Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[CH:32](OCC)=[O:33]>O1CCCC1>[C:2]1([CH:1]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:32]=[O:33])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Reactant: CCOC=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=CC(c1ccccc1)c1nc(-c2ccncc2)cs1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a solution of 2-benzyl-4-(4-pyridyl)thiazole (4.00 g, 0.016 mol) and tetramethylethylenediamine (2.5 mL) in dry tetrahydrofuran (35 mL) at -78° C. under nitrogen atmosphere was added dropwise n-butyl lithium (1.6M in hexane, 11.4 mL). The resulting dark mixture was allowed to stir at -78° C. for 15 minutes, warmed to 0° C. for 2 hours, then cooled to -78° C. Ethyl formate (1.47 mL) was added dropwise and the mixture allowed to stir at -78° C. for 30 minutes then at 0° C. for one hour. The reaction mixture was quenched with methanol, concentrated, and chromatographed over silica gel. Recrystallization from hexane/ethyl acetate afforded 2-phenyl-2-[4-(4-pyridyl)-2-thiazolyl]acetaldehyde (1.76 g, 39%). mp. 163°-164° C.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].CC1(C)[O:27][C:26](=O)[CH:25]=[C:24]([CH3:29])O1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:29])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 160 °C
Reaction time: 0.33 h

Procedure:
Alternatively, (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione was prepared as follows: To a mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (2.1 g, 7.41 mmol) in xylenes (70 ml) heated to 160° C. was added over 30 minutes a solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.0 ml, 15.3 mmol) in xylenes (30 ml). After stirring at 160° C. for 20 minutes, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-toluene to afford(R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.37 g, 53% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.25-1.71 (m, 6H), 2.00 (s, 3H), 2.46 (s, 3H), 3.62 (s, 3H), 4.00 (t, 2H), 4.86 (sextet, 1H), 6.49 (s, 1H), 12.15 (s, 1H).13C NMR (75 MHz, CDCl3) δ 19.64, 20.96, 22.46, 25.02, 27.19, 29.15, 35.19, 40.67, 70.29, 94.48, 105.71, 150.09, 150.73, 164.92, 165.18, 167.82, 170.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:40]2[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2ccc(CC(NC(=O)C(CC(C)C)NC(=O)N3CCCCCC3)C(=O)OC(C)(C)C)cc2)cc1
Yield: 135.9 %

Procedure:
In a manner similar to the procedure described in Example 27, the product from Example 24 (0.2 g, 0.42 mmol) and 4-methoxybenzyl chloride (75 mg, 0.42 mmol) were converted to the title compound (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:28]1[CH:32]=[CH:31][CH2:30][CH2:29]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:29]4[CH2:30][CH2:31][CH2:32][O:28]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1=COCC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Temperature: 25 °C

Procedure:
In a solution of 1.25 g of N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Synthetic Example 29 and 0.32 g of 2,3-dihydrofuran in 30 ml of dichloromethane, 0.01 g of p-toluene sulfonic acid monohydrate was added with stirring at room temperature, and stirred at room temperature for 3 days. After the completion of the reaction, 30 ml of saturated sodium hydrogen carbonate aqueous solution was added in the reaction mixture, and extracted with ethyl acetate (30 ml×2), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 1.18 g of the aimed product as colorless resinous substance.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C1(C(C2C=CC=CC=2)=N[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[O:36][CH3:37])C=CC=CC=1>C(O)C>[F:35][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[C:29]2[NH:28][C:16]3[CH2:15][CH2:14][NH:13][CH2:18][C:17]=3[C:34]=2[CH:33]=1
Reactant: O=C1CCNCC1
Reactant: COc1cc(F)ccc1NN=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1cc(F)cc2c3c([nH]c12)CCNC3
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
p-Toluenesulfonic acid (129 mg, 0.75 mmol) was added to piperidin-4-one hydrochloride (50.8 mg, 0.37 mmol) and 1-(diphenylmethylene)-2-(4-fluoro-2-methoxyphenyl)hydrazine (80.0 mg, 0.25 mmol) in ethanol (1.25 mL) at 25° C. over a period of 1 min under air. The resulting suspension was stirred at 80° C. for 16 hours. The reaction mixture was diluted with EtOH (20 mL), and EtOAC (100 mL) then washed sequentially with saturated NaHCO3 (75 mL), saturated NaHCO3 (75 mL), and saturated brine (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (containing 0.1% NH3, CH3CN/H2O) as eluents. Fractions containing the desired compound were evaporated to dryness to afford 8-fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (25.0 mg, 46%) as an off-white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[C:8]#[N:9].[OH2:18].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[C:8]([NH2:9])=[O:18]
Reactant: N#CC(N)c1ccc(Cl)cc1F
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(Cl)cc1F
Reaction time: 3 h
Yield: 82 %

