant: CO
Reactant: CC1(c2ccccc2)OC(C(=O)O)=CC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1=CC(=O)C(C)(c2ccccc2)O1

Procedure:
A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (0.4 g, described in Example 4), absolute methanol (50 ml), and sulfuric acid (3 drops) is refluxed overnight and evaporated. The residue is diluted with 50 ml of diethyl ether, and the solution is washed quickly with saturated sodium bicarbonate and water, dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from diethyl ether to obtain the title compound (0.32 g) mp 60°-62° C. and nmr (CDCl3) δ1.81(s), 3.99(s), 6.25(s) and 7.42(m).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 51 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 51% of theory, C33H39N7O5 (613.7) Rf value: 0.56 (silica gel; dichloromethane/methanol=9:1) ##EQU76##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][CH:12]2[NH:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]2=3)=[CH:7][C:8]=1[O:9][CH3:10].[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>C(Cl)(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:11][CH:12]1[C:13]2[C:18](=[CH:17][C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[CH:14]=2)[CH2:19][CH2:20][N:21]1[C:30](=[O:31])[NH:29][CH2:28][CH2:27][Cl:26]
Reactant: O=C=NCCCl
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2C(=O)NCCCl)cc1OC
Reaction time: 24 h

Procedure:
2.86 g of tetrahydropapaverine are dissolved in 15 ml chloroform, then are added 0.7 ml of chlorethylisocyanate and the reaction mixture is stirred at ambient temmperature for 24 hours. The chloroform is distilled to dryness under vacuum. The thus obtained oily residue is suspended in ether and is left there to stay at a temperature about 0° C. for two days. A solid amorphous product is obtained that is filtered, washed several times with ether and dried at ambient temperature. Thus is prepared 1 g of compound 1c with melting point 73°-76° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH2:28][CH3:29].[CH3:30][CH:31]1[CH2:35][C:34]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=2[O:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:37]2[CH:38]=[CH:39][C:33]3[O:32][CH:31]([CH3:30])[CH2:35][C:34]=3[CH:36]=2)=[C:3]([CH2:28][CH3:29])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(CC)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 2-methyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.30 g) in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.46 g, 82%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH3:24])=C(Cl)[N:16]=1>>[Cl:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH3:24])=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:16]=1
Reactant: O=CNc1ccc(C(F)(F)F)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-trifluoromethyl-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C.O>[CH:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[C:4]([O:3][CH3:16])=[O:15])=[O:1]
Reactant: O=C1OC(O)c2cccc(C(F)(F)F)c21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of (±)-3-hydroxy-7-(trifluoromethyl)isobenzofuran-1 (3H)-one, from Example 1, Part B, (3.31 g, 15.2 mmol) in 20 mL of DMF was added potassium carbonate (4.2 g, 30.4 mmol) followed by iodomethane (1.04 mL, 16.7 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was cooled to 0° C. and carefully acidified with 6N HCl, diluted with water and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 3.1 g (89%) of the title compound which was used without purification. 1H NMR (CDCl3): δ 10.05 (s, 1H), 8.12 (d, 1H, J=7.7 Hz), 7.95 (d, 1H, J=7.7 Hz), 7.76 (t, 1H, J=7.7 Hz), 4.02 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:9])[CH2:4][CH2:3]1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[CH2:3][CH2:4]1)=[O:9]
Reactant: N[C@H]1CC[C@H](C(=O)c2nc3ccccc3s2)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: O=C(c1nc2ccccc2s1)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1

