Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[S:3].[P:6]([O:11]C)([O:9][CH3:10])[O:7][CH3:8]>C1(C)C=CC=CC=1>[CH3:8][O:7][P:6]([C:2]([O:4][CH3:5])=[S:3])([O:9][CH3:10])=[O:11]
Reactant: COP(OC)OC
Reactant: COC(=S)Cl
Solvent: Cc1ccccc1
Product: COC(=S)P(=O)(OC)OC
Reaction time: 2 h
Yield: 56.5 %

Procedure:
While cooled externally with cold water, 34 g of the crude oil described above was treated with 9 g of chlorine. The temperature should not exceed 30° C. to avoid over-chlorination. The mixture was heated slowly, then fractionated. The fraction boiling at 84-86° C./760 mm was collected, giving 12.7 g of O-methyl chlorothioformate, Y=72%. 1H NMR: δ (ppm) 4.16. [See, Dieter Martin and Wolfgang Mocke, Chemishe Berichte, 98 (7), 2059 (1965).4] A solution of 0.55 g (5 mmol) of O-methyl chlorothioformate in 8 mL of dry toluene was added over 10 min to a solution of 0.62 g (5 mmol) trimethyl phosphite in 15 mL of dry toluene under N2. The mixture was stirred and left for 2 hr at room temperature. The solvent was rotary-evaporated, and the residue distilled in vacuo, giving 0.52 g of a yellow oil, 80-81° C./100μ, Y=56.5%. 1H NMR: δ (ppm) 4.18 (d, 3H, 4JHP=2 Hz, COCH3), 3.87 (d, 6H, 3JHP=11 Hz POCH3); 13C NMR: δ (ppm) 212.5 (d, 1JCP=223 Hz, PC), 59.1 (d, 2JCP=8 Hz, POCH3), 54.8 (d, 3JCP=6 Hz, COCH3); 31P NMR {H }: δ (ppm) −1.14 (s); 31P NMR: δ (ppm) −1.14 (m, 3JPH=11 Hz); HRMS: 185.0031 (MH+, Found); 185.0037 (MH+, Calcd).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[C@@H:14]([C:18]([F:19])([F:20])[F:21])[O:15]2)=[CH:10][C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc1Cc1ccccc1)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: C[C@@H](N)c1cccc2ccccc12
Product: Cc1cc2c(cc1Cc1ccccc1)O[C@H](C(F)(F)F)C(C(=O)O)=C2

Procedure:
A racemic mixture of the compound prepared in Example 42a, Step 2 was chirally resolved using the same protocol as for Example 609e, Step 1, identified as peak 2 with retention time 10.00 min. ESHRMS m/z 347.0894 (M−H, C19H14F3O3 Calc'd 347.0890). 1HNMR (DMSO-d6/400 MHz) 13.19 (brs, 1H), 7.74 (s, 1H), 7.11-7.27 (m, 7H), 6.74 (q, 1H, J=7.1 Hz), 3.91 (s, 2H), 2.11 (s, 3H). S-isomer: 19F NMR (d6-benzene; 6 eq of (R)-(+)-1-(1-naphthyl)ethylamine) d −77.76 (d, 3F, J=6.8 Hz, R-enantiomer), −77.74 (d, 3F, J=6.8 Hz, S-enantiomer).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12]OC(OC)N(C)C.CO>CN(C)C=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][CH:12]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Fe]
Solvent: CN(C)C=O
Solvent: CO
Product: Brc1cnc2cc[nH]c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitro-pyridine (1.58 g, 7.28 mmol) [prepared according to WO 2006/103449] in dimethylformamide (10 mL) was added dimethylformamide dimethyl acetal (1.65 mL, 12.37 mmol). The reaction mixture was stirred at 100° C. for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in glacial acetic acid (25 mL) and iron powder (3.25 g, 58.24 mmol) was added. The reaction mixture was stirred at 100° C. for 21 h, then it was cooled to room temperature. Methanol (25 mL) was added and the suspension was filtered and washed with Methanol. The filtrate was concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification on silica gel by flash chromatography using a gradient of 0-70% ethyl acetate/hexane provided 869 mg of the title compound as an ivory solid (60% yield): 1H NMR (DMSO-d6): δ 6.77 (s, 1H), 7.68 (s, 1H), 8.00 (s, 1H), 8.36 (s, 1H), 11.46 (broad s, 1H); MS (m/z) 197, 199 [M+H+]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][C:8]3[CH:18]=[N:19][NH:20][C:7]=3[C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][C:8]3[CH:18]=[N:19][NH:20][C:7]=3[C:6]=2[CH:5]=1
Reactant: CCC(=O)N1Cc2cn[nH]c2-c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N1Cc2cn[nH]c2-c2cc(N)ccc21
Yield: 81.1 %

Procedure:
