Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: COc1ccnc(Cl)n1
Product: COc1ccnc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=326.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-4-methoxy-pyrimidine.
Reaction SMILES: C(N(CC(O)=O)CCN[C:12]([C@:14]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:45])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])C1C=CC=CC=1.[C:56]1([NH:62][CH2:63][CH2:64][NH2:65])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[C:40]([CH2:39][N:62]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:63][CH2:64][NH:65][C:12]([C@:14]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:45])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])([OH:42])=[O:41]
Reactant: NCCNc1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)O)Cc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(benzyl(carboxymethyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (example 89) using N1-phenylethane-1,2-diamine as amine. The product was isolated as a white solid (0.9 mg, 9%). LCMS: m/e 735.5 (M+H)+, 1.80 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 7.26-7.19 (m, 2H), 6.86-6.70 (m, 3H), 5.37 (d, J=4.58 Hz, 1H), 4.77 (s, 1H), 4.63 (s, 1H), 4.22 (s, 2H), 3.82-3.43 (m, 4H), 3.21-3.07 (m, 1H), 2.69-2.53 (m, 1H), 2.23-2.13 (m, 2H), 1.73 (s, 3H), 2.05-1.07 (m, 19H), 1.06 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:14])[CH:3]=1.O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([CH3:14])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Br)cc1C
Reaction time: 120 h

Procedure:
14.3 g of 4-bromo-2-methyl-5-nitrobenzoic acid were dissolved in 250 ml of MeOH and 11.6 g of SOCl2 were slowly added dropwise. The mixture was allowed to stand at RT for 5 days, the volatile components were removed in vacuo and the residue is recrystallized from DIP.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCN
Solvent: ClCCl
Product: O=C(NCCCCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Under N2, 1,5-diaminopentane (2.86 ml., 2.5 g., 0.0245 mol) was dissolved in 50 ml. CH2Cl2 and cooled to 0° . With stirring, benzyloxycarbonyl chloride (3.67 ml., 4.17 g., 0.0245 mol) was added dropwise, maintaining the temperature near 0° . The mixture was warmed to room temperature, washed 2×50 ml. 5% HCl, 1×50 ml. saturated NaHCO3, and 1×50 ml. brine, dried (MgSO4) and stripped to yield title product as a white solid, 4 g.; 1H-nmr (CDCl3) includes delta 5.2 ppm (s, 4H, two benzyl CH2 groups). The yield is greatly enhanced by use of two molar equivalents of the acid chloride.
Reaction SMILES: [CH2:1]1[C:11]2[C:5]([C:6]([C:16](O)=[O:17])=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)=[CH:4][CH:3]=[CH:2]1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1>>[C:27]1([CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][C@H:20]([NH:19][C:16]([C:6]3[C:5]4=[CH:4][CH:3]=[CH:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=34)=[O:17])[CH2:21]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)C1=c2ccccc2=CC=C2CC=CC=C21
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1=c2ccccc2=CC=C2CC=CC=C21

Procedure:
Dibenzo[a,d]cycloheptene-5-carboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)dibenzo[a,d]cycloheptene-5-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: O=C(O)c1cc(Cl)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(Cl)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 78 mg (0.276 mmol) of the compound of Example 33A gave 101 mg (66% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[NH2:10][C@H:11]([CH2:13][OH:14])[CH3:12].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:12][C@H:11]([NH:10][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][OH:14]
Reactant: C[C@H](N)CO
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Yield: 66.3 %

Procedure:
In 20 ml of dry tetrahydrofuran were dissolved 1.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 0.56 g of L-alaninol, 2.8 ml of triethylamine and 1.8 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography employing ethyl acetate as an eluent and further purified by silica gel column chromatography employing dichloromethane-methanol (95:5) as an eluent to obtain 0.92 g of the desired compound as colorless crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[NH:21]1[CH2:31][CH2:30][CH2:29][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22]1>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([N:21]2[CH2:31][CH2:30][CH2:29][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22]2)=[O:8])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: CCOC(=O)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
Commercially available 3-thiophene carboxylic acid (166.5 mg; 1.30 mmol) was suspended in dichloromethane (7 ml), and commercially available 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (252.8 mg; 1.32 mmol) was added. This mixture was allowed to stir at ambient temperature for 1 hour. Ethyl nipecotate (201 μl; 1.3 mmol) was then added, and stirring was continued for approximately 18 hours. The reaction mixture was then diluted with fresh dichloromethane and washed with water. The dichloromethane was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure. The crude material was purified by high-vacuum distillation at approximately 225° C./0.1 torr, and further by chromatography on silica, eluting with 50% ethyl acetate in hexane, giving ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate (66.3 mg) as a colorless oil. MS m/z (positive ion) 268 (MH+; 100).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[Cl:18])[CH3:9].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>CCOC(C)=O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:20]=[O:22])=[CH:13][C:12]=1[Cl:18])[CH3:9]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1ccc(N)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(N=C=O)cc1Cl

