Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=2[C:6]([C:16]([O:18]C)=[O:17])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CCCc1ccc2c(C(=O)OC)ccc(OC)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCc1ccc2c(C(=O)O)ccc(OC)c2n1
Yield: 45.5 %

Procedure:
A mixture of methyl 8-methoxy-2-n-propylquinoline-5-carboxylate (1.0 g, Reference Example 27), potassium carbonate (0.8 g), methanol (30 ml), and water (2 ml) was refluxed or 5 hours. The solution was concentrated, then diluted with water and then washed with diethyl ether. The pH of the aqueous phase was adjusted to 6 by addition of hydrochloric acid (6M). The resulting cream precipitate was washed with water and then dried at 60° C. to give the title compound (0.43 g) as a cream coloured solid, m.p. 214-217° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12](I)=[CH:11][N:10]=[C:9]([NH2:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[N:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1>>[CH:1]1([NH:6][C:7]2[C:12]([C:21]3[CH:20]=[C:19]([Cl:22])[N:18]=[N:17][C:16]=3[Cl:15])=[CH:11][N:10]=[C:9]([NH2:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc(Cl)nn1
Reactant: Nc1ncc(I)c(NC2CCCC2)n1
Product: Nc1ncc(-c2cc(Cl)nnc2Cl)c(NC2CCCC2)n1

Procedure:
Compound 323 was prepared from compound 243 and 3,6-dichloropyridazine using chemistry similar to that described in example 200. LCMS-ESI (POS), M/Z, M+1: Found 325.0.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)(C)C.Cl.FC1C=C(C=CC=1OCCN1CCCCC1)C(O)=O.[F:45][C:46]1[CH:47]=[C:48]([CH:74]=[CH:75][C:76]=1[O:77][CH2:78][CH2:79][N:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[CH2:49][N:50]([CH:71]([CH3:73])[CH3:72])[C:51]1[CH:56]=[C:55]([O:57]C)[CH:54]=[CH:53][C:52]=1[CH:59]1[CH2:68][CH2:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([O:69]C)[CH:65]=2)[CH2:60]1>>[F:45][C:46]1[CH:47]=[C:48]([CH:74]=[CH:75][C:76]=1[O:77][CH2:78][CH2:79][N:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[CH2:49][N:50]([CH:71]([CH3:73])[CH3:72])[C:51]1[CH:56]=[C:55]([OH:57])[CH:54]=[CH:53][C:52]=1[CH:59]1[CH2:68][CH2:67][C:66]2[CH:65]=[C:64]([OH:69])[CH:63]=[CH:62][C:61]=2[CH2:60]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(Cc1ccc(OCCN3CCCCC3)c(F)c1)C(C)C)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)C)C2
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Product: CC(C)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 68.6 %

Procedure:
Synthesized from isopropyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]isopropyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (402 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (262 mg).
Reaction SMILES: [OH:1][C:2]1([C:31](O)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(NC(C)C)(C)C>C1COCC1>[CH:34]1([NH:39][C:31]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[C:16]([NH:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=4[F:26])=[N:15][C:14]4[C:9]3=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=4)[CH2:4][CH2:3]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)NC4CCCC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-Hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat followed by di-isopropyl amine (0.105 mL, 0.6 mmol). Benzotriazol-1-yloxytris (dimethylamino)phosphponium hexafluorophosphate (BOP) was added last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confirmed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66% yield) M+1: 532.
Reaction SMILES: CCOCC.[CH3:6][N:7]([CH2:9][CH2:10][CH2:11]Cl)[CH3:8].[CH3:13][C:14]1([C:19]2[C:29]3[CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:24](=[O:34])[C:23]=3[CH:22]=[CH:21][CH:20]=2)[O:18][CH2:17][CH2:16][O:15]1>O1CCCC1>[CH3:13][C:14]1([C:19]2[C:29]3[CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:24]([CH2:11][CH2:10][CH2:9][N:7]([CH3:8])[CH3:6])([OH:34])[C:23]=3[CH:22]=[CH:21][CH:20]=2)[O:15][CH2:16][CH2:17][O:18]1
Reactant: CN(C)CCCCl
Reactant: CC1(c2cccc3c2CCc2ccccc2C3=O)OCCO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2CCc2c(C3(C)OCCO3)cccc21
Temperature: 0 °C