A solution of 4,5-dihydro-8-nitro-5-propionyl-1H-pyrazolo[4,3-c]quinoline (1.36 g) in methanol (250 ml) was hydrogenated over 5% palladium on carbon (0.4 g) under atmospheric pressure at ambient temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residual solid was recrystallized from a mixture of methanol and chloroform to give 8-amino-4,5-dihydro-5-propionyl-1H-pyrazolo-[4,3-c]quinoline (0.981 g).
Reaction SMILES: [OH-].[Li+].C([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3/[CH:31]=[CH:32]\[CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])(=[O:23])=[O:22])[C:14]=2[C:16]([O:18]C)=[O:17])[C@H:9]2[CH2:39][CH2:40][O:41][C@H:8]2[CH2:7]1)(=O)C>O1CCOCC1.O>[CH2:37]([N:34]([CH2:35][CH3:36])[CH2:33]/[CH:32]=[CH:31]\[C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[S:21]([NH:20][C:13]1[C:14]([C:16]([OH:18])=[O:17])=[C:15]2[C:10]([C@H:9]3[CH2:39][CH2:40][O:41][C@H:8]3[CH2:7][NH:6]2)=[CH:11][CH:12]=1)(=[O:23])=[O:22])[CH3:38]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)N(C(C)=O)C[C@@H]1OCC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)NC[C@@H]1OCC[C@H]21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
Lithium hydroxide (0.09 g) was added to a solution of methyl cis-(3aRS,9bRS)-5-acetyl-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 27, 0.06 g) in a mixture of dioxane (5 mL) and water (1 mL) and the mixture was stirred and heated at 80° C. overnight. The mixture was then irradiated in the microwave at 150° C. for 30 minutes and then at 180° C. for 30 minutes. After cooling, the mixture was filtered and the filtrate was acidified by addition of formic acid (1 mL) and then evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 10-98%. The isolated product was dissolved in DCM and evaporated to dryness then dissolved in ether and evaporated to dryness to give cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid (0.005 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18]C)=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:3]=1.Cl>[OH-].[Na+].C1COCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:3]=1
Reactant: COC(=O)C1CCCC(c2cc(-c3ccccc3O)nc(N)c2C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(C2CCCC(C(=O)O)C2)cc(-c2ccccc2O)nc1N
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A suspension of methyl 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]cyclohexanecarboxylate (151 mg, 0.43 mmol) in 2N NaOH (1 mL) and THF (2 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was neutralized with 1N HCl (2 mL), and then diluted with water. The resulting precipitates were collected by filtration, washed with EtOH, and dried (60° C., 2 hrs, under reduced pressure) to give 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]cyclohexanecarboxylic acid as a yellow solid (105 mg, yield; 72%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:15]1[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:18][S:17][N:16]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:15]1[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:18][S:17][N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-butoxyethoxy)ethanol (1.46 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: FC(F)(F)C([O-])=O.OC1C=CC=CC=1/C=[N:12]\[C@@H:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][C:17]([S:34][C:35]1[S:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][N+:43]([CH3:46])=[CH:42][CH:41]=3)[N:39]=1)=[C:18]2[C:22]([O:24]CC1C=CC(OC)=CC=1)=[O:23].O.CS(O[C:57](=[O:73])/[C:58](/[C:63]1[N:67]=[C:66]([NH:68][P:69]([OH:72])([OH:71])=[O:70])[S:65][N:64]=1)=[N:59]\[O:60][CH2:61][CH3:62])(=O)=O.ClCCl>C(OC)(C)(C)C>[CH2:61]([O:60]/[N:59]=[C:58](/[C:63]1[N:67]=[C:66]([NH:68][P:69]([OH:71])([OH:72])=[O:70])[S:65][N:64]=1)\[C:57]([NH:12][C@@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[S:15][CH2:16][C:17]([S:34][C:35]1[S:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][N+:43]([CH3:46])=[CH:42][CH:41]=3)[N:39]=1)=[C:18]2[C:22]([O-:24])=[O:23])=[O:73])[CH3:62]
