Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:13][C:9]1[CH:8]=[C:7]2[C:12]([C:3]([C:17]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[O:15][CH3:14])=[CH:4][N:5]=[N:6]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc2c(Cl)cnnc2c1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(Cl)ccc12
Yield: 36.8 %

Procedure:
A microwave vial charged with 4,7-dichlorocinnoline hydrochloride (HDH Pharma, Morrisville, N.C.) (0.400 g, 1.7 mmol), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (Combi-Blocks, San Diego, Calif.) (0.513 g, 1.7 mmol), potassium carbonate (1.172 g, 8.49 mmol), dioxane (6.36 ml) and water (2.1 ml); the system was purged with argon prior to the addition of Pd(PPh3)4 (0.196 g, 0.168 mmol). The mixture was irradiated for 30 min at 100° C. The organic layer was decanted and the aqueous phase was rinsed once with EtOAc. The combined organics were dried under reduced pressure and purified with a 40 g silicycle HP column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 35%, 10% DCM throughout) providing 7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)cinnoline (0.212 g, 0.626 mmol, 36.8% yield) as a light yellow solid. m/z (ESI) 339.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[N:22]=[CH:23][S:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4ncsc4c3)n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5ncsc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.36 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzothiazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzothiazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-tert-butyl-benzamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)=[O:26])=[CH:20][CH:19]=1)[NH:6]C(=O)C1C(C)=CC=CC=1Cl.CCN(C(C)C)C(C)C.[OH:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>C1COCC1>[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:25](=[O:26])[C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[CH:48]2[C:47]2[CH:50]=[CH:51][C:44]([OH:43])=[CH:45][CH:46]=2)=[CH:22][CH:23]=1)[NH2:6]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)C2CCCCN2)cc1)NC(=O)c1c(C)cccc1Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)Cc1ccc(N2C(=O)[C@@H]3CCCCN3C2c2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
(S)-N-(2-chloro-6-methylbenzoyl)-4-[[(2-piperidinyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride (100 mg, 0.2 mmol), DIPEA (0.10 mL, 0.54 mmol) and 4-hydroxybenzaldehyde (30 mg, 0.25 mmol) was added to a suspension of activated 3 Å molecular sieves (100 mg) in THF (1.5 mL). The resulting mixture was stirred room temperature overnight and at 60° C. for 3 hr. After it was cooled to room temperature, the mixture was transferred onto a silica gel column and eluted with ethyl acetate:hexane (2:1) to give N-[(2-chloro-6-methylphenyl)carbonyl]]-4-[(8aS)-hexahydro-3-(4-hydroxyphenyl)-1-oxoimidazo[1.5-a]pyridin-2-yl]-L-phenylalanine methyl ester (17.5 mg, 0.031 mmol) as a foam. The methyl ester (17.5 mg, 0.031 mmol) was hydrolyzed with 1N NaOH (0.1 mL, 0.1 mmol) in 0.5 mL of ethanol at room temperature for 6 hr. The reaction mixture was acidified to pH<2 with TFA and was purified on RP-HPLC to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-[(8aS)-hexahydro-3-(4-hydroxyphenyl)-1-oxoimidazo[1.5-a]pyridin-2-yl]-L-phenylalanine (8.3 mg, 0.015 mmol), in 7.5% yield. HRMS: calcd. 548.1952. Obs. 548.1938 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:9]=1)(=O)=O.[SH:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][S:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Tert-butyl (4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)acetate (5.454 g, 17.347 mmol) was dissolved in acetonitrile (100 ml), methyl 2-mercaptobenzoate (3.502 g, 20.816 mmol) and dipotassium carbonate (4.795 g, 34.694 mmol) was added. The solution was stirred for 10 hours at 60° C. EtOAc (40 ml) was added and the organic phase was washed with two portions of brine (2×40 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 6.931 g crude of methyl 2-({2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethyl}thio)benzoate. The crude was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:21])/[CH:5]=[CH:6]/[CH:7]=[C:8]([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)C.[OH-].[K+]>CO>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:21])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccccc1)c1ccccc1
Yield: 86.7 %

