Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[N+:17]([O-])=O)=[O:5])[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1onc(-c2ccccc2)c1N
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of 4-nitro-3-phenyl-isoxazole-5-carboxylic acid ethyl ester (62.3 mg, 0.238 mmol) in EtOH (2.0 mL) is added Raney Ni and the mixture is stirred under hydrogen (balloon) for overnight. The reaction mixture is then filtered through celite and evaporated in vacuo to provide crude 4-amino-3-phenyl-isoxazole-5-carboxylic acid ethyl ester (53.3 mg, 97% yield); HPLC-MS calculated for C12H12N2O3 (M+H+) 233.1. Found: 233.1.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[C:22]([C:23](Cl)=[N:24]O)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:16][C:17]1[C:22]([C:23]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:24]=2)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: ON=C(Cl)c1c(Cl)ccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2c(Cl)ccnc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A solution of methyl isobutyrylacetate (1.37 mL, 10.2 mmol) in THF (2.1 mL) was stirred at 0° C. as a 0.5 N solution of sodium methoxide in methanol (20.3 mL, 10.2 mmol) was added. A solution of 2,4-dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (1.94 g, 8.64 mmol) in THF (19 mL) was added and the resulting solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexanes to 3:7 ethyl acetate:hexanes gradient elution) and fractions containing the product concentrated. The residue was azetroped with methanol then dichloromethane to provide methyl 3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.64 g, 66% as 0.15 dichloromethane). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J=5 Hz, 1H), 7.82 (d, J=5 Hz, 1H), 3.79 (septet, J=7 Hz, 1H), 3.63 (s, 3H), 1.34 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:19]([CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)([OH:21])=[O:20]
Reactant: COC(=O)CCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 194.9 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(3-methoxycarbonylpropyl)propanamide (15.8 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (16.2 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.I[CH2:16][CH2:17][CH3:18]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:16][CH2:17][CH3:18])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Reactant: CCCI
Product: CCCN(C(C)=O)c1ccc(CCCl)cc1C
Yield: 90 %

Procedure:
N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-propyl-acetamide was prepared according to the general method as outlined in Preparation 43 starting from N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-acetamide (0.400 g, 1.89 mmol) and iodopropane (0.230 mL, 2.36 mmol). After chromatographic purification, the product was isolated as a viscous oil (0.432 g, 1.701 mmol). Yield=90%. MS (APCI): 254 [M+H]+; 1H NMR (400 MHz, CDCl3D2O) δ 7.13 (bs, 1H), 7.07 (bd, J=7.77 Hz, 1H), 7.00 (d, J=7.77 Hz, 1H), 4.8 (bs, H2O/D20), 4.03–3.91 (m, 1H), 3.71 (t, J=8.12 Hz, 2H), 3.11–2.99 (m, 3H), 2.20 (s, 3H), 1.72 (s, 3H), 1.64–1.41 (m, 2H), 0.87 (t, J=6.34 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](OS(C1C=CC(C)=CC=1)(=O)=O)[C@H:21]1[O:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[O:19][CH2:20][C@H:21]1[CH2:22][O:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1OCc1ccccc1
Product: FC(F)(F)c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared from compound C and (S)-glycidyl-p-toluene sulfonate (B) employing the procedure used for the preparation of compound 5′.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:52][C:53]1([C:58](O)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1)=O)(C)(C)C>CN(C=O)C>[NH2:52][C:53]1([C:58]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:6])=[O:7])[CH2:19][CH2:20]2)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC1(C(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (14) (0.400 g, 1.15 mmol) was taken up in 10 mL of dry DMF. To this mixture, HOBt (0.154 g, 1.15 mmol), EDCI (0.218 g, 1.15 mmol), and 1-tert-butoxycarbonylaminocyclopentane-1-carboxylic acid (0.263 g, 1.15 mmol) were added. The mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and the crude material was chromatographed on silica eluting with 25% ethyl acetate/hexane. The combined product fractions were concentrated to dryness and the pure BOC-protected material was deprotected in 40 mL of ethyl acetate/concentrated HCl (19:1). The solvent was removed leaving a white solid material. This material was triturated with diethyl ether and vacuum filtered affording the desired sulfonamide (48) as the HCl-salt. LC: 97%. MS (e/z): 460 (M+H+). 1H NMR of salt (CD3OD): δ 8.02 (m, 2H), 7.83 (d, 1H, J=7.86 Hz), 7.66 (t, 1H, J=7.86 Hz), 4.01 (m, 2.5H), 2.80 (bs, 1.5H), 2.11 (m, 2H), 1.7-2.0 (m, 10H), 1.51 (m, 2H), 0.60 (m, 2H), 0.50 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]3)=[CH:13][CH:14]=2)[C:5]([C:28]2[CH:29]=[CH:30][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([OH:36])=[O:35])=[CH:46][CH:47]=2)=[CH:4][CH:3]=1