Reactant: CCO/N=C(\C(=O)OS(C)(=O)=O)c1nsc(NP(=O)(O)O)n1
Reactant: COc1ccc(COC(=O)C2=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CSC3[C@H](/N=C\c4ccccc4O)C(=O)N23)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: COC(C)(C)C
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CS[C@H]12)c1nsc(NP(=O)(O)O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with 4-(2-(((7R)-7-((Z)-(2-hydroxybenzylidene)amino)-2-(((4-methoxybenzyl)oxy)carbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium trifluoroacetate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(5-(phosphonoamino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:5].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[O:1]1[C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[C:4](=[O:5])[N:6]([CH2:7][CH2:8][S:9][C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[C:23]1=[O:24]
Reactant: O=C(NCCSc1cccc2nccn12)c1ccccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1oc2ccccc2c(=O)n1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
To a solution of 5-[2-[2-(hydroxy)benzoylamino]ethylthio]imidazo[1,2-a]pyridine (627 mg, 2.00 mmoles) in dry tetrahydrofuran (30 ml) was added 1,1'-carbonyldiimidazole (649 mg, 4.00 mmoles) and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 528 mg of the desired product (77.8%, colorless crystals).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[CH2:10][N:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1.[N:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1>[F:17][C:14]1([F:18])[CH2:15][CH2:16][N:11]([CH2:10][C:9]2[CH:8]=[C:7]([N:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: FC1(F)CCN(Cc2cccc(Br)c2)CC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1cccc(CN2CCC(F)(F)CC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at −78° C. for 20 min, then allowed to warm to RT over 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z 442 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9](I)=[CH:10][C:3]=12.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1c(I)cc2c(Cl)ccnc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(-c2ccccc2)cc2c(Cl)ccnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
4-Chloro-2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (329 mg, 0.805 mmol) and phenylboronic acid (118 mg, 0.966 mmol) were dissolved in dioxane and then Pd(PPh3)4 (46 mg, 0.04 mmol) was added. After adding 1 M potassium carbonate aqueous solution (1.61 mL), the resulting reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with sodium chloride aqueous solution, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1) to give the target compound as a yellow oil (182 mg, 0.51 mmol, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:34])=[CH:12][C:11]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Nc1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 89.2 %

Procedure:
In N,N-dimethylformamide, 2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one (100 mg) was stirred at 80° C. for 1 hour in the presence of methyl iodide and potassium carbonate. The procedures of Example 1 were then repeated likewise, whereby the title compound (92 mg, 89.2%) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17](=[O:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:17](=[O:18])[CH2:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH2:9]4)[CH2:4][CH2:3]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=C1Cc2ccccc2CN1C1CCNCC1
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4CC3=O)CC2)C1=O
Yield: 35 %

Procedure:
