Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:25][CH2:26][NH:27][CH3:28].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]([CH3:28])[CH2:26][CH2:25][N:24]([CH3:23])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNCCN(C)c1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N(C)CCN(C)c2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N,N′-dimethyl-N-(2-pyridyl)-1,2-ethanediamine (355 mg, 2.15 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. Triethylamine (0.300 mL, 2.15 mmol) was added and the mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL). The resulting precipitate was collected by filtration, washed with water and dried to give 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[methyl[2-[methyl(2-pyridyl)amino]ethyl]amino]-4-oxoquinoline-3-carboxylic acid (480 mg, 73%) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH3:26][S:27]([OH:30])(=[O:29])=[O:28]>CCO>[S:27]([OH:30])(=[O:29])(=[O:28])[CH3:26].[NH:12]([C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2cccnc12
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(Nc2ncnc3cccnc23)cc1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A solution of 4-chloropyrido[3,2-d]pyrimidine (84 mg, 0.5 mmol), aniline (56 mg, 0.6 mmol) and triethylamine (62 mg, 0.6 mmol) in EtOH (2 mL) are refluxed under N2 with stirring for 2 h. The crude reaction mixture is purified on a preparative tlc plate (silica), eluting once with 3% MeOH in CHCl3. The major band is extracted, and evaporated to dryness under reduced pressure, and the residual solid is dissolved in acetone, (5 mL), filtered, and methanesulfonic acid (32 μL, 0.5 mmol) is added slowly with swirling. The precipitate is collected by suction filtration, rinsed with acetone and dried in a vacuum oven to give 4-anilinopyrido[3,2-d]pyrimidine mesylate (91 mg, 57%) as dull yellow needles. 1H NMR (DMSO) δ 11.75 (1H, slbrs), 9.11 (1H, dd, J=1.5, 4.3 Hz), 8.97 (1H, s), 8.32 (1H, dd, J=1.5, 8.4 Hz), 8.12 (1H, dd, J=4.3, 8.5 Hz), 7.88 (2H, d, J=8.2 Hz), 7.49 (2E, t, J=8.0 Hz), 7.32 (1H, t, J=7.0 Hz), 2.34 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]=1[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)O.[OH-].[Na+]>I.C(Cl)(Cl)Cl.C(O)(C)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(O)c1cccc2cccnc12
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1[nH]cnc1Cc1cccc2cccnc12
Temperature: 160 °C
Yield: 70.9 %

Procedure:
A mixture of (4) (0.71 g, 1.48 mmol) and red phosphorus (0.46 g, 14.18 mmol) in hydroiodic acid (57% in water, 6 mL) was heated in a sealed tube at 160° C. overnight. The reaction mixture was cooled to room temperature, and the sealed tube was slowly opened to release the gas built up inside. The content was poured into crushed ice, and carefully basified with NaOH (aq) to pH>7. The aqueous layer was diluted with chloroform/isopropanol (3:1, 100 mL). The mixture was filtered through a bed of Celite to removed phosphorus. The layers were separated and the aqueous layer was extracted twice with chloroform/isopropanol (3:1, 100 mL). The pooled to organic layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 2% ammonia saturated methanol in dichloromethane to give 8-((5-methyl-1H-imidazol-4-yl)methyl)quinoline (5) as a light yellow solid (0.23 g, 1.05 mmol, 71% yield). 30 mg of (5) was passed through reverse phase HPLC to give 26.5 mg of an analytically pure sample.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:6]([NH2:8])[CH:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(Cc1ccc(Cl)cc1N)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(Cc1ccc(Cl)cc1NC1CCN(C(=O)OC(C)(C)C)CC1)OC
Reaction time: 5 h
Yield: 40.6 %

Procedure:
To a stirred solution of 2 g of 5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamine, (9.27 mmol) in 50 mL of acetic acid was added 3.7 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (18.5 mmol). The reaction mixture was allowed to stir for 1 h at room temperature before the portion wise addition of 5.9 g of sodium triacetoxyborohydride (27.9 mmol). The reaction mixture was allowed to stir an additional 5 h before removing the solvent under reduced pressure. The crude product was partitioned between CH2Cl2 (250 mL) and water. The aqueous layer was further extracted with CH2Cl2 (2×75 mL). The combined organic layers were then washed with 1 N NaOH (2×50 mL), brine, dried over Na2SO4, and concentrated. Purification by chromatography (silica, 10-25% EtOAc/hexanes) afforded 1.5 g (71%) of desired product. TLC (silica, 35% EtOAc/hexanes): Rf=0.49. MS (electrospray): exact mass calculated for C20H31ClN2O4, 398.20. m/z found, 399.2 [M+H]+. 1H NMR (CDCl3, 400 MHz): 6.94 (d, J=7.83 Hz, 1H), 6.61 (dd, J=7.83, 2.02 Hz, 1H), 6.57 (d, J=2.02 Hz, 1H), 4.87 (br s, 1H), 4.40 (t, J=5.31 Hz, 1H), 3.97 (br m, 2H), 3.36 (s, 6H), 3.02 (m, 2H), 2.78 (d, J=5.05 Hz, 2H), 2.00 (m, 2H), 1.47 (s, 9H), 1.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[N:11](OCCC(C)C)=O>O1CCOCC1>[Cl:1][C:2]1[C:3]2[NH:10][N:11]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CC(C)CCON=O
Reactant: Nc1nc(N)c(N)c(Cl)n1
Solvent: C1COCCO1
Product: Nc1nc(Cl)c2[nH]nnc2n1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 6-chloro-2,4,5-pyrimidinetriamine (10.94 g, 0.0686 mol) and isoamyl nitrite (9.20 ml, 0.0686 mol)in dioxane (500 ml, freshly purified by passage through basic alumina) was heated under nitrogen with stirring for 2 hours at 90°. The reaction mixture was cooled, treated with activated carbon, filtered, and concentrated to 150 ml. Petroleum ether (250 ml, bp 35-60°) was added. The precipitate was filtered, washed the petroleum ether (50 ml) and dried in vacuo over P2O5 at 40° for 16 hours to give 9.23 g of crude desired product which was then used in the next step.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7](O)=O)=[N:4][N:3]=[N:2]1.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:5]4[NH:1][N:2]=[N:3][N:4]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 1H-tetrazole-5-acetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C[Si](Cl)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1S
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 90 °C
Yield: 42 %

