Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]([CH2:50][CH3:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:43])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])([OH:3])=[O:2].I[CH2:53]CC>>[C:1]([CH2:4][CH2:5][N:6]([CH2:50][CH2:51][CH3:53])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:43])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])([OH:3])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)O)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
Reactant: CCCI
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC)CCC(=O)O)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-((2-carboxyethyl)(ethyl)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 1-iodopropane as alkylating reagent. The product was isolated as a white solid (10 mg, 49%). LCMS: m/e 715.50 (M+H)+, 2.08 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=7.93 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 3.88-3.72 (m, 2H), 3.55 (t, J=7.02 Hz, 2H), 3.44 (q, J=6.51 Hz, 2H), 3.32-3.21 (m, 2H), 3.13 (td, J=11.22, 3.51 Hz, 1H), 2.97 (t, J=6.71 Hz, 2H), 2.55 (td, J=12.13, 3.81 Hz, 1H), 2.25-2.13 (m, 2H), 1.75 (s, 3H), 2.04-1.10 (m, 21H), 1.08 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 1.03 (t, J=5 Hz, 2H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:24][CH2:25][C:26](=O)[CH3:27])[N:18]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.O>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:26]([CH2:25][CH2:24][C:17]1[N:18]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=1)[CH3:27]
Reactant: CON
Reactant: CC(=O)CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=C(C)CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
Methoxylamine hydrochloride (0.26 g, 3.1 mmol) was added to a stirred solution of 4-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one (0.600 g, 1.84 mmol) in pyridine (9 mL), and the reaction was stirred at room temperature for 45 minutes. Water (50 mL) was added. The aqueous layer was separated, extracted with dichloromethane (2×50 mL), adjusted to pH 10 with the addition of saturated aqueous sodium carbonate, and extracted with dichloromethane (2×25 mL). The combined organic fractions were washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting white powder was stirred with diethyl ether for one hour, isolated by filtration, and washed with diethyl ether. The resulting solid (0.45 g) was recrystallized from acetonitrile (20 mL), and the crystals were isolated by filtration, washed with acetonitrile, and dried for 15 hours under vacuum at 60° C. to provide 0.40 g of 4-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one O-methyloxime as white needles, mp 182-184° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Product: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
0.3 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [synthesized as described in Example 42(g)], was N-alkylated using 0.6 g of benzyl 2-bromo-4-phenylbutyrate by the procedure described in Example 42(h). The reaction product was chromatographed on a silica gel column eluted with a 1:40 by volume mixture of ethyl acetate and methylene chloride, to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)(OC(C)(C)C)=O.[CH2:32]([C:34]1[NH:38]N=[N:36][N:35]=1)[CH3:33]>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:36]=[N:35][C:34]([CH2:32][CH3:33])=[N:38]3)[CH:10]=[CH:11]2)=[C:19]([Cl:23])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCc1nnn[nH]1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1

Procedure:
The title compound is prepared analogously to di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine (AA3) by replacing di-t-butyliminodicarboxylate with 5-ethyltetrazole. MS (ES+) m/e 351.2 (MH+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:22]=2)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Yield: 64.3 %

Procedure:
Methyl 2-{[4-(3-hydroxypropyl)phenoxy]methyl}benzoate (0.50 g, 1.66 mmol) and 4-(benzyloxy)phenol (0.33 g, 1.66 mmol) was added to a dry round bottomed flask and fitted with septa. Dry toluene (10 ml) was added and N2 was flushed through the mixture for 5 minutes. (Tributylphosphoranylidene)acetonitrile (0.80 g, 3.33 mmol) was added dropwise and the reaction was performed in a single node microwave oven. After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.515 gram of methyl 2-[(4-{3-[4-(benzyloxy)phenoxy]-propyl}phenoxy)methyl]benzoate (yield 64.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6](=[S:7])[C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[O:3]1>C(O)(=O)C.O.[Fe]>[NH2:12][C:11]1[C:4]2[O:3][C:2]([CH3:1])([CH3:15])[C:6](=[S:7])[C:5]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=S
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2c(N)cccc2C1=S

