Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH:33]=[O:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH2:33][OH:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To an ethanol (10 mL) solution of intermediate (1c) (738 mg, 1.25 mmol) was added solid sodium borohydride (62 mg, 1.6 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to 0° C., the reaction was quenched by dropwise addition of a 50/50 solution of acetic acid/water until no effervescence was observed. EtOAc (100 mL) was added and the organic was washed 3 times with saturated aqueous NaCl (100 mL) and dried over anhydrous Na2SO4. The solvent was removed to provide intermediate (1d) as a white solid (600 mg). Anal. HPLC: retention time=3.3 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C28H35ClN4O6S, 591.20; found 591.2.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[OH:29])[CH2:22][CH2:21]4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:45][C@@H:46]2[CH2:48][O:47]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:45][C@@H:46]5[CH2:48][O:47]5)[CH2:22][CH2:21]4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@@H]3CO3)CC2)c1=O

Procedure:
The subtitle compound was prepared using a similar method to that described for Example 299a from N-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 167d) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[C@@H:19]1[O:24][C:23](=[O:25])[CH2:22][C@@H:21]([OH:26])[CH2:20]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[CH2:17][CH2:18][C@@H:19]1[O:24][C:23](=[O:25])[CH2:22][C@@H:21]([OH:26])[CH2:20]1
Reactant: O=C1C[C@@H](O)C[C@H](/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Solvent: C1CCOC1
Product: O=C1C[C@@H](O)C[C@H](CCc2c(Cl)cc(Cl)cc2OCc2ccccc2)O1

Procedure:
A solution of trans-(E)-6-[2-(2,4-dichloro-6-phenylmethoxyphenyl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1.1 g, 28 mmole) in tetrahydrofuran (50 ml) was magnetically stirred and hydrogenated at room temperature and atmospheric pressure in the presence of 110 mg of 5% rhodium on carbon catalyst until 1.5 molar equivalents of hydrogen had been consumed. After removing the catalyst by filtration, the filtrate was evaporated in vacuo leaving the title compound as a pale yellow oil. The oil was chromatographed on a silica gel column (200 g). Elution with acetone-methylene chloride (1:9, v:v; 560 ml) provided a forerun which was discarded. Continued elution with the same eluant (240 ml) gave the title compound as a colorless oil which solidified when it was triturated with ether. The title compound was purified by recrystallization from ether-hexane (1:1, v:v; 20 ml) to give colorless needles (0.67 g, 61%) melting at 99°-101° C.: pmr (CDCl3)δ1.83 (4H, m), 2.60 (2H, m), 2.90 (2H, m), 4.30 (H, m), 4.62 (H, m), 5.05 (2H, s), 7.42 (5H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH3:16][C@H:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:25](=[O:26])[NH:24][C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Reactant: C[C@H](N=C=O)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 19, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and (S)-(−)-α-methylbenzyl isocyanate.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH2:11]1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH2:11]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: NC1CNc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)NC1CNc2ccccc2C1