Procedure:
A mixture of 4-bromobenzoyl chloride (3.0 g, 24 mmol), 2-aminobenzenethiol (4.44 g, 24 mmol) and TMSCl (6.52 g, 60 mmol) in DMF (45 mL) was heated at about 90° C. overnight under argon. The mixture was poured into ice (300 g), and the whole was sonicated for about 20 min and yellow precipitate formed. After filtration, the solid were collected and dissolved in dichloromethane, then washed with aqueous NaHCO3 (150 mL), water (150 mL) and brine (100 mL). The organic phase was dried over Na2SO4, loaded on silica gel, and purified by flash chromatography (hexanes/ethyl acetate 20:1). The fraction one was collected and concentrated and white solid (16) was obtained (2.89 g, 42% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:14](=O)[CH2:15]Br)([CH3:10])([CH3:9])[CH3:8].N.O>C(O)C>[C:22]([C:19]1[CH:18]=[C:13]([C:14]2[N:1]=[C:2]3[N:6]([CH:15]=2)[CH:5]=[CH:4][S:3]3)[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:20]=1[OH:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1nccs1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(-c2cn3ccsc3n2)cc(C(C)(C)C)c1O
Yield: 38.3 %

Procedure:
In 20 ml of ethanol were dissolved 1.2 g of 2-aminothiazole and 3.9 g of 3,5-di-tert-butyl-4-hydroxyphenacyl bromide, and the solution was refluxed for 2 hours. The reaction mixture was neutralized by the addition of aqueous ammonia and added 30 ml of water. The crystals thus precipitated were recovered by filtration and recrystallized from ethanol to provide 1.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][P:17]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([NH2:28])=[CH:22][CH:21]=1)([CH3:19])=[O:18]>>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][C:2]([NH:28][C:23]2[C:24]([O:26][CH3:27])=[N:25][C:20]([P:17]([CH3:16])([CH3:19])=[O:18])=[CH:21][CH:22]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2)n1

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-phenylpyrimidin-4-amine with 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16]>CO>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]3[CH2:21][CH2:22][N:17]([CH:15]=[O:16])[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: O=CN1CCNCC1
Solvent: CO
Product: O=CN1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1
Yield: 86 %

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-formylpiperazine in 86% yield. mp 106°-107°. FDMS m/e=303 (M+ of free base). α[D]589 =-1.98 (c=1.0, methanol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH2:20]([C:27]1([N:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[S:1]1[C:5]([C:30]2([OH:33])[CH2:31][CH2:32][C:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([N:34]([CH3:36])[CH3:35])[CH2:28][CH2:29]2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3s2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A solution of benzo[b]thiophene (1.50 mg, 3.73 mmol) in 20 ml dry THF was cooled to −5° C. under a stream of argon. tert-Butyllithium (4.47 mmol, 2.63 ml of a 1.7 molar pentane solution) was then added dropwise such that a reaction temperature of 0° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for two hours at 0° C. Thereafter, a solution of 4-benzyl-4-dimethylaminocyclohexanone (3.86 mg, 3.73 mmol) in dry THF (8 ml) was added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then for five hours at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase was extracted four times with methylene chloride (25 ml). The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=9:1). 517 mg 1-benzo[b]thiophen-2-yl-4-benzyl-4-dimethylaminocyclohexanol with a melting point of 128-131° C. were obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[F:20][C:21]([F:29])([F:28])[CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25]>O1CCCC1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:25][CH2:24][CH2:23][CH:22]([C:21]([F:29])([F:28])[F:20])[CH2:26][CH3:27])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCC(CCO)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 96 h