Procedure:
Then, 20 g of concentrated sulfuric acid was added to 1.03 g of water, to which 17 g of 2-amino-2-(4-chloro-2-fluorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 100 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 15.3 g (yield, 82%) of 2-amino-2-(4-chloro-2-fluorophenyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.[CH:10](O)([CH3:12])[CH3:11]>>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:8][CH:10]([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: Cc1nc(O)ccc1Br
Reactant: CC(C)O
Product: Cc1nc(OC(C)C)ccc1Br

Procedure:
The title compound was prepared from 3-bromo-6-hydroxy-2-methylpyridine and isopropanol in analogy to Example 9c): colorless liquid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C>C(O)C.[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[N:5][N:4]([CH3:10])[C:3](=[O:11])[CH:2]=1
Reactant: COc1cnn(C)c(=O)c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cnn(C)c(=O)c1
Yield: 89.1 %

Procedure:
A solution of 3.90 g (22.34 mmol) of 4-chloro-5-methoxy-2-methyl-2H-pyridazin-3-one and 3.74 ml (2.71 g, 26.8 mmol) of triethylamine in 60 ml of ethanol was hydrogenated at atmospheric pressure over 950 mg (0.894 mmol) of 10% palladium on charcoal for 20 h at 55° C. The suspension was filtered hot and the catalyst was washed three times with 10 ml of ethanol. The filtrate was concentrated in vaccuo, and the residue was taken up in 70 ml of methylene chloride, which was washed four times with 20 ml of water, dried over magnesium sulfate and concentrated to yield 2.79 g (19.9 mmol, 89%) of the title compound as a crystalline white solid, MS: 141.2 (M+H+).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.12 g, 0.28 mmol) (from Example 12 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in dichloromethane to give recovered staring material (25 mg) and 4-amino-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.053 g, 44%). HRMS (ES+) m/z Calcd for C21H20N4O4S+H [(M+H)+]: 425.1278. Found: 425.1274.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].CN([CH:23]=[O:24])C>>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:1][CH2:2][C:7]([O:24][CH3:23])=[O:9])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
0.22 mole of Z-Leu-OH are dissolved in 500 ml of DMF. To this solution are successively added:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:16][S:17]([O:15][CH2:14][CH2:13][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=1)(=[O:19])=[O:18]
Reactant: COCOc1ccc(CCCO)cc1Cl
Reactant: CS(=O)(=O)Cl
Product: COCOc1ccc(CCCOS(C)(=O)=O)cc1Cl

Procedure:
In substantially the same manner as in Reference Example 85, 3-(3-chloro-4-methoxymethoxyphenyl)propanol was reacted with methanesulfonyl chloride to obtain 3-(3-chloro-4-methoxymethoxyphenyl)propyl methanesulfonate as an oil. The yield was quantitative.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:28]=1[CH:29]=O.CC(C)([O-])C.[K+].O>O1CCCC1>[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:28]=1[CH:29]=[CH:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C=CCC(=O)O)c(C)c1
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
(2-Carboxyethyl)triphenylphosphonium bromide (150 g, 361 mmol) was suspended in tetrahydrofuran (500 mL) and 2,4-dimethylbenzaldehyde (55.4 mL, 397 mmol) was added thereto. A solution of potassium t-butoxide (81.1 g, 722 mmol) in tetrahydrofuran (300 mL) was added thereto under nitrogen atmosphere over 10 minutes and the mixture was stirred under ice-cooling for 3 hours. Water was added to the reaction mixture to stop the reaction and the temperature of the liquid was returned to room temperature. The mixture was concentrated under reduced pressure, a 8N aqueous sodium hydroxide solution was added thereto to bring pH to 11 and ether was added thereto to separate it. A 12N aqueous hydrochloric acid solution was added to an aqueous phase to bring pH to 2 and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-6:1) to obtain 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, yield: 54%). 10% Palladium-carbon (7.96 g, 50% hydrous) was added to a solution of the obtained 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, 195 mmol) in methanol (400 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain the title compound (64.4 g, yield: 84%).
Reaction SMILES: CCO.[C:4]([C:9]1[S:10][C:11]([C:16]([O:18]CC)=[O:17])=[C:12]([OH:15])[C:13]=1[OH:14])([O:6]CC)=[O:5].[OH-].[Na+]>O>[C:16]([C:11]1[S:10][C:9]([C:4]([OH:6])=[O:5])=[C:13]([OH:14])[C:12]=1[OH:15])([OH:18])=[O:17]
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1sc(C(=O)O)c(O)c1O

Procedure:
EtOH (30 mL) was added to 2,5-dicarbethoxy-3,4-dihydroxythiophene (1 g). A solution of NaOH (4.0 g) in H2O (20 mL) was added and refluxed under N for 20 h. Upon cooling to ambient temperature the EtOH was removed by distillation and the residue was redissolved in H2O then acidified with 15% HClaq when a white ppt was obtained This product was collected by filtration and washed with cold H2O then crystallized from dilute MeOH to give colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:38]5[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccncc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and pyridine-4-boronic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]1([CH:16]([NH2:26])[C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:16]([C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccccn1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1ccccn1
Yield: 6 %