Procedure:
1-Ethoxy-2-chloro-4-isocyanato-benzene is prepared by addition of triethylamine to a solution of 4-ethoxy-3-chlorophenylamine in EtOAc at 0-5° C. Triphosgene is added and the reaction mixture is slowly heated to reflux over 2 h. The solvent is removed in vacuo and the crude product is filtered through silica to afford the title compound.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10].S(=O)(=O)(O)O.O.C(#[N:20])C>>[NH2:20][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: CC#N
Reactant: O[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Cis-1,2-indandiol (1.0 g) was dissolved in acetonitrile (20 mL), cooled to -40° C., and fuming sulfuric acid (21% SO3, 0.8 mL) was added. The mixture was aged for 1 hour with gradual warming to 0° C. Water was added and the mixture heated to 80° C. for 1 hour to provide an aqueous solution of cis-1-amino-2-indanol.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])=[O:15])([O-:12])=[O:11].I[CH2:26][C:27]([CH2:29]I)=[CH2:28]>CN(C)C=O>[CH2:26]=[C:27]1[CH2:29][C:13]([N+:10]([O-:12])=[O:11])=[C:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[O:15][CH2:28]1
Reactant: O=C(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Reactant: C=C(CI)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) and sodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at room temperature for 20 h, evaporated under reduced pressure and dissolved in dichloromethane (150 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil. N,N-diisopropylethylamine (0.20 mL) was added to a solution of 2-nitro-1-(2,4,5-trifluorophenyl)ethanone (110 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (170 mg, 0.55 mmol) and the mixture was heated at 60° C. for 2.5 h, evaporated and purified by chromatography on a Biotage Horizon® system (silica gel, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=O.C([BH3-])#N.[Na+]>C(O)C.CO>[CH:7]1([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C1Cc2ccccc2C1
Reactant: COC(=O)CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)CNC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glycine methyl ester (0.053 moles, 6.64 g) is dissolved in absolute ethanol (420 ml) and methanol (42 ml), added with 2-indanone (0.053 moles, 7 g), and with sodium cyanoborohydride (0.058 moles, 3.7 g) under stirring, in 40 minutes. The mixture is left under stirring at r.t. overnight, evaporated to dryness under vacuum and the residue is taken up with water (500 ml) and ethyl acetate (500 ml). The phases are separated and the organic phase is extracted with a 0.1N HCl solution (3×200 ml). The acidic solution is adjusted to pH 8.5-9 with a sodium bicarbonate saturated solution and 20 extracted with ethyl acetate (3×250 ml). The organic solution is separated, dried over sodium sulfate and evaporated under vacuum. The resulting product is dried under vacuum at r.t. Yield: 5.8 g (53.4%)
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]C)=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:15][C:16]1[CH:17]=[C:18]([CH:54]=[CH:55][CH:56]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:23]=1[C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][N:53]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:38])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]([C:18]3[CH:17]=[C:16]([CH:56]=[CH:55][CH:54]=3)[CH2:15][N:1]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=4[CH:3]=[CH:2]3)=[O:20])=[C:23]([C:34]3[CH:35]=[C:36]([C:37](=[O:38])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[CH:51]=[CH:52][N:53]=3)[CH:24]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3ccc4c(C(=O)O)cccc43)c2)c1
Reaction time: 24 h
Yield: 48.3 %

Procedure:
A mixture of 10.5 mg of methyl 1H-indole-4-carboxylate, 18.2 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide 8.1a, and excess potassium carbonate in 300 μL of DMF was stirred for 24 h. The solvent was evaporated and the residue was purified by silica gel chromatography. The product was dissolved in 1 mL of 4:1 THF/water and treated with 10 mg of LiOH.H2O. After stirring 4 days at 70° C. the reaction mixture was acidified with 3.0 N hydrochloric acid and then extracted with ethyl acetate. The aqueous phase was washed with ethyl acetate, and the combined organic extracts washed with brine and dried (NaSO4). The residue was purified by reverse phase HPLC eluting with 0.1% TFA in a water/acetonitrile gradient to give 10.6 mg of product. MS (ES, m/z) 732.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]1[N:37]=[C:24]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:12]2)[O:25][N:36]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4F)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 60 mg (0.33 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (60% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH2:19][CH2:20][CH2:21][OH:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([NH:19][CH2:20][CH2:21][OH:22])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: NCCO
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(NCCO)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and 2-aminoethanol. m/z 296.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:23](Cl)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:23](=[O:25])[CH3:24])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Yield: 47.4 %