Procedure:
The solution of 3-(trifluoromethyl)-1-pentanol in diethyl ether obtained in Step 4 and 26.8 g of p-toluenesulfonyl chloride were dissolved in 300 ml of tetrahydrofuran. To the solution was added dropwise 20 ml of triethylamine at room temperature, and stirred at the same temperature for 4 days. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was sequentially washed with 10% hydrochloric acid and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain 18.4 g of 3-trifluoromethyl-pentyl p-toluenesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C:33]([CH3:38])([C:34]([OH:36])=[O:35])[CH3:37])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: CC(C)(N)C(=O)O
Product: CC(C)(NCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1)C(=O)O

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 2-amino-2-methylpropanoic acid (100 mg; 0.97 mmol), to give Example 174 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 8.00 (2H, d, J=8.1 Hz), 7.94-7.87 (1H, m), 7.77-7.60 (5H, m), 7.55-7.47 (2H, m), 3.96 (2H, s), 1.36 (6H, s). LC/MS (Method C): 498 (M+H)+. HPLC (Method E) Rt 2.35 min (Purity: 98.9%).
Reaction SMILES: [N+:1]([C:4]1[C:22]([NH2:23])=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1)([O-:3])=[O:2].C(C1C(N)=C[C:29]2[O:30]C(C)(C)[C@@H](O)[C@H](N3CCCC3=O)[C:28]=2C=1)#N>>[N+:1]([C:4]1[C:22]([NH:23][C:29](=[O:30])[CH3:28])=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2cc(N)c(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: CC1(C)Oc2cc(N)c([N+](=O)[O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2

Procedure:
6-nitro-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically salt thereof; or 6-cyano-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically acceptable salt thereof.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=1.[Br:17][C:18]1[CH:19]=[C:20](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=1.Cl>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2([C:7]3[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: Cc1cc(Br)cc(C(F)F)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Reaction time: 1 h
Yield: 12 %

Procedure:
n-Butyllithium (0.359 mL, 0.90 mmol) was added to 4-bromo-2-(difluoromethyl)-6-methylpyridine (166 mg, 0.75 mmol) in THF (5 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 30 min before (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (335 mg, 0.82 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. The reaction was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine and concentrated in vacuo. The residue was dissolved in methanol (2.0 mL) and then hydrochloric acid (2.0 M in diethyl ether, 0.393 mL, 0.79 mmol) was added at room temperature. The mixture was stirred over night and then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (saturated) and ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 10% (3.5 M ammonia in methanol) in dichloromethane gave the title compound 40 mg (12%). MS (ES+) m/z 446, 448 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]([C:9]([CH3:19])([CH3:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([CH3:8])[O:4]1.[OH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>C(O)C.[I-].[K+]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([C:5]2([CH3:8])[O:4][CH:3]([CH2:2][N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][OH:20])[CH2:23]3)[CH2:7][O:6]2)([CH3:19])[CH3:18])=[CH:12][CH:13]=1
Reactant: OCC1CCCNC1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(C)OCC(CCl)O1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(Cc1ccc(Cl)cc1)C1(C)OCC(CN2CCCC(CO)C2)O1
Yield: 99.5 %

Procedure:
30.3 g (0.1 mol) of 4-chloromethyl-2-[1-(4-chlorophenyl)-2-methyl-prop-2-yl]-2-methyl-1,3-dioxolane, 23 g (0.2 mol) of 3-hydroxymethylpiperidine and 0.1 g of potassium iodide in 100 ml of ethanol are heated at 150° C. under pressure (2 bar) for 15 hours. For working up, the solvent is removed in vacuo, the residue is taken up in 100 ml of methylene chloride, the mixture is washed twice with 100 ml of water each time and dried over sodium sulphate and the solvent is removed again in vacuo. 38 g (100% of theory) of 2-[1-(4-chlorophenyl)-2-methyl-prop-2-yl]-4-[(3-hydroxymethylpiperidin-1-yl)-methyl]-2-methyl-1,3-dioxolane of refractive index n20 1.5226 are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:33])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24]([CH3:32])([CH3:31])[CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[CH3:32][C:24]1([CH3:31])[C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:33])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22][CH2:23]1)[CH:28]=[CH:27][CH:26]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)C(C)(C)CC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c3cccc1c32

Procedure:
Beginning with (indol-3-yl)acetamide and (6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cn1
Reactant: CN1CCC(NC(=O)c2cc(Cl)ccn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN1CCC(NC(=O)c2cc(Oc3ccc(N)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.557 g, 5.06 mmol) in DMA (8.5 mL) was treated with potassium tert-butoxide (0.639 g, 5.69 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-(1-methylpiperidin-4-yl)picolinamide (1.07 g, 4.22 mmol) in DMA (8.5 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM/NH4OH) to afford 4-((6-aminopyridin-3-yl)oxy)-N-(1-methylpiperidin-4-yl)picolinamide (0.654 g, 47%). 1H NMR (400 MHz, DMSO-d6): δ 8.49-8.48 (m, 2H), 7.81 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 3.69 (d, J=9.9 Hz, 1H), 2.69 (d, J=11.1 Hz, 2H), 2.13 (s, 3H), 1.93 (t, J=11.2 Hz, 2H), 1.68-1.62 (m, 4H); MS (ESI) m/z: 328.2 (M+H+).