Procedure:
A solution of (E)-5,5-diphenyl-2,4-pentadieneoic acid ethyl ester (15 g) in methanol (80 mL) was treated with a 4N potassium hydroxide solution (20 mL) and the mixture was stirred at reflux for 45 minutes. Most of the methanol was removed under reduced pressure, then the residual solution was poured over ice containing 3N hydrochloric acid (30 mL). The resulting solid was collected by filtration, washed with water and dried. Crystallization of the crude material from 2-propanol furnished 11.7 g of (E)-5,5-diphenyl-2,4-pentadienoic acid mp 193°-194° C. Recrystallization from the same solvent did not affect the melting point.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC#N.O>ClCCCl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:27][CH:24]([CH3:26])[CH3:25])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCCl
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step F, from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 56.1 mmol), isopropylamine (14.5 mL, 168 mmol) and NaBH(OAc)3 (29.7 g, 140 mmol) in 1,2-dichloroethane (0.5 L) as a yellowish oil. MS: 387.2 [M+H]+. tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.34 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([NH2:14])[CH:3]=1.N1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:5]=[C:4]([NH:14][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:3]=1
Reactant: CC(C)Cc1nc(N)cc(N)c1C#N
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(CC(=O)Nc2cc(N)c(C#N)c(CC(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
To a solution of 20 mg (0.11 mmol) of 4,6-diamino-2-isobutyl-nicotinonitrile in 1 mL of CH2Cl2 was added 40 μL (0.49 mmol) of pyridine, then 30 μL (0.19 mmol) of (3-methoxyphenyl)acetyl chloride. The solution was stirred at ambient temperature for 10 minutes then 0.5 mL of water was added. The mixture was concentrated under reduced pressure, then the residue was taken up in 5 mL of ethyl acetate and extracted with water (2×2 mL), saturated NaHCO3(aq.), and brine (1×2 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was partially purified via silica gel chromatography, eluting with 30% ethyl acetate:hexanes to provide a solid. This was recrystallized from methanol to provide 8 mg (23%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.48 (s, 1H), 7.37 (s, 1H), 7.22 (t, 1H, J=7.8 Hz), 6.84 (m, 5H), 3.73 (s, 3H), 3.66 (s, 2H), 2.54 (d, 2H, J=7.1 Hz), 2.09 (m, 1H), 0.92 (d, 6H, J=6.1 Hz); MS (ESI) m/e 339 (M+H)+, 337 (M−H)−.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[CH2:15][O:16][CH3:17])=[CH:11][C:10]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:9][CH:8]=3.[BrH:26].C(ON=O)CC(C)C>C(Br)(Br)Br.C(Cl)Cl.[Cu]Br>[Br:26][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[CH2:15][O:16][CH3:17])=[CH:11][C:10]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:9][CH:8]=3
Reactant: COCc1c(N)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: Br
Agent: [Cu]Br
Agent: CC(C)CCON=O
Solvent: BrC(Br)Br
Solvent: ClCCl
Product: COCc1c(Br)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C

Procedure:
1 g of 3-amino-6-benzyloxy-4-methoxymethyl-β-carboline in 32 ml of bromoform is mixed with 0.6 ml of HBr/glacial acetic acid (33%) and 5 g of PGE200. 0.46 ml of isoamylnitrite is added at 9° C. and it is maintained for 30 minutes at this temperature. Then 0.56 g of copper(I) bromide is added to this batch. After heating of the batch to room temperature it is diluted with methylene chloride within one hour and extracted once each with dilute ammonia solution and with water. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride: ethanol=15:1. The corresponding combined fractions are concentrated by evaporation and absorptively precipitated with ethyl acetate/hexane. 0.54 g of 3-bromo-6-benzyloxy-4-methoxymethyl-β-carboline is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH:6]2[CH3:30].CI.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[N:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[N:17]([CH3:33])[C:18](=[O:19])[N:8]1[CH2:7][CH:6]2[CH3:30]
Reactant: COc1cc2c(cc1OC)C(C)Cn1c-2cc(Nc2c(C)cc(C)cc2C)nc1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc2c(cc1OC)C(C)Cn1c-2cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Yield: 50.5 %