Reactant: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)OCC)cc3)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a mixed solution of ethyl (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate (550 mg, 0.865 mmol) in THF (20 ml) and methanol (10 ml) was added 1N aqueous potassium hydroxide solution (15 ml, 15 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 342 mg (yield: 65.0%)
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC1C=NC(C2C=CC(O[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][CH2:50][C:51]([O:54][C:55]([F:68])([F:67])[C:56]([F:66])([F:65])[O:57][C:58]([F:64])([F:63])[C:59]([F:62])([F:61])[F:60])([F:53])[F:52])=CC=2)=NC=1)CCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][CH2:50][C:51]([O:54][C:55]([F:67])([F:68])[C:56]([F:65])([F:66])[O:57][C:58]([F:63])([F:64])[C:59]([F:60])([F:61])[F:62])([F:53])[F:52])=[C:18]([F:23])[CH:17]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)c(F)c2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)c(F)c2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-[4-hydroxy-3-fluorophenyl)pyrimidine (1.5 g, 4.7 mmol) with 5-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)pentyl chloride (2.45 g, 5.1 mmol, Example 22). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210° C. at 0.5 torr), to provide a yield of 2.6 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].Cl[CH2:30][C:31](=O)[CH3:32]>CN(C)C=O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:28][CH2:30][C:31]([CH3:32])=[N:27][N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reactant: CC(=O)CCl
Solvent: CN(C)C=O
Product: CC1=NN=C(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A mixture of 1.00 g (2.50 mmol) of the starting material XVIII, 20 ml of dimethylformamide and 0.57 g (6.16 mmol) of chloroacetone was stirred at room temperature for 2 h. After dilution with water the precipitated crystals were filtered off and purified by refluxing in ethyl acetate to yield 0.73 g (67%) of the title compound; Mp.: 203-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=3)[S:10][C:3]=12.C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([NH:26][CH3:25])=[O:18])[N:15]=3)[S:10][C:3]=12
Reactant: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylic acid 43a (0.123 g, 0.41 mmole) in CH2Cl2 cooled at 0° C. was added 2.0 M oxalyl chloride in CH2Cl2 (0.520 ml, 1.04 mmole) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1 h, concentrated and dried. The residue was taken into CH2Cl2 (10 ml), and 2.0 M methylamine in CH2Cl2 (0.250 ml, 0.492 mmole) was added. The reaction mixture was stirred at room temperature for 1 h, and then partitioned between H2O (100 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 2–8% CH3OH in CH2Cl2 to give yellow solid (0.116 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.62 (1H, d, J=5.1 Hz), 8.19 (1H, s), 7.96 (1H, s), 7.33 (1H, d, J=5.1 Hz), 3.06 (3H, d, J=4.9 Hz); ESIMS (MH+): 309.95.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[CH:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].CC(O)=O>CO>[O:16]=[C:13]1[C:12]2[CH:17]=[CH:18][C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([CH2:20][CH2:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:3][CH2:2]3)=[CH:10][C:11]=2[CH2:15][O:14]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: N#Cc1ccc(CC=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1

Procedure:
A mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (50 mg, 0.20 mmol), 4-(2-Oxoethyl)benzonitrile (30 mg, 0.20 mmol), Sodium Cyanoborohydride (13 mg, 0.20 mmol), and a drop of HOAc was stirred together in Methanol for 2 hours. LC showed formation of the desired product. The crude was diluted with EtOAc, washed with water, adsorbed onto silica gel, and purified by silica gel chromatography. LC-MS (IE, m/z): 376 [M+1]+. (0.30 μM)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=C[C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[N:34]1C=CN=CC=1N>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[N:34][CH:19]=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: Nc1cnccn1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1cnccn1

Procedure:
The product from Example 11, Part D (100 mg, 0.3 mmol) and pyrazin-2-ylamine (43 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (8 mg, 7%). 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 8.31 (d, J=3 Hz, 1H), 8.15 (m, 1H), 7.83 (s, 1H), 7.68 (d, J=8 Hz, 1H), 7.46 (m, 1H), 7.32 (m, 2H), 7.20 (t, J=9, 1H), 7.02 (t, J=7 Hz, 2H), 5.25 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.25 (d, J=15 Hz, 1H), 2.61 (m, 1H), 2.52 (m, 1H), 2.00 (m, 2H). MS: m/z (MH+) 409.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([CH3:36])[N:30]=1>>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:32]=[C:31]([CH3:36])[N:30]=1
Reactant: Cc1cc(I)cc(C)n1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: Cc1cc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cc(C)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and 2,6-dimethyl-4-iodo-pyridine [CAS-No. 22282-67-3] (0.23 g, 1.0 mmol) according to the general procedure IVc. Obtained as a light yellow solid (0.057 g, 12%). MS (ISP) 474.2 [(M+H)+]; mp 159° C.