Procedure:
3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.77 g of acetyl chloride and 20 ml of pyridine are treated in the same manner as described in Preparation 7. The crude product is recrystallized from a mixture of ether and n-hexane. 1.6 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][O:11][C:7]=2[C:6]([OH:17])=[C:5]([C:18]([O:20]CC)=O)[N:4]=1)#[N:2].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+].Cl>>[C:1]([C:3]1[C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][O:11][C:7]=2[C:6]([OH:17])=[C:5]([C:18]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])[N:4]=1)#[N:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(-c3cccs3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3cccs3)c12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Ethyl 4-cyano-7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (136 mg, 0.432 mmol) and glycine (648 mg, 8.63 mmol) were added to sodium methoxide solution (13 mL, 6.48 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 101 mg of the title compound. MS: (−) m/z 343.28 (M−1).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=2[C:4]([OH:6])=[O:5])[N:15]=1
Reactant: Cc1cccc(S)c1C(=O)O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Sc2cccc(C)c2C(=O)O)n1
Temperature: 115 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
Then, 3.6 g of 2-mercapto-6-methylbenzoic acid, 4.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 3.5 g of unhydrous potassium carbonate were dissolved in 20 ml of dimethylformamide, and then the mixture was stirred at from 110 to 120° C. for one hour. The reaction solution was poured into a large amount of water, and concentrated hydrochloric acid was added thereto. Then, the mixture was extracted with chloroform. The chloroform layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The crude crystals were purified by column chromatography by using a developing solvent of hexane/ethyl acetate and recrystallized from ethyl acetate to obtain 0.8 g of 2-[(4,6-dimethoxypyrimidin-2-yl)thio]-6-methylbenzoic acid as white powder. Melting point: 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([OH:27])[CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:35][C:33]=2[N:34]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([OH:27])[CH2:23][CH2:22]2)[C:5]2[C:10]([C:37]3[CH:36]=[CH:35][C:33]4[N:34]=[C:30]([CH3:29])[O:31][C:32]=4[CH:38]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CC1(O)CCC(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CC1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCC(C)(O)CC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a degassed mixture of 4-((2-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1-methylcyclohexanol (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1.2 equiv) and tripotassium phosphate trihydrate (3 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.18 M) was added palladium 1,1-bis(diphenylphosphion)ferrocene dichloride (0.1 equiv). The reaction mixture was stirred at 70° C. for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-2% DCM in MeOH) to afford the title compound (95% yield) as a red oil. MS (ESI) m/z 543.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:19])[C@@H:6]([CH3:20])[N:5]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:4]=2[N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:37])[CH:31]=[C:32]2[C:36]=1[NH:35][N:34]=[CH:33]2.C(O)C(F)(F)F.FC(F)(F)C(O)=O>>[CH:21]1([N:5]2[C:4]3[N:3]=[C:2]([NH:37][C:30]4[CH:31]=[C:32]5[C:36](=[C:28]([F:27])[CH:29]=4)[NH:35][N:34]=[CH:33]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:19])[C@H:6]2[CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Cl)nc2N1C1CCCCC1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Nc3cc(F)c4[nH]ncc4c3)nc2N1C1CCCCC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one (30.4 mg, 0.081 mmol) and 7-fluoro-1H-indazol-5-amine (37.2 mg, 0.25 mmol) in trifluoroethanol (2.0 mL, 27 mmol) in a microwave reactor vial was added trifluoroacetic acid (42 mg, 0.37 mmol). The vial was then sealed, and the mixture was stirred at 100° C. (oil bath). More 7-fluoro-1H-indazol-5-amine (29.5 mg, 0.195 mmol) and trifluoroacetic acid (0.025 mL, 0.32 mmol) was added after 15 h, and heating at 100° C. was continued for additional 24 h. The reaction mixture was cooled to rt and quenched with saturated aq. NaHCO3 solution (5 mL). The resulting mixture was extracted with 5% MeOH in dichloromethane (15 mL×4). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue, which was then purified by silica gel column chromatography (eluent: 8% methanol in dichloromethane) to give the desired product (24%).