Procedure:
18 g of 6,7-dihydro-9,10-dimethoxy-2-mesitylamino-7-methyl-4H-pyrimido[6,1-a]isoquinolin-4-one are boiled under reflux in 1.5 l of acetone with 270 ml of methyl iodide in the presence of 90 g of potassium carbonate. The mixture is then filtered and the filtrate is evaporated. The residue is dissolved in chloroform and purified by chromatography on a silica gel column. There are obtained 9.4 g of pure 9,10-dimethoxy-3,7-dimethyl-2-mesitylimino-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one, m.p. 156°-157° C. The corresponding hydrochloride of the compound melts at 224° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([O:12]C)=O)[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1.[C:18]([C:22]1[CH:23]=[C:24]([NH:33][C:34]([C:36]([NH:38][NH2:39])=[O:37])=[O:35])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19]>CO>[CH3:17][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([NH:39][NH:38][C:36](=[O:37])[C:34]([NH:33][C:24]2[CH:25]=[C:26]([C:29]([CH3:31])([CH3:32])[CH3:30])[C:27]([OH:28])=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:23]=2)=[O:35])=[O:12])[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1
Reactant: CC(C)(C)c1cc(NC(=O)C(=O)NN)cc(C(C)(C)C)c1O
Reactant: COC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)C(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 15 °C

Procedure:
Into a 3-necked 300 ml flask was introduced a 58% solution of methyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol (8.3 g, 0.02 mole), N-(3,5-di-t-butyl-4-hydroxyphenyl)-N'-aminooxamide (6.1 g, 0.02 mole) and 100 ml of anhydrous methanol. The flask was equipped with a magnetic stirrer, a thermometer and a Dean Stark trap containing a reflux condenser. The reaction mixture was heated in an oil bath to reflux for 31/2 hours. At this point, the Dean Stark trap was periodically drained until 40 ml of methanol was collected and solid material formed in the reaction mixture. An additional 10 ml of methanol was distilled from the reaction mixture. The reaction mixture was cooled to 15° C. and the resulting thick slurry was filtered. The filter cake was rinsed with 20 ml of cold methanol and air dried. The product was a white solid weighing 6.2 grams and had a melting range of 196°-202° C. The infrared scan (nujol mull) contained sharp carbonyl bands at 1665, 1585 and 1510 cm-1.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 42 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (30 mg, 0.089 mmol), 4-(trifluoromethyl)aniline (44 mg, 0.27 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 4-(dimethylamino)pyridine (17 mg, 0.14 mmol) and pyridine (1.0 mL) as starting materials and in the same manner as in Example 318, the title compound (18 mg, 42%) was obtained as a white powder.
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12]([C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[O:1])[N:4]=2)[NH:9][CH:10]=1)=[O:17]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(C(O)c3cccnc3)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(C(=O)c3cccnc3)nc12