Reaction SMILES: S(O)(C)(=O)=O.[OH:6][C:7]1[C:8]([CH3:23])=[C:9]([S:14][CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:10]=[C:11]([CH3:13])[CH:12]=1>>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:16]1[C:10]2[C:11]([CH3:13])=[CH:12][C:7]([OH:6])=[C:8]([CH3:23])[C:9]=2[S:14][CH:15]=1
Reactant: COC(=O)CC(=O)CSc1cc(C)cc(O)c1C
Agent: CS(=O)(=O)O
Product: COC(=O)Cc1csc2c(C)c(O)cc(C)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
MsOH (1.0 mL) was added to methyl 4-((3-hydroxy-2,5-dimethylphenyl)sulfanyl)-3-oxobutanoate (175.1 mg) at 0°. The mixture was stirred at 0° C. for 15 min, and then poured into ice water. The mixture was extracted with EtOAc. The organic layer was separated, washed successively with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (130.3 mg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][N:10]([CH2:15][C:16](O)=O)[CH2:11][C:12](O)=O>C(O)CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:12]1[CH2:11][N:10]([CH2:15][C:16]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH3:9]
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: Nc1ccccc1N
Solvent: OCCO
Product: CN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1

Procedure:
2b was synthesised by an analogous procedure to that described for 2a using o-phenylenediamine (5.88 g, 54.40 mmol) and methyliminodiacetic acid (4.00 g, 27.2 mmol) in ethyleneglycol (20 ml). Yield 6.88 g (87%). 1H NMR (250.13 MHz, CD3OD, r.t.), δ 2.29 (s, 3H, NCH3), 3.92 (s, 4H, N(CH2)), 7.19-7.23 (m, J3=3.35 Hz, 4H, ArH), 7.52-7.56 (m, J3=3.35 Hz, 4H, ArH). 13C NMR (62.9 MHz, DMSO-d6, r.t.) δ 47.31 (CH3), 59.97 (NCH2), 126.66 (ArC), 157.45 (ArCq). Anal. Calc. for C17H17N5 (in %) C, 70.10; H, 5.84; N, 24.05. Found C, 70.22; H, 6.05; N, 23.76. +CI MS: (m/z): 292 ([MH+]).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:27][NH:28]2)=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([N:31]3[CH2:32][CH2:33][N:34]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]5[C:20]6[C:15](=[N:16][CH:17]=[CH:18][CH:19]=6)[O:14][N:13]=5)[CH:7]=4)[CH2:35][CH2:36]3)=[N:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=489.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: O=N[O-]
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
Following generally the procedure reported by Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73, 2-ethyl-5-nitroaniline (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 424 mg) in water (1 ml) was added all at once. Stirring was continued for 15 minutes at 25° C. After 3 hours, residual solids were filtered off and discarded, and the filtrate was allowed to stand for 3 days at room temperature. The solution was concentrate in vacuo, and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was filtered and washed thoroughly with cold water, dried and purified by flash chromatography (4:1 hexanes/ethyl acetate) to give 3-methyl-6-nitro-1H-indazole (436 mg, 40.5%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[O:22])=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](O)=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH3:51])=[O:49].C(N(CC)CC)C>O>[CH:24]1([NH:23][C:21](=[O:22])/[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([NH:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[O:19])=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)CCCCCN
Reactant: O=C(O)C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=CCCCNC(=O)C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a suspension of 3-(1E)-(4-(2-(4-fluorophenyl)-3-(cyclopropylamino)-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (prepared according to the procedure described in Example 59, step-I) (0.35 g, 1 mmol) in DMF (15 mL) EDCI (0.83 g, 2 mmol), HOBt (0.13 g, 1 mmol), methyl 6-aminocaproate (0.16 g, 0.9 mmol), were added, followed by triethylamine (0.4 mL, 3 mmol). The reaction mixture was stirred for 2 hours after which the mixture was added to cold water (50 mL). The aqueous layer was extracted with ethyl organic layer was dried over anhydrous Na2SO4 and concentrated to get the crude compound. The crude yellow colored compound was washed with ethyl acetate/hexane (0.5/9.5, 2×20 mL) to afford the title compound as a yellow solid (0.25 g, 52% yield).
Reaction SMILES: [CH2:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:8]=1)[CH:2]=[CH2:3].FC(F)(F)S(O)(=O)=O.[OH2:33]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][N:4]2[C:1]3[C:21](=[CH:22][CH:23]=[CH:3][CH:2]=3)[CH2:20][CH:19]2[CH3:24])=[O:33])=[CH:8][C:9]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Reactant: O
Agent: O=S(=O)(O)C(F)(F)F
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
In a 50 ml reaction vessel was placed 1 gram (2.73 mmols) of 1-allyl-1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine and 10 ml of trifluoromethane sulfonic acid. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperatures. After 15 minutes the solid dissolved and the reaction was allowed to proceed for a total of 4.75 hours. The reaction mixture was worked up by pouring the acid solution into 250 ml of water, extracting the precipitate into ethyl acetate, washing the ethyl acetate several times with water and sodium bicarbonate solution. The ethyl acetate phase was separated and dried with magnesium sulfate and clarified. The isolated product was further purified by dry column chromatography and then crystallized from 50% w/w methanol-acetone.