Procedure:
The title compound was prepared according to the same protocol as for example 1, step 1.c, using however (trans-4-amino-cyclohexyl)-benzothiazol-2-yl-methanone (0.3 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol). 93 mg (68%) of a beige solid were obtained.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[CH3:26][C:27]1[O:31][N:30]=[C:29]([NH2:32])[CH:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:32][C:29]3[CH:28]=[C:27]([CH3:26])[O:31][N:30]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(N)no1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3cc(F)ccc32)no1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-methyl-isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.040 gms. 5-methyl-isoxazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0147 gms.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1>C(O)C>[Br:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3Br)cc2N)cc1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(OCc4ccccc4Br)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 2g (35 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 157a (75 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (18 mg, 29%). 1H NMR (300 MHz, DMSO-d6), ppm: 0.97 (t, J=7.35 Hz, 3H), 1.72-1.92 (m, 2 H) 2.02 (s, 3 H), 2.99 (t, J=7.35 Hz, 2 H), 5.17 (s, 2 H), 6.33 (d, J=6.99 Hz, 1 H), 7.16 (d, J=8.46 Hz, 2 H), 7.18-7.28 (m, 2 H), 7.28-7.51 (m, 5 H), 7.60 (dd, J=7.54, 1.65 Hz, 1 H), 7.69 (d, J=6.99 Hz, 1 H), 7.81 (d, J=8.82 Hz, 1 H), 8.39 (d, J=6.99 Hz, 1 H), 8.97 (d, J=8.82 Hz, 1 H), 9.99 (s, 1 H), 11.02 (s, 1 H), 14.37 (s, 1 H): MS (ESI+) m/z 613M+H)+.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:20]([N:22]([CH3:38])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[N+:35]([O-:37])=[O:36])=[CH:25][CH:24]=3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.NCC1CCNCC1>C(Cl)Cl>[NH2:18][C@H:19]([CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:20]([N:22]([CH3:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N+:35]([O-:37])=[O:36])=[CH:25][CH:24]=1)=[O:21]
Reactant: CN(C(=O)[C@@H](CCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: NCC1CCNCC1
Solvent: ClCCl
Product: CN(C(=O)[C@H](N)CCc1ccccc1)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
The FMOC amide from Step F (1.15 g; 1.88 mmol) was dissolved in methylene chloride (10 ml) and 4-(aminomethyl)piperidine (1 ml) added. The reaction mixture was stirred at room temperature. The reaction mixture was stirred for 15 minutes and then quenched by adding water. The methylene chloride phase was separated, dried over ahnydrous potassium carbonate powder, filtered and evaprated under reduced pressure to afford an orange-yellow oil. The oil was chromatographed on silica gel using an eluant of ethyl acetate and methanol (9:1 v/v). A pale yellow oil (517 mg; 70.6%) was isolated of the amine. FAB-MS:- calculated for C23H23N3 O3 389.2 found 389.9 (M).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](F)[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cc(Br)cc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-bromo-3-fluoro-5-(trifluoromethyl)-benzene (100 g, 0.41 moles), piperazine (194.9 g, 2.26 moles) in DMSO (800 ml) was heated at 100° C. for 5 hours, cooled at room temperature and stirred overnight. The mixture was poured into water and the yellow solid which separeted was filtered. The solid was suspended in a 5% THF solution in water (300 ml) water/THF, stirred for 1 hour and filtered again.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[C:10]([CH2:12]C(O)=O)#[N:11]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([CH2:12][C:10]#[N:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: N#CCC(=O)O
Reactant: CCN1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CCN1CC=C(CC#N)CC1
Yield: 122.6 %

Procedure:
2.9 g of 1-ethyl-4-piperidone, 3.3 g of cyanoacetic acid and 36 ml of toluene are placed in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. The mixture is refluxed for 4 hours, while removing the water using Markusson apparatus. The solvent is evaporated off under vacuum. 4.2 g of oil are obtained.
Reaction SMILES: P(Br)(Br)Br.[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][N+:9]([O-])=[C:8]([CH2:15][CH3:16])[CH:7]=1.[OH-].[Na+]>C(Cl)Cl>[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][N:9]=[C:8]([CH2:15][CH3:16])[CH:7]=1
Reactant: CCc1cc(Br)c(OC)c[n+]1[O-]
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1cc(Br)c(OC)cn1
Temperature: 50 °C

Procedure:
Phosphorous tribromide (5.5 mL) was added to a solution of 4-bromo-2-ethyl-5-methoxy-pyridine 1-oxide (1.25 g, 5.4 mmol) dissolved in CH2Cl2 (40 mL). The reaction mixture was heated to 50° C. for 1 hour. After cooling to room temperature the mixture was poured into ice and made basic with 15% NaOH and extracted with CH2Cl2. The organic extracts were dried over Na2SO4 and concentrated to a clear oil (1.13 g, 97%). 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J=7.6 Hz, 3 H), 2.75 (q, J=7.6 Hz, 2 H), 3.97 (s, 3 H), 7.37 (s, 1 H), 8.13 (s, 1 H)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=1.C([Li])CCC.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22].O>O1CCCC1.CCCCCC>[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:11][C:7]=2[N:8]=1)[OH:22]
Reactant: CC(C)(C)C=O
Reactant: FC(F)(F)c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(O)c1nc2cc(C(F)(F)F)ccc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a stirred solution of 3.8 g (19.0 mmol) of 5-(trifluoromethyl)-1,3-benzothiazole in 30 mL of tetrahydrofuran at −78° C. was added 13.1 mL (21.0 mmol) of a 1.6 M solution of n-butyllithium in hexane over 45 min. Then, 1.8 g (21.0 mmol) of trimethylacetaldehyde in 10 mL of tetrahydrofuran was added dropwise over 30 min. The reaction mixture was stirred for 1 h at −78° C., and then allowed to warm to 0° C. Then, 25 mL of water was added and the mixture was extracted with 80 mL of ether. The ether was washed with 40 mL of water (3×), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (1:9) to afford 1.8 g (33%) of 2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]-1-propanol as an off-white solid. The enantiomers were separated in 98.8% ee using a Chiralpak AD, 10 micron column with a mobile phase of 90% carbon dioxide: 10% methanol and a flow rate of 2.0 mL/minute. 1H-NMR (400MHz, DMSO-d6): δ 8.33–8.29 (m, 2H), 7.71 (d, J=8 Hz, 1H), 6.61 (d, J=5 Hz, 1H), 4.60 (d, J=5 Hz, 1H), 0.97 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[S:13][C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)cs2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Cl)s2)CC1

