Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14].[OH-].[Na+]>C(O)C.O>[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]2[CH2:25][C:26](=[O:28])[CH:27]=[C:3]([OH:4])[CH2:2]2)[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)cc(C)c(C(C)=O)c1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Yield: 79 %

Procedure:
Diethyl malonate (10.16 g; 69 mmole) was added to a solution of sodium metal (1.46 g; 63 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(3-acetyl-2,4,6-trimethylphenyl)but-1-en-3-one (14.60 g; 63 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. A 30% aqueous solution of sodium hydroxide (100 ml) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was washed with diethyl ether (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The product, 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxycyclohex-2-en-1-one (13.55 g; 84.0%), was obtained as a glassy solid. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.20 (3H, s); 2.24 (3H, s); 2.38 (3H, s); 2.45 (3H, s); 2.45-3.40 (4H, m); 3.90 (1H, m); 5.25 (1H, s); 6.85 (1H, s); 11.0 (1h, br.s).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:23]=[C:24]([C:29](OC)=[O:30])[C:25](Cl)=[N:26][CH:27]=2)=[CH:16][CH:15]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(O)(C)(C)C.C(O)C>[NH2:5][C:4]1[N:6]=[C:29]([OH:30])[C:24]2[CH:23]=[C:22]([C:21]#[C:20][C:17]3[CH:18]=[CH:19][C:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])=[CH:15][CH:16]=3)[CH:27]=[N:26][C:25]=2[N:3]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cnc1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(N)nc(O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution containing 0.11 g of sodium in 30 ml of anhydrous tert.-butanol is added 0.45 g of guanidine hydrochloride. After stirring the mixture at room temperature for 15 minutes, 0.35 g of methyl 5-(4-tert.-butoxycarbonylphenyl)ethynyl-2-chloro-3-pyridinecarboxylate is added in one portion. The mixture is heated under reflux under nitrogen for 4 hours, cooled, diluted with ethanol, and the solvent removed under reduced pressure. The residue is dissolved in water and filtered to remove a small amount of insoluble material. The filtrate is acidified with a 3N hydrochloric acid solution and the precipitate that forms is collected by filtration, washed with water, and dried under reduced pressure to give 0.15 g (44%) of 2-amino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish solid: m.p. >260° C.; NMR (DMSO-d6, 80 MHz) delta 1.55 (s, 9H), 7.71 (d, 2H, J=8.6 Hz), 7.96 (d, 2H, J= 8.6 Hz), 8.36 (d, 1H, J=2.5 Hz), 8.73 (d, 1H, J=2.5 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:36]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[O:42])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.5 g, 5.49 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (1.66 g, 7.14 mmol) and HOAc (329 mg, 5.49 mmol) in DCE (40 mL) was added NaB(OAc)3H (2.33 g, 11 mmol) in one portion. Then the resulting reaction mixture was stirred at rt overnight. Saturated aqueous NaHCO3 (40 mL) was added to quench the reaction, then was extracted with DCM (50 mL×3), dried over anhydrous Na2SO4 and concentrated. The crude was purified by SGC (DCM:MeOH=100:1 to 50:1) to afford the desired compound (2.3 g, yield: 64%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.14 (d, J=2.5 Hz, 1H), 7.35-7.28 (m, 5H), 7.20 (d, J=4.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.64 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.40-5.39 (m, 1H), 5.08-5.07 (m, 2H), 4.96-4.94 (m, 1H), 4.64 (s, 2H), 4.26-4.24 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.10-3.05 (m, 0.55H), 2.86-2.82 (m, 2H), 2.26-2.20 (m, 3H), 2.10-1.59 (m, 5H), 1.58 (s, 3H), 1.37 (s, 3H), 1.35-1.25 (m, 0.6H), 1.15-1.08 (m, 0.5H) ppm; LC-MS (m/z): 672.4 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21]O)[N:19]=2)=[CH:11][CH:10]=1.Cl.[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:21][CH2:20][C:18]1[N:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][CH:13]=2)[O:16][CH:17]=1
Reactant: OCCc1coc(-c2ccc(OCc3ccccn3)cc2)n1
Reactant: C[C@@H]1CCCN1
Agent: Cl
Product: C[C@@H]1CCCN1CCc1coc(-c2ccc(OCc3ccccn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Example 53 from 2-{2-[4-(Pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol (See Intermediate 66) and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 364.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 350 mg, 1.544 mmol) was dissolved in DMSO (10 mL). Sodium tert-butoxide (223 mg, 2.316 mmol) was added, followed 5 minutes later by the addition of methyl 4-(bromomethyl)benzoate (531 mg, 2.316 mmol) to give a brown suspension. The reaction mixture was heated to 100° C. in a microwave on high absorbance for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (2×15 mL) and brine (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (24 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (133 mg, 23%). ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O3, 375.1. found 375.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[Se](=O)=[O:21].OO.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[Se]=O
Reactant: COc1cccc(CSc2nc3cnccc3[nH]2)c1
Agent: OO
Solvent: CO
Solvent: O
Product: COc1cccc(CS(=O)c2nc3cnccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[(3-Methoxyphenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine (9.88 g, 0.036 mol) was dissolved in 130 mL of methanol by heating. An oxidizing solution was prepared by dissolving 4.0 g (0.036 mol) of selenium dioxide in 150 mL of methanol with heating followed by the addition of 4.07 g (0.036 mol) of 30% hydrogen peroxide and 2.5 mL of water. The oxidizing solution was cooled to room temperature and was added dropwise to the sulfide solution. The reaction mixture was stirred overnight. The precipitate which had formed was collected on a filter and rinsed with petroleum ether giving 4.68 g of product. An analytical sample (m.p. 176°-179° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][C@H:26]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27](O)=[O:28].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:25][C@H:26]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.74 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0° C. internal temperature. Under an N2 atmosphere, (R)-2-hydroxy-4,4-dimethylpentanoic acid (125.4 mg, 0.858 mmol) was added followed by triethylamine (0.218 mL, 1.56 mmol). To this stirring solution was added HATU (356 mg, 0.936 mmol). After the complete addition of HATU, the mixture was allowed to warm to 10° C. After 45 min the reaction was complete, and it was quenched with an equal portion of ice water. A yellow precipitate formed which was collected by vacuum filtration and dissolved in CH2Cl2. This solution was desiccated with Na2SO4, filtered, and concentrated to give a viscous yellow-orange oil. The crude material was purified via silica gel chromatography using 88% CH2Cl2-hexanes (1:1) and 12% EtOAc to afford (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-one as a faint yellow foam (265 mg, 76%). LC/MS: m/z 449.3 (M+H)+ at 2.75 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J=8.2, 1.8 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.41-7.37 (m, 2H), 6.97-6.93 (m, 2H), 4.89 (d, J=7.2 Hz, 1H), 4.49-4.44 (m, 1H), 4.06-3.67 (m, 8), 2.52 (s, 3H), 1.56 (dd, J=14.3, 3.0 Hz, 1H), 1.42 (dd, J=14.3, 8.8 Hz, 1H), 0.97 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:22][CH2:21][C:15]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[CH:27]([C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)[OH:28]>>[F:25][C:26]([F:36])([F:37])[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([N:18]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:22][N:12]([S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:23])[F:24])(=[O:11])=[O:10])[CH2:13][CH2:14]3)[C:19]2=[O:20])=[CH:31][CH:30]=1)[OH:28]
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2