Procedure:
10 ml of a 10% sodium hydroxide solution and 0.34 ml of ethyl chloroformate are added in succession to a solution of 0.5 g of 3(R,S)-amino-1,2,3,4-tetrahydroquinoline in 6 ml of toluene, while stirring vigorously, and when the addition has ended, the mixture is stirred for a further 5 min. Customary working up and chromatography of the crude product over 25 g of silica gel with methylene chloride as the mobile phase gives the title compound: Rf (P)=0.78; MS: M+ =220.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:13][N:12]2[C@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@H:15]3[C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5]1.I[CH3:26]>CCCCCC.CN(C)C=O>[CH3:26][N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C@@H:15]4[CH2:16][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19][C@@H:14]4[N:12]([C:11]=23)[CH2:13][C:4]1=[O:3]
Reactant: CI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Sodium hydride (900 mg of 60% dispersion in oil; 22.5 mmol) was washed with hexane, and suspended in anhydrous dimethylformamide (5 mL). The suspension was added to a stirred solution of ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (6.02 g, 20 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen. After gas evolution had subsided, the mixture was cooled in ice-water bath and treated with iodomethane (3.55 g., 25 mmol). The mixture was stirred at room temperature for 1 h and then concentrated. The residue was treated with water and extracted with dichloromethane (2×) and the extract was washed with brine, dried over magnesium sulfate and evaporated to dryness to yield 5.48 g (87%) of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as a tan solid, m.p. 149–151° C. (dec.). [M+H] calc. 316; found 316. 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J=7.3 Hz, 3H), 1.85 to 1.93 (m,1H), 2.65 to 2.82 (m, 1H),3.08 to 3.25 (m, 1H), 3.25 to 3.40 (m, 1H), 3.30–3.50 (m, 1H), 3.34 (s, 3H), 3.42 (d, J=14.3 Hz, 1H), 3.85 to 4.0 (m,1H), 4.02 (d, J=14.3 Hz, 1H, 4.15 (q, J=7.2 Hz, 4H), 6.76 (d, J=8.1 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H). MS (CI): 316 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1>C(Cl)Cl>[C:8]([NH:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(N)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)no1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Triethylamine (10 ml., 71.9 mmol) is added dropwise to an ice cold solution of 20.0 g. (71.6 mmol) of trityl chloride in 200 ml. of methylene chloride and the resulting solution is stirred at ice bath temperature for 5 minutes. 3-Amino-5-methylisoxazole (7.0 g., 71.5 mmol) in 50 ml. of methylene chloride is then added dropwise over 10 minutes. After the addition, the ice bath is removed and the stirring continued for 1.5 hours. The solution is washed with ice cold 1N HCl, dried (MgSO4) and the solvent concentrated under reduced pressure until a white solid is present. Diethyl ether is added and the solid collected and dried to give 21 g. (85%) of the title compound as a white crystalline material; m.p. 196°-199° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([N:18]2[CH2:17][CH2:16][O:15][CH2:20][CH2:19]2)=[N:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(N2CCOCC2)nc1
Yield: 56.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.042 g, 0.178 mmol), 6-morpholinonicotinoyl chloride (0.045 g; 0.178 mmol), and triethylamine (0.062 mL; 0.446 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) furnished 0.039 g (57%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][C:26]#[CH:27]>CCCCCCC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][OH:28])[CH:2]=1
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2cnc3ccccc3c2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: OCCCCC#Cc1cnc2ccccc2c1

Procedure:
This product was prepared from toluene-4-sulfonic acid quinolin-3-yl ester and hex-5-yn-1-ol following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 6:4; yield (110 mg, 98%); 1H NMR δ (CDCl3): 8.89 (s, 1H), 8.21 (s, 1H), 8.11 (d, J=8.62 Hz, 1H), 7.80-7.68 (dm, 2H), 7.62-7.52 (m, 1H), 3.74 (t, J=7.17 Hz, 2H), 2.52 (t, J=7.13 Hz, 2H), 1.83-1.67 (br m, 5H); LCMS m/z: 225.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccc(Cl)cc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](F)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:29][CH2:30]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(OC(F)F)c21
Reactant: c1cnc(N2CCNCC2)nc1
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21

Procedure:
The same reaction as in Example 1 was carried out by using 1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-(2-pyrimidinyl)piperazine to obtain the title compound as white powder.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.36 g (0.01 mol) of 7β-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 4 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6 N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is treated with Amberlite IR-120H ionexchange resin and lyophilized to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:38]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Reactant: CCOC(=O)CCCCCCBr
Product: CCOC(=O)CCCCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Yield: 98 %

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121), was alkylated with ethyl 7-bromoheptanoate giving the title compound as a pale-yellow oil, in 98% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[C:16]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])=[O:2].[N+:28]([CH2:31][CH3:32])([O-:30])=[O:29]>>[OH:2][CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[C:16]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH:31]([N+:28]([O-:30])=[O:29])[CH3:32]
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)c(C(=O)N2CCc3ccccc3C2)c1
Product: CC(C(O)c1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223C, tert-butyl 4-formyl-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (59 mg, 0.16 mmol) and nitroethane (0.023 mL, 0.32 mmol) were converted to the title compound as a crude brown oil (1:1 mixture of diastereomers by LC-MS) which was used directly without further purification. MS(ESI+) m/z 441.3 (M+H)+.
Reaction SMILES: Cl.[C:2]([Cl:10])(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:34]3[CH2:39][CH2:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:36][CH2:35]3)[N:24]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]>>[ClH:10].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:34]3[CH2:35][CH2:36][N:37]([C:2]([C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)=[O:9])[CH2:38][CH2:39]3)[N:24]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)c4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from isonicotinoyl chloride hydrochloride and starting compound A2 as described for compound 1. After evaporating the dichloromethane solution, the residue is dissolved in diethyl ether. After addition of a saturated solution of hydrochloric acid in ether, the titel compound precipitates. M.p. 66-68° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl.[CH3:13]N(C)CCCN=C=NCC.CO>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.8 %