Procedure:
By the method of Example 1, Step E, 3.35 g (0.015 mole) of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-thione is reacted with 3.35 g (0.060 mole) of powdered iron in 50 mL of glacial acetic acid and 8 mL of water, yielding 7-amino-2,3-dihydro-2,2-dimethylbenzofuran-3-thione.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.O.C(OCC)(=O)C.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100° C. and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)-palladium(0) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10% aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10% ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:25]3=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]3[CH2:23][CH2:22][O:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:25]5=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]5[CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: C1=CCC2CCOC3(CCNCC3)C2=C1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CC1)OCCC1CC=CC=C12

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1,5-dihydrospiro[4H-2-benzopyran-1,4′-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 58% overall yield. FDMS m/e=392 (M+ of free base). α[D]589=−23.56 (c=0.51, methanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH:6](Br)[CH2:7][CH2:8][CH3:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[N:21]=[C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)[S:20][C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCCC(Br)C(=O)CC(=O)OC
Solvent: CCO
Product: CCCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(=O)OC
Temperature: 25 °C
Yield: 99.2 %

Procedure:
4-Bromo-3-oxo-heptanoic acid methyl ester (6.0 g, 25.0 mmol) is dissolved into denatured ethanol (100 mL) and para-trifluoromethyl thiobenzamide (5.0 g, 24.4 mmol) is added in one portion. The reaction is purged of air and flushed with nitrogen then heated to reflux. The reaction is monitored by TLC and HPLC and when complete, the reaction is allowed to cool to room temperature. The solvent is removed and the reaction is diluted with ethyl acetate (200 mL), followed by washes with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution is dried over anhydrous sodium sulfate, then concentrated and further purified using flash column chromatography (10% EtOAc/Hexanes) to yield pure [[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester (8.66 g, 24.2 mmol) or 98% yield.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH3:10])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[BH4-].[Na+].CO.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]([CH2:9][CH3:10])=[CH:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7]
Reactant: CCC(C)=CCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(C)=CCCC(C)O
Reaction time: 2 h

Procedure:
Six grams of 6-methyl-5-octen-2-one is added to a solution of 3.0 g. of sodium borohydride, 80 ml. of methanol and 6 ml. of 2N sodium hydroxide solution. After about two hours, acetic acid is added to destroy excess sodium borohydride and the solution poured into water and extracted with ether. The combined ether extracts are washed with aqueous sodium bicarbonate, water and brine, dried and evaporated to yield 6-methyl-5-octen-2-ol which is purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(F)ccn1
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(F)ccn12
Temperature: 60 °C

Procedure:
4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40 mL) in a reaction flask, under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL, Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 4 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (300 mL) and sodium bicarbonate solution (75 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (75 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate. Fractions containing the product were concentrated to give ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-bromopyridine-2-carbaldehyde (300 mg) in methanol (10 mL) was added sodium borohydride (61 mg) and the reaction stirred at room temperature for 72 h. The reaction was quenched with saturated aqueous sodium carbonate solution (20 mL) and water (20 mL) and extracted into dichloromethane (3×30 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give (5-bromo-pyridin-2-yl)-methanol as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16][C:17](O)=[O:18])=[N:14][N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12](=[O:26])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>O>[Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16][C:17]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:18])=[N:14][N:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:12](=[O:26])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c2cccc(Br)c2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: Cn1c2cccc(Br)c2c2c(CC(=O)N3CCCC3)nn(-c3ccccc3)c(=O)c21

Procedure:
The preparation is carried out as in Example 3.2, from 3.1 g (7.5 mmol) of 9-bromo-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid, from 1.4 g of 1,1′-carbonylbis-1H-imidazole and from 0.7 ml of pyrrolidine. After reaction, water is added and the precipitate is collected by filtration and dried under reduced pressure. It is recrystallized from propan-2-ol and washed with ether and pentane. It is dried under reduced pressure. 2.3 g (4.9 mmol) of solid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([CH3:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c[nH]c2cc(C(=O)O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(COC[C@H](N)c2ccccc2)CC1
Product: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)ccc12

Procedure:
Using coupling method A, 4-[(R)-2-amino-2-phenylethoxy-methyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.0 mmol) and 3-methylindole-6-carboxylic acid (0.54 g, 3.0 mmol) afforded the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21]Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>CN(C=O)C>[CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][N:27]3[C:23](=[O:33])[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:26]3=[O:28])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=S(=O)(NC1CCCCC1)c1ccc(CBr)c2ccccc12
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Temperature: 100 °C
Yield: 36 %