Procedure:
Using the procedure described for Example 43 with picolinic acid at room temperature, the reaction was stopped once 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Purification by Biotage chromatography provided N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]-2-pyridinecarboxamide (8 mg, 6%) as an off-white solid: mp 102-110° C.; 1H NMR (300 MHz, CD3OD) δ 6.42 (1H, s), 6.64 (1H, s), 7.36-7.62 (7H, m), 7.98-8.03 (2H, m), 8.13-8.16 (1H, m), 8.59 (1H, s), 8.63-8.67 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=15.8 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C:27]1([F:35])[CH2:30][C:29]([CH2:33][NH2:34])([CH2:31][NH2:32])[CH2:28]1>>[NH2:32][CH2:31][C:29]1([CH2:33][NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:30][C:27]([F:35])([F:26])[CH2:28]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(CN)CC(F)(F)C1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)CC(F)(F)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3,3-difluorocyclobutane-1,1-diyl)dimethanamine. MS obsd. (ESI+) [(M+H)+] 487, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (dd, J=7.83, 1.01 Hz, 1 H), 8.08 (s, 1 H), 7.89 (d, J=7.07 Hz, 1 H), 7.80-7.68 (m, 2 H), 7.68-7.56 (m, 2 H), 6.15 (s, 1 H), 5.37 (s, 2 H), 4.55 (brs, 2 H), 3.80 (s, 2 H), 3.79-3.67 (m, 2 H), 3.44 (s, 2 H), 2.76 (t, J=12.25 Hz, 4 H), 2.51 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([NH2:30])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:38]([O-])=O.[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:22]3[NH:30][N:38]=[N:29][C:23]3=[CH:24][CH:25]=4)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nn[nH]c54)c3=O)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a suspension of {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) in glacial acetic acid (2 mL) and water (1 mL) at 0° C. was added NaNO2 (14 mg, 0.20 mmol). The resulting mixture was stirred at 0° C. for 30 mins, before allowing to warm to RT. After 16 hours, further NaNO2 (14 mg, 0.20 mmol) was added and the reaction mixture stirred at RT for a further 3 hours. The resultant mixture was poured onto water and the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with NaHCO3 (2×30 mL), brine, dried (NaSO4), filtered, and the solvent removed in vacuo to give the title compound as a brown solid (51 mg, 63%). LCMS (Method G): RT=3.76 min, [M+H]+=509.
Reaction SMILES: [CH2:1]([CH:4]1[C:8]([OH:10])([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:12]([O:10][C:8]1([CH3:9])[CH:7]=[CH:6][C:5](=[O:11])[CH:4]1[CH2:1][CH:2]=[CH2:3])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCC1C(=O)C=CC1(C)OC(C)=O
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (152 g), p-toluenesulfonic acid (1 g) and acetic anhydride (320 g) were charged, and stirring was continued for 2 hours at 100° C. After completion of the reaction, acetic anhydride was removed under reduced pressure, and the residue was extracted with toluene. The toluene layer was washed with 1% aqueous sodium carbonate solution and water in order and concentrated to give dl-3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (186 g). Yield, 96%. B.P., 72°-75° C./0.2-0.3 mmHg.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:12][CH2:13][C:14]1[C:15](=[O:35])[N:16]2[C:28](=[CH:29][C:30]=1[C:31](=[O:34])[CH2:32][CH3:33])[C:19]1=[N:20][C:21]3[C:26]([CH:27]=[C:18]1[CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=O.[Cl-].[NH4+]>C1COCC1.[Zn]>[F:8][C:2]([F:9])([C:31]([OH:34])([C:30]1[CH:29]=[C:28]2[N:16]([CH2:17][C:18]3[C:19]2=[N:20][C:21]2[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:35])[C:14]=1[CH2:13][OH:12])[CH2:32][CH3:33])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCC(=O)c1cc2n(c(=O)c1COC=O)Cc1cc3ccccc3nc1-2
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)(CC)c1cc2n(c(=O)c1CO)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Yield: 26 %

Procedure:
Approximately half of a total quantity of ethyl bromodifluoroacetate (1.8 ml, 14 mmol), (9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methyl formate (2.0 g, 5.75 mmol, as obtained in Stage 1.b.) in suspension in anhydrous THF (10 ml), are added dropwise under argon to a suspension of zinc (1.25 g, 17.2 mmol) in anhydrous THF under reflux (40 ml) then the remaining part of the ethyl bromodifluoroacetate is added. The reaction mixture is maintained under reflux for another half an hour. After cooling down to ambient temperature, the reaction is stopped by the addition of saturated ammonium chloride (20 ml) and the reaction mixture is extracted with dichloromethane (3×20 ml). The combined organic extracts are dried and concentrated. The residue is taken up in diethyl ether (10 ml), filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH:98/2), which produces 664 mg (26%) of product in the form of a yellow solid, m.p. 208-209° C.