Procedure:
This material was prepared in analogy to example 162 B) from 8-(2-trifluoromethyl-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. White solid. MS (ESI): 537.12 MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[CH3:14][O:13][C:11]([NH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])=[O:12]
Reactant: COC(=O)Cl
Reactant: NCc1ccccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCc1ccccc1N

Procedure:
The amine component employed is obtained starting from 2.0 g of 2-(aminomethyl)aniline, dissolved in 30 ml of methylene chloride, by reaction with 1.3 ml of methyl chloroformate in the presence of 3.1 ml of diisopropylethylamine at 5° C. After purification over 80 g of silica gel (mobile phase A), 2-(methoxycarbonylaminomethyl)aniline is obtained: Rf (A)=0.23; Rf (Z)=0.31.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[NH:12][C:11]2[CH:13]=[C:14]([Cl:21])[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:10]=2[S:9](=[O:23])(=[O:22])[NH:8]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][CH:7]1[NH:12][C:11]2[CH:13]=[C:14]([Cl:21])[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:10]=2[S:9](=[O:22])(=[O:23])[NH:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC1Nc2cc(Cl)c(S(N)(=O)=O)cc2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(CC(=O)O)NS2(=O)=O

Procedure:
Combine 3-ethoxycarbonylmethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (7.7 g) with ethanol (EtOH) (250 ml) and 1N sodium hydroxide (NaOH) (70 ml) for 4 hours. Concentrate to 50 ml, add 1N hydrochloric acid (HCl) (70 ml), and extract with ethyl acetate (EtOAc). Dry the EtOAc extract over anhydrous magnesium sulfate and concentrate to obtain 3-carboxymethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)CCCCC1
Yield: 95 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.98 g (10 mmol) of cyclohexanone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.76 g of the desired product (yield 95%).
Reaction SMILES: C([SiH](CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20](=O)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][NH:15]2)([O-:10])=[O:9]>C(O)(C(F)(F)F)=O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][NH:15]2)([O-:10])=[O:9]
Reactant: CCOC(=O)CCC(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCC1CNc2cccc([N+](=O)[O-])c21
Reaction time: 3 h