Procedure:
Utilizing 1.13 g. of Gilman alloy, 5 ml. of absolute ether, 5.2 g. of dimethylaminoproyl chloride and 5 ml. of absolute tetrahydrofuran, in a similar manner, is obtained the corresponding Grignard compound. After cooling to 0°C., there is added dropwise a solution containing 7.2 g. of 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 40 ml. of absolute tetrahydrofuran. Subsequently, the mixture is heated for 3 hours at reflux, cooled to about 0°C., hydrolyzed with 4 ml. of water, filtered, and then washed with ether. The ethereal solution is dried over sodium sulfate, filtered and concentrated under reduced pressure, whereby 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oil which is crystallized from 50 ml. of high-boiling petroleum ether and has a melting point of 122°-124°C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:1]1([CH2:6][CH:7]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C=CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Product: O=S(=O)(CCN1CCOCC1)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-ethenesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 92, 50 mg, 0.13 mmol) and morpholine (1.5 ml) was stirred at 25° C. for 20 min. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-cyclopentyl-1-[4-(2-morpholin-4-yl-ethanesulfonyl)-phenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine (4 mg, 6%) as a white solid: LC/MS m/e calcd for C26H33N3O3S [M+H]+ 468.64, observed 468.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=4.3 Hz, 1H), 7.87-7.93 (m, 3H), 7.63 (d, J=8.3 Hz, 2H), 7.06 (dd, J=7.8, 5.1 Hz, 1H), 6.42 (s, 1H), 4.34 (t, J=8.0 Hz, 1H), 3.40-3.50 (m, 6H), 3.27-3.30 (m, 1H), 2.81 (t, J=6.4 Hz, 2H), 2.42 (br. s., 4H), 2.30 (dt, J=13.9, 7.2 Hz, 1H), 2.11-2.19 (m, 1H), 1.62-1.89 (m, 5H), 1.46-1.57 (m, 2H), 1.19-1.31 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(=O)OCC>>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-phenylpiperazine (193 mg, 1.2 mmol), and D1 EA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=O.[CH3:27][CH2:28][O:29][C:30]([CH:32](P(OCC)(OCC)=O)[CH3:33])=[O:31].Cl.C(O)C>O1CCCC1>[CH2:28]([O:29][C:30](/[C:32](/[CH3:33])=[CH:3]/[C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=[O:31])[CH3:27]
Reactant: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
0.52 g (0.013 mol) of sodium hydride was added to a solution of 4.00 g (0.0117 mol) of 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 250 ml of tetrahydrofuran. 2.8 ml (0.013 mol) of triethyl 2-phosphonopropionate was dropped into the mixture prepared above under stirring and cooling with ice. The mixture thus prepared was stirred under cooling with ice for a while, heated to room temperature and stirred for additional one hour, followed by the addition of 1.5 ml of 8M hydrochloric acid/ethanol. The obtained mixture was passed through a small amount of silica gel and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 2.00 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21](=O)[CH2:22][C:23](=O)[CH3:24])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.Cl.[CH2:51]([NH:58][NH2:59])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21]1[N:58]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:59]=[C:23]([CH3:24])[CH:22]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O
Reactant: NNCc1ccccc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 375b) was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and benzylhydrazine dihydrochloride (CAS Reg. No. 20570-96-1) to give the title compound as yellow oil. MS (ESI): m/z=492.3 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC(C)([O-])C.[K+].[H][H]>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2
Reactant: [H][H]
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of {[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(diphenylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by carrying out a degassing procedure and stirring for 30 minutes at room temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 16 hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess are indicated below.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][C:27]([C:25]3[CH:26]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]4)[N:22]=[C:23]([NH2:37])[N:24]=3)=[CH:28][CH:29]=2)[CH2:34]1)=[O:5]
Reactant: O=C(O)C(F)(F)c1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)C(F)(F)c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from difluoro(phenyl)acetic acid (Matrix Scientific, Cat. #018321) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=479.2.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:27].[OH-]>CO>[C:17]1([N:16]2[C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]=[C:12]2[CH2:11][N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:27])[C:3]=3[CH:10]=[CH:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Yield: 22 %

Procedure:
A solution of 4-chloro-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]-pyrimidine (1.0 g, 2.7 mmol) in NH4OH (5 mL) and MeOH (10 mL) was stirred at 90° C. in a sealed tube overnight. Then the mixture was concentrated in vacuo. The residue was purified by P-TLC to give 139 (0.2 g, yield 22%) as a white solid. LCMS (ESI), M+H+=339.14. 1HNMR (400 MHz, CDCl3) δ 5.505 (s, 1H), 6.503 (s, 1H), 6.936 (s, 2H), 7.031 (s, 1H), 7.205-7.209 (q, J=1.6 Hz, 1H), 7.219-7.228 (m, 2H), 7.490-7.540 (m, 5H), 7.555-7.559 (d, J=1.6 Hz, 1H), 7.910 (s, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>CS(C)=O>[N+:28]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8]2)=[CH:22][CH:23]=1)([O-:30])=[O:29]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc(C2CNCCO2)nc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1nc(N2CCOC(c3ccccn3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)morpholine (0.1 g, 0.609 mmol) in dimethylsulfoxide (5 mL) was added triethylamine (0.17 mL, 1.2 mmol). The resulting solution was stirred for 10 min at room temperature, and then 6-chloro-3-nitropyridin-2-amine (105 mg, 0.609 mmol) was added. The reaction mixture was heated at 110° C. for 4 h, and then was cooled to room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (80% ethyl acetate in petroleum ether) to afford the title compound (0.1 g, 55%). MS (ES+) (M+H) 302.25.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:41]([C:45](O)=[O:46])=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]1=[O:48])[CH3:31].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:45]([C:41]1[C:42]2[CH2:43][CH2:44][N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:36](=[O:48])[C:37]=2[CH:38]=[CH:39][CH:40]=1)=[O:46])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCOCCN1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 29.5 %