Procedure:
A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid (2.0 g, 12.7 mmol) in dichloromethane at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g, 14.0 mmol), methanol (8.2 mL), and 4-dimethylaminopyridine (155 mg, 1.27 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane and was washed with a 1N aqueous hydrochloric acid solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 45:55 ethyl acetate/petroleum ether) afforded 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.06 g, 48.8%) as a white solid: LR-MS for C5H5N3O4 (M−H)+ at m/z=170.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[N:14]1.S(Cl)(Cl)=O.[NH3:25]>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([C:18]([NH2:25])=[O:19])[CH:15]=[N:14]1
Reactant: O=C(O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxylic acid (8.18 g) was treated with thionyl chloride (150 ml) to give crude acid chloride. A solution of this in tetrahydrofuran was added to ammonia with ice cooling. The mixture was stirred at room temperature for one hour, solvent was removed and the product extracted with ethyl acetate and worked up in conventional manner to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxamide, m.p. 239° (Compound 14 ).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C:15]2[C:16]3[N:17]([CH:24]=[CH:25][N:26]=3)[C:18]([NH:22][CH3:23])=[C:19]([Cl:21])[CH:20]=2)=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3]C.[CH3:27][O:28]CCCN1CCC(CN)CC1>>[Cl:21][C:19]1[CH:20]=[C:15]([C:13]([NH:12][CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][O:28][CH3:27])[CH2:6][CH2:7]2)=[O:14])[C:16]2[N:17]([CH:24]=[CH:25][N:26]=2)[C:18]=1[NH:22][CH3:23]
Reactant: COCCCN1CCC(CN)CC1
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(NC)n3ccnc23)CC1
Product: CNc1c(Cl)cc(C(=O)NCC2CCN(CCCOC)CC2)c2nccn12

Procedure:
The title compound was prepared, according to the procedure described in the step 3 of EXAMPLE 5, from 6-chloro-5-(methylamino)imidazo[1,2-a]pyridine-8-carboxylic acid hydrochloride (EXAMPLE 8, Step 4) and {1-[3-(methyloxy)propyl]-4-piperidinyl}methylamine (EXAMPLE 7, Step 2).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(C(C)c3ccccc3)ccc2c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of the product of Example 11 (200 mg), potassium carbonate (260 mg) and (1-bromoethyl)benzene (0.100 mL) in DMF (2 mL) was stirred at 80° C. for 17 hours. Further (1-bromoethyl)benzene (0.100 mL) and potassium carbonate (260 mg) was added and stirred at 80° C. for a further 24 hours. Additional (1-bromoethyl)benzene (0.5 mL) and potassium carbonate (500 mg) were added and the reaction stirred at 80° C. for a further 48 hours. The reaction mixture was filtered and purified by HPLC to yield the title compound (14 mg) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[C:16]([O:19][CH2:20][C:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22])(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC(C1C=CC(S(N)(=O)=O)=CC=1)(C)C)(=O)C.CS(C)=O>[C:16]([O:19][CH2:20][C:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:33][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=2)(=[O:31])=[O:32])=[CH:28][CH:29]=1)([CH3:23])[CH3:22])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(Cl)c2-c2ccc(C)cc2)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A mixture of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (10.0 g), 4-(2-acetoxy-1,1-dimethylethyl)benzenesulfonamide (11.58 g), potassium carbonate (14.45 g) and dimethyl-sulfoxide (50 ml) is stirred at 75° C. (bulk temperature) for 3 hours, and thereto is further added 4-(2-acetoxy-1,1-dimethylethyl)benzenesulfonamide (0.34 g). The mixture is stirred at 70-75° C. for 1.5 hour, and the reaction mixture is cooled, and poured into a mixture of ice (100 g) and conc. hydrochloric acid (60 ml). The mixture is extracted with ethyl acetate, and the organic layer is washed, dried, and concentrated under reduced pressure. The residue is crystallized from a mixture of ethyl acetate and diisopropyl ether to give 4-(2-acetoxy-1,1-dimethylethyl)-N-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (14.97 g) as colorless needles.