Procedure:
Triethylsilane (11 mL, 68 mmol) was added to a solution of ethyl 4-(4-nitro-1H-indol-3-yl)-4-oxobutanoate from Step A (960 mg, 3.31 mmol) in TFA (15 mL). After 3 h, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of CHCl3:MeOH-100:0 to 94:6, to give the title compound. MS: m/z=279 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].O.CC(=O)OCC.C[N:36](C=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:36])[CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1[nH]cc(Cc2cccc(F)c2C)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c(Cc2cccc(F)c2C)cn1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound of step 4 (6.748 g, 20.00 mmol) in 60 ml of anhydrous DMF under a nitrogen atmosphere at 0° C. was added sodium hydride (60% in mineral oil, 0.960 g, 24 mmol) in small portions. After stirring for 10 min at 0° C., the mixture was allowed to warm to room temperature over 15 min. After cooling to 0° C. again, 0-(2,4-dinitro-phenyl)-hydroxylamine (cf. C. Legault et al., J. Org. Chem. 68 (2003), 7119; P. H. Boyle et al., ARKIVOC (2003) (vii), 67; 4.779 g, 24.00 mmol) was added in small portions and the mixture was stirred at room temperature for 1 h. Water (250 ml) and EA (250 ml) were added and the organic phase was washed twice with 125 ml each of a 1 N sodium hydroxide solution and 125 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel, first eluting with cyclohexane/DCM (40:60, then 20:80, then 0:100), then with DCM/EA (97.5:2.5, then 95:5) to give 6.33 g of the title compound as a beige solid melting at 87-88° C.
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]2=[CH:3]1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C

Procedure:
A mixture of the compound of formula (De), 3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (4.0 g, 19.3 mmol) and POCl3 (20 mL) was refluxed for 2 h. After cooling to ambient temperature, the volatiles were evaporated. The residue was poured into a mixture of ice water and sodium bicarbonate, CH2Cl2 (200 mL) was added to dissolve the solid. The layers were separated, and the aqueous layer was extracted with CH2Cl2 one more time. The combined organic layers were washed with brine. After being dried (MgSO4), filtered, and concentrated, the compound of formula (Df), 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was obtained as a yellow solid (4.3 g, 99%), 1H NMR (300 MHz, CDCl3) δ: 7.82 (m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m, 4H), 2.27 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 231 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]([Mg]Br)([CH3:30])[CH3:29]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([OH:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:28]([CH3:30])[CH3:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)C(C)C)c2[nH]c(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Isopropylmagnesium bromide (2.0 M, 0.14 mL, 0.28 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water and concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL), heated to 65° C. for two hours, concentrated, then purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[CH3:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])[CH:31]=[CH:32][C:33]=1[CH3:34]
Reactant: Cc1ccc(B(O)O)cc1Cl
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1Cl

Procedure:
The title compound was synthesized in analogy to Example 83 using 5-bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (example BP) and B-(3-chloro-4-methylphenyl)-boronic acid, (CAN 175883-63-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 493.0516 (M+H)+.
Reaction SMILES: [CH:1]1([C:6](=[O:18])[CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.O>C(O)(=O)C>[CH:1]1([C:6]2[O:18][C:11]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=3[C:8](=[O:9])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccc(C(=O)CC(=O)C2CCCC2)c1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(=O)cc(C3CCCC3)oc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
1-Cyclopentyl-3-(2-hydroxy-3-methylphenyl)-1,3-propanedione (14 g) was dissolved in acetic acid (70 ml) and conc. sulfuric acid (3 ml) was added to the solution. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with water, aqueous saturated sodium bicarbonate and then water and dried (MgSO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (4:1)) to obtain the title compound (12.7 g) as crystals, yield 97.4%. The crystals were recrystallized from methanol to obtain prisms, m.p. 51°-52° C.
Reaction SMILES: [C:1]1(C)[CH:6]=CC=C[CH:2]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.CC(C)=O>[Pt].O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:1]([CH3:6])[CH3:2])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccccc1
Agent: [Pt]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 42.5 °C
Reaction time: 2 h

Procedure:
520 parts of toluene, 423 parts (3 mol) of 4-fluoronitrobenzene, 192 parts (3.3 mol) of acetone and 8 parts of catalyst (5% Pt on charcoal, water-moist, water content 50%) are placed in a hydrogenation autoclave. After the gas space has been flushed three times with each of nitrogen and hydrogen, the mixture is heated to from 80°=0 to 85° C. with stirring and reduced at a hydrogen pressure of from 0.2 to 1.0 MPa. When after about 2 hours the uptake of hydrogen falls sharply, the pressure is raised to 2.0 MPa and stirring is continued at 85° C for 30 minutes until there is no longer any drop in pressure. The batch is cooled to 60° C., the autoclave is let down and flushed with nitrogen, and the catalyst is filtered off on a pressure filter at from 50° to 60° C. The aqueous phase is separated off from the filtrate and toluene is distilled off until the water content of the solution is <0.02%. The solution is processed further in accordance with Example 2.