Title compound was prepared from 2-(piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as yellow solid in 35% yield. MS m/e (M+H)+=576.2. 1H NMR (500 MHz, DMSO-D6): δ=13.55 (s, 1H), 8.37 (s, 1H), 7.29 (s, 1H), 7.23 (dd, J1=7.63, J2=6.10, 4H), 5.37 (dd, J1=16.48, J2=7.63, 1H), 4.64 (d, J=17.70, 2H), 4.48 (s, 1H), 4.38 (s, 2H), 4.09 (m, 1H), 3.57 (m, 1H), 3.54 (s, 2H), 3.11 (m, 3H), 3.00 (m, 2H), 2.89 (m, 1H), 2.61 (m, 1H), 2.36 (m, 1H), 1.54 (m, 2H), 0.74 (d, J=28.08, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[N:12]=[C:13]([Cl:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:15][C:13]1[CH:14]=[C:9]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[C:10](=[O:17])[N:11]([CH3:16])[N:12]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Cc1cc(N)no1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Cl)nn(C)c2=O)no1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), 5-methylisoxazol-3-amine (559 mg, 5.7 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.89 g, 8.55 mmol), Pd2(dba)3 (521 mg, 0.57 mmol), XantPhos (329 mg, 0.57 mmol), and cesium carbonate (3.72 g, 11.4 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. Then the mixture was cooled to 80° C. and filtered. The filtrate was cooled to room temperature. It was then filtered to afford 141a (600 mg, 44%) as a yellow solid. MS-ESI: [M+H]+ 241.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(OCC)(=O)C.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.[Cu]I>[CH3:27][Si:28]([C:31]#[C:32][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCOCCc1cccc(C#C[Si](C)(C)C)c1
Temperature: 100 °C

Procedure:
tert-Butyl 3-(3-bromophenethoxy)propanoate (1.5 g), triethylamine (6 mL), trimethylsilylacetylene (1.92 mL), Pd(Ph3P)4 (0.26 g) and copper (I) iodide (0.04 g) was sealed into a microwave tube. The reaction was heated to 100° C. over a period of 5 min in the microwave reactor. The reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-10% ethyl acetate in isohexane to afford tert-butyl 3-(3-((trimethylsilyl)ethynyl)phenethoxy)propanoate as a yellow liquid (1.56 g). 1H NMR (300 MHz, CDCl3) δ 7.41-7.12 (m, 4H), 3.67 (t, J=6.3 Hz, 2H), 3.63 (t, J=7.1 Hz, 2H), 2.83 (t, J=7.1 Hz, 2H), 2.47 (t, J=6.5 Hz, 2H), 1.44 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:17]([NH:20][C:29](=[O:30])[CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc1-c1ccccc1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenyl-propanoyl chloride, gave 5-formyl-6-methoxy-N-(3-phenyl-propanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[CH3:35])=[O:21]>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:32]3[CH2:33][CH2:34][CH:29]([C:27]4[CH:26]=[CH:25][C:24]([CH3:35])=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:36])[CH3:18])[CH:28]=4)[CH2:30][CH2:31]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Cc1ccc(C2CCNCC2)cc1NC(=O)C(C)C
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(C)c(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure AA and Scheme AJ using 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 468.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>O>[CH:29]1([NH:33][CH:15]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:28][CH2:27][C:5]2=3)[CH2:32][CH2:31][CH2:30]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: NC1CCC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(NC2CCC2)c2ccncc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Methanesulfonicacid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (300 mg, 0.75 mmol) was dissolved in 70% cyclobutylamine in water (6 mL) and heated at 100° C. for 18 h. The reaction mixture was concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtained 90 mg of cyclobutyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine as the TFA salt. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.6 (dd, 2H), 7.63 (d, 1H), 7.54 (d, 1H), 7.19 (s, 1H), 7.10 (d, 1H), 6.99 (d, 1H), 4.82 (m, 2H), 4.72 (m, 1H), 4.6 (m, 1H), 4.23 (t, 1H), 3.8 (m, 2H), 3.5 (m, 1H), 3.2 (m, 1H), 3.07 (d, 3H), 2.7 (m, 1H), 2.37 (s, 3H), 2.5 (m, 3H), 2.1 (m, 1H), 1.8 (m, 2H). Chiral HPLC separated the racemate into enantiomers II-13a-b.