Procedure:
1-[2-(Hydroxy-pyridin-3-yl-methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was treated with Dess-Martin periodinane, following general procedures described in these Examples MP=218-220 C, (M+H)+=309.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)#[CH:19]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:19]=[CH:18]\[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1)[C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2cccc(C(F)(F)F)c2)CC2CCCC1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (1132 mg, 5.0 mmol; Example 118A) and 1-ethynyl-3-(trifluoromethyl)benzene (1701 mg, 10.0 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound as the minor isomeric product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.26-1.44 (m, J=27, 14, 4, 4 Hz, 1H), 1.46-1.58 (m, 1H), 1.67 (dd, J=15, 2 Hz, 1H), 1.86-2.18 (m, 3H), 2.40 (s, 3H), 2.68 (d, J=18 Hz, 1H), 3.24-3.31 (m, 1H), 4.01 (t, J=6 Hz, 1H), 5.04 (t, J=3 Hz, 1H), 6.84 (d, J=9 Hz, 1H), 6.92-7.03 (m, 3H), 7.18-7.24 (m, 2H), 7.29-7.39 (m, 2H), 7.44-7.50 (m, 1H); MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Agent: Cl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccnc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and nicotinoyl chloride hydrochloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide as a white powder, m.p. 188.6-189.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (dd, J=2.2, 0.7 Hz, 1H), 8.70-8.65 (m, 2H), 8.22 (s, 1H), 8.11 (dt, J=8.3, 2.0 Hz, 1H), 8.04 (dd, J=8.2, 0.9 Hz, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.50-7.39 (m, 2H), 7.23-7.18 (m, 1H), 6.58 (broad s, 2H), 4.64 (t, J=7.0 Hz, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.60 (m, 2H); MS (EI) m/e 360.1696 (360.1699 calcd for C20H20N6O).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[C:11]2[N:12]=[C:13]([S:15][CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[S:14][C:10]=2[C:9]([F:26])=[CH:8][C:7]=1[F:27].Br[CH2:29][C:30]([OH:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]1[C:11]2[N:12]=[C:13]([S:15][CH2:16][C:17]([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:29][C:30]([OH:32])=[O:31])=[O:18])[S:14][C:10]=2[C:9]([F:26])=[CH:8][C:7]=1[F:27]
Reactant: O=C(O)CBr
Reactant: O=C(CSc1nc2c(F)c(F)cc(F)c2s1)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CN(C(=O)CSc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.4 %

Procedure:
To DMSO (5 ml) was added 2-(4,5,7-trifluorobenzothiazol-2-ylthio)-N-phenylacetamide (354 mg, 1 mmol), bromoacetic acid (278 mg, 2 mmol) and potassium carbonate (414 mg, 3 mmol) and the mixture was stirred at room temperature for 5 hours under a nitrogen stream. The resultant reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and then evaporated to yield crude crystals, which were recrystallized from ethyl acetate-hexane to give N-[2-(4,5,7-trifluorobenzothiazol-2-ylthio)acetyl]-N-phenylglycine (80 mg, 19%) as slightly yellow crystals.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:27]1([CH3:36])[C:28]([C:33](Cl)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[CH3:36][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][CH:19]=3)[C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][C:3]([C:33](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36])=[CH:2][CH:1]=3)=[O:34]
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccc(C(=O)c4ccccc4C)cc3c3cc(C(=O)c4ccccc4C)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-carbazol-9-yl-phenyl)-ethanone (2.0 g) in CH2Cl2 (100 mL) is added AlCl3 (3.3 g) and o-toluoyl chloride (2.3 g) at 0° C. After stirring overnight at room temperature, the reaction mixture is poured into ice-water. The product is extracted twice with CH2Cl2, and the combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated to give the residue, which is further dried in vacuo. The product thus obtained is used for the next reaction without further purification. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.35 (s, 6H), 2.72 (s, 3H), 7.26-7.38 (m, 6H), 7.40-7.46 (m, 4H), 7.70 (d, 2H), 7.97 (dd, 2H), 8.26 (d, 2H), 8.59 (d, 2H).
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:11]=[CH:10]C=C[C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[N+:48]([C:51]1C=CC(CS)=C[CH:52]=1)([O-:50])=[O:49]>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:12][CH2:7][C:6]3[CH:4]=[CH:52][C:51]([N+:48]([O-:50])=[O:49])=[CH:10][CH:11]=3)[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 81 %

Procedure:
Following a procedure similar to that described in Example 1, but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 4-nitrobenzylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 81%. Recrystallization of this product from a mixture of ethyl acetate and diisopropyl ether the title compound in the form of crystals, melting at 150.5° to 151° C.