Procedure:
Poured into a suspension of 255 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 113.5 mg of 2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 9 mg of hydroxybenzotriazole, 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7.6 cm3 of dichloromethane is 0.3 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed once with 5 cm3 of dichloromethane, twice with 5 cm3 of diisopropyl ether, then dried under vacuum. 82 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH3:10][O:11][C:12](=[O:16])[C:13](Cl)=[O:14].O>O1CCCC1>[CH3:10][O:11][C:12]([C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])=[O:14])=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cccc(CO)c1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.93 g of m-aminobenzyl alcohol in 50 ml of tetrahydrofuran was added dropwise a solution of 3.7 ml of chloroglyoxylic acid methyl ester in 20 ml of tetrahydrofuran, and this was stirred at room temperature for 1.5 hours. To the reaction solution was added water, and this was extracted with ethyl acetate, and washed with an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 5.10 g of 3-[(methoxycarbonyl)carbonylamino]benzyl alcohol as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[NH2:13][OH:14].Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:12][C:5]1[CH:4]=[C:3]([C:1](=[NH:2])[NH:13][OH:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(C(=O)O)c(F)c1
Yield: 64.2 %

Procedure:
To a solution of 4-Cyano-2-fluorobenzoic acid (1 g, 6.06 mmol) in EtOH (10.09 mL) was added NH2OH.HCl (0.884 g, 12.72 mmol) previously dissolved in water (5 mL) and aqueous solution K2CO3 (1.339 g, 9.69 mmol) in water (15 mL). Then 8-hydroxyquinone (0.011 g, 0.079 mmol) was added. The resulting solution was stirred at reflux for 4 h. EtOH was evaporated from the reaction mixture, then acidified to pH 3 with aqueous HCl (2 N) solution. The precipitate was filtered, washed with water and dried to yield 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic acid (786.3 mg, 3.89 mmol, 64.2% yield) as yellowish solid. The crude was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.21 (m, 1 H), 10.01 (s, 1 H), 7.85 (t, J=7.95 Hz, 1 H), 7.44-7.69 (m, 2 H), 5.99 (br. s., 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)N2CCC(N)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCC(NS(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 73 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-amine (20 mg, 0.043 mmol, 1 eq.), triethylamine (0.02 mL, 0.129 mmol, 3 eq.), and the methanesulfonyl chloride (0.007 mL, 0.086 mmol, 2 eq.) were stirred in dichloromethane (2 mL) for 16 h. The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 17 mg (74%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 (dd, J=14.60, 7.06 Hz, 2H) 2.05-2.36 (m, 5H) 2.93-3.10 (m, 3H) 3.35-3.76 (m, 2H) 4.45 (br. s., 2H) 4.71 (br. s., 1H) 7.07 (d, J=7.91 Hz, 2H) 7.15 (d, J=7.72 Hz, 1H) 7.20-7.35 (m, 3H) 7.45 (s, 1H); [M+H]+ 541.3.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1B(O)O>O1CCOCC1.O>[CH3:20][C:3]1[C:2]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][C:33]=2[O:35][CH3:36])=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:6]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(Br)c1C
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCCCCNC(=O)c1cccc(-c2ccc(OC)cc2OC)c1C
Yield: 77.6 %

Procedure:
The procedure of the step 1 in Example 92 was repeated except that the methyl 6-(3-bromo-2-methylbenzamido)hexanoate (34 mg, 0.10 mmol), tetrakis(triphenylphosphin)palladium (12 mg, 0.010 mmol), sodium carbonate (21 mg, 0.20 mmol), and 2,4-dimethoxyphenyl boronic acid (27 mg, 0.15 mmol) instead of phenyl boronic acid were dissolved in 3 mL of dioxane/H2O (4:1, v/v) to obtain the title compound (31 mg, 80%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][S:25](Br)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][S:25]([O:23][CH2:22][CH2:21][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:12]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Br
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CCCO)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCCOS(C)(=O)=O)c2ccccc21
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
To a solution of 3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-3-yl]propan-1-ol (Intermediate 41; 3.2 g, 0.009 mol) in CH2Cl2 (25 mL) was added at −40° C. methanesulfonyl bromide (0.93 mL, 0.011 mol) and triethylamine (1.74 mL, 0.012 mol). The reaction mixture was stirred for 5 minutes. More CH2Cl2 was added into the mixture and the organic layer was washed with water. The solvent was removed under reduced pressure giving the title compound (3.5 g, 88%), which was used in the next step without further purification.