Procedure:
To a solution of 4-bromomethyl-naphthalene-1-sulfonic acid cyclohexylamide 41 (150 mg, 0.39 mmol) in DMF (5 mL) was added potassium phthalimide (109 mg, 0.58 mmol). The resultant solution was stirred at room temperature and then heated to 100° C. for 3 hr. The reaction was quenched with water and extracted with CH2Cl2. The organic layers were dried and concentrated in vacuo. HPLC purification of the residue gave the title compound (G-4) (63 mg) as white foam. 1H NMR (300 MHz, MeOD) δ 8.67 (d, 1H), 8.42 (d, 1H), 8.22 (d, 1H), 7.88 (m, 23H), 7.76 (m, 4H), 5.48 (s, 2H), 4.48 (d, 1H), 3.12 (d, 1H), 1.58 (m, 6H), 1.10 (m, 4H); LC/MS m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1.[CH2:15](C1N=C(S(C)(=O)=O)N=C(C(O)=O)C=1)C(C)C>>[CH2:12]([C:5]1[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CCCc1cc(C(=O)O)nc(NC)n1
Reactant: CC(C)Cc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Product: CNc1nc(CC(C)C)cc(C(=O)O)n1

Procedure:
The title compound is obtained as a beige solid (84 mg) in analogy to 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.63 min, [M+H]+=209.99.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([OH:21])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CC(=O)OCC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
A solution of methanesulfonyl chloride (0.145 ml, 1.87 mMol) in anhydrous CH2Cl2 (2 ml.) is added dropwise over 10 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate (0.65 g., 1.44 mMol) and Et3N (0.30 ml, 2.16 mMol) in anhydrous CH2Cl2 (10 ml.). After stirring 15 more min. in the cold, the solution is diluted with ice-cold CH2Cl2 (10 ml.), washed with ice-cold H2O (10 ml.), ice-cold 5% HCl (10 ml.), and ice-cold 5% NaHCO3 (10 ml.), dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-acetoxymethyl-cepham-4-carboxylate.
Reaction SMILES: [Li+].[CH3:2]CC[CH2-].[Cl:6][C:7]1[CH:15]=[C:14]([CH:16]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:17]=O)[C:13]2[C:9](=[CH:10][N:11]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:12]=2)[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[Cl:6][C:7]1[CH:15]=[C:14]([CH:16]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]2)[CH:17]=[CH2:2])[C:13]2[C:9](=[CH:10][N:11]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:12]=2)[CH:8]=1
Reactant: [CH2-]CCC
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 0.17 h
Yield: 30.4 %

Procedure:
To a suspension of methyltriphenylphosphoniumbromide (470 mg, 1.314 mmol) in THF (17 ml) was added N-BUTYLLITHIUM (0.526 ml, 1.314 mmol). The ice bath was removed and the suspension was stirred for 10 min. To this was added tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (277 mg, 0.438 mmol) in 2.5 mL THF. The reaction was allowed to stir 1 hour before diluted with ether (100 mL) and filtered out the solid, the ether layer was washed with water, brine and dried over magnesium sulfate, filtered and concentrated. It was then purified by Biotage LC (20-25% EtOAc/Hex) to give title compound (84 mg, 0.133 mmol, 30.4% yield) as light yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.29 (m, 2H), 7.00 T, J=8.8 Hz, 2H), 6.85 (s, 1H), 5.88 (ddd, J=17.2, 10.6, 5.9 Hz, 1H), 5.63(d, J=4.0 Hz, 1H), 5.60 (d, J=3.7 Hz, 1H), 5.30 (d, J=5.5 Hz, 1H), 5.23 (d, J=17.2 Hz, 1H), 5.02 (d, J=10.3 Hz, 1H), 3.69 (m, 2H), 3.58 (t, J=8.4 Hz, 2H), 3.42 (AB, Δν=28.5 Hz, J=8.8 Hz, 2H), 3.04 (m, 2H), 1.80-2.25 (m,4H), 1.41 (s, 9H), 0.88 (t, J=9.2 Hz, 2H), −0.07 (s, 9H). LC/MS (HPLC method 3): tR=4.43 min, 630.3(MH)+.