Procedure:
A solution of cis/trans-4-(4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (200 mg, 0.789 mmol) and N-chlorosuccinimide (116 mg, 0.868 mmol) in N,N-dimethylformamide (1.6 ml) was stirred for 1 h at 50° C. The reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with one 25-ml portion of tert-butyl methyl ether. The combined organic layers were washed with three 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (209 mg, 92%) as light yellow solid, which was used in the next step without further purification. MS m/e: 288 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.C1([Li])C=CC=CC=1.[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])[CH2:25][CH2:24]1)#[N:22]>C1C=CC=CC=1.C(OCC)C>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[O:30])[CH2:27][CH2:28]2)[N:22]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: N#CN1CCN(C(=O)c2ccco2)CC1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Reaction time: 0.75 h

Procedure:
To 3.6 g. of 6-aminoveratronitrile, dissolved in 75 ml. of anhydrous benzene, a solution of phenyl lithium (prepared from 0.35 g. of lithium and 3.9 g. of bromobenzene) in 60 ml. of anhydrous diethyl ether is added under a nitrogen atmosphere. After 45 minutes 4.4 g. of 1-cyano-4-(2-furoyl)piperazine in 50 ml. of anhydrous benzene are added. The ether and part of the benzene are distilled off and 100 ml. of tetrahydrofuran are added. The mixture is refluxed under the nitrogen atmosphere for 20 hours and then decomposed with water. The liquid is distilled off and 75 ml. of water are added to the residue. The mixture is extracted with chloroform and the extract is concentrated by evaporation of the solvent. 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)4-(2-furoyl)piperazine is obtained. The product after crystallization from a mixture of ethanol and water melts at 258°-260°C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([O:34][CH3:35])[CH:25]=1)([O-:23])=[O:22].O>C1COCC1>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][C:26]=3[O:34][CH3:35])(=[O:31])=[O:32])[C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCCC2)c2cc(Cl)ccc21
Reaction time: 18 h
Yield: 64.4 %

Procedure:
600 mg of sodium hydride as a 60% dispersion in oil were added in portions, with stirring, to a solution of 3 g of 5-chloro-3-cycloheptyl-1,3-dihydro-2H- benzimidazol-2-one in 30 ml of THF. 3 g of 4-nitro-2- methoxybenzenesulfonyl chloride were then added and the reaction mixture was stirred for 18 hours. The reaction mixture was then poured into a water+ ice mixture, extracted with ethyl acetate and washed with water and the organic phase was dried over sodium sulfate and concentrated to dryness. 3.5 g of the expected product were obtained by crystallization from an iso ether/AcOEt mixture (60/40; v/v). M.p.=193° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([OH:23])=O)[CH:20]=1)[N:17]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:16]=[CH:15]2)=[O:10].CN(C(O[N:42]1N=N[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCCC1>CN(C=O)C>[CH:43]1([NH:42][C:21]([C:19]2[CH:20]=[C:12]([NH:11][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:33])[F:32])=[O:10])[CH:13]=[C:14]3[C:18]=2[N:17]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[N:16]=[CH:15]3)=[O:23])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1ncc2cc(NC(=O)c3ccccc3C(F)(F)F)cc(C(=O)O)c21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: C[Si](C)(C)CCOCn1ncc2cc(NC(=O)c3ccccc3C(F)(F)F)cc(C(=O)NC3CCCCC3)c21
Temperature: 25 °C
Yield: 105.1 %

Procedure:
To a solution of 5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid (obtained in Step 5) (48 mg) in DMF (2 mL) were added HBTU (46 mg) and triethylamine (17 μL), and the mixture was stirred at room temperature, cyclohexylamine (12.5 μL) was added, and it was stirred at the same temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was triturated in n-hexane/ethyl acetate (10:1), and collected by filtration to obtain 59 mg of N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1-[2-(trimethylsilyl)ethoxymethyl]-indazole-7-carboxamide as colorless powder. This was dissolved in MeOH (2 mL), 6N hydrochloric acid (2 mL) was added, and the solution was stirred on oil bath at 60-80° C. for 10 hours. The solvent was removed, and ice water was added to the residue. The precipitate was collected by filtration and dried to obtain the titled compound (33 mg) as colorless powder.