Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[N:24]=1>N1CCCCC1.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][C@@:28]([OH:32])([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)[CH3:29])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[C:5]([Cl:21])=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Nc1ncc(Cl)c(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(=O)O)nn(-c4nc(N)ncc4Cl)c3c2)no1
Temperature: 35 °C

Procedure:
To a solution of 1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (400 mg, 0.96 mmol) in piperidine (4 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (111 mg, 0.10 mmol), copper(I) iodide (18.3 mg, 0.10 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (292 mg, 1.92 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (eluent: DCM containing a 1-15% MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). The partially purified compound was dissolved in DCM (20 mL) and washed with 2M aqueous citric acid (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound as a dark oil: 1H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.62 (3H, s), 6.80 (1H, s), 7.53-7.35 (3H, m), 8.09 (1H, s), 8.23 (1H, d, J=8.4 Hz), 8.56 (1H, s); LC-MS: m/z=+439.90 (M+H)+. This compound, with LC-MS purity=65% UV, was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:29](=O)[CH3:30])[C:25]([O:27][CH3:28])=[O:26].CC(O)=O>CCO>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([NH:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH3:3])[CH3:30]
Reactant: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)C(C(C)=O)c1ccccc1Br
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C(=C(C)NC(C)C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1Br
Temperature: 85 °C
Yield: 49.1 %

Procedure:
To a round bottomed flask was added (R or S)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (9.35 g, 40.9 mmol), EtOH (75 mL), and methyl 2-(2-bromophenyl)-3-oxobutanoate (7.40 g, 27.3 mmol) (from Step 4). To this solution was added AcOH (1.563 ml, 27.3 mmol) and the reaction was heated overnight at 85° C. before cooling to room temperature and concentrating. The crude residue was purified via silica gel chromatography (330 g, 100% hexanes to 25% EA in hexanes) to afford the title compound (6.45 g, 13.40 mmol, 49.1% yield).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: OC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Cl)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To 3.5 g of N,N-dimethylformamide were added 2.00 g of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.00 g of 3-hydroxyazetidine hydrochloride, and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture was stirred at 85° C. for 10 minutes. The solvent and the like were distilled off under reduced pressure. After adding 10 ml. of ethanol to the residue, the mixture was heated under reflux for 10 minutes and allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 2.10 g of the title compound as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:16].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[N:6]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])[C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1ccc(Br)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.7 %

Procedure:
To a solution of methyl 5-bromopyrrole-2-carboxylate (340 mg, 1.7 mmol) in dry DMF (8 mL) was added sodium hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) portionwise under nitrogen. After 1 hour at 0° C. a solution of 2-bromo-1-(4-methoxyphenyl)ethanone (500 mg, 2.2 mmol) in DMF (4 mL) was added. The resulting yellow solution was then stirred at room temperature for 2.5 hours. Saturated aqueous solution of NH4Cl (30 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (35 mL), dried (MgSO4), filtered and concentrated in vacuo to give a liquid that was purified by flash chromatography (Biotage SP4, 40 g silica cartridge, 0 to 50% EtOAc gradient in hexanes) to give methyl 5-bromo-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate as a white solid (525 mg, yield 88%).
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=O)[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C(O)(=O)C.C([O-])(=O)C.[NH4+].[C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:20]>C1(C)C=CC=CC=1.O>[N:1]12[CH2:9][CH:5]([C:6](=[C:21]([C:19]#[N:20])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)CC#N
Reactant: O=C1CN2CCCC1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CN2CCCC1C2
Reaction time: 40 h

Procedure:
A solution of 1-azabicyclo[3.2.1]octan-6-one (41.25 g, 0.33 mol), acetic acid (2 ml), ammonium acetate (1.25 g) and ethyl cyanoacetate (37 g, 0.33 mol) in toluene (500 ml) was refluxed with a Dean-Stark water separator for 40 h. The toluene phase was extracted with 3×200 ml 5M HCl solution. The water phase was basified with 28% ammonium hydroxide solution and extracted with ether (4×200 ml). The organic phases were dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (eluent CH2Cl2 /MeOH (9:1), yield 41 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C.O>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccnc2cc(Cl)ccc12)c1ccccc1F
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A solution of 2.52 g (18 mmol) of 1-(2-fluorophenyl)ethanol in DMF was added dropwise to a mixture of 2.97 g (15mmol) of 4,7-dichloroquinoline and 0.50 g (21 mmol) of sodium hydride in 15 ml of DMF. After addition was complete, the mixture was heated to 160° C. After four hours the mixture was allowed to cool and 0.1 g of sodium hydride was added. Upon completion of the reaction, a few drops of water were carefully added to destroy excess sodium hydride. Then the solution was poured into water. The product was extracted into ethyl acetate, the ethyl acetate solution was washed three times with water, then dried, and evaporated, producing an oil that crystallized from heptane/ethyl acetate. Yield: 0.77 g M.P. 53°-54° C.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])[OH:5].[N:9]#[C:10][NH2:11].[O-]CC.[Na+].O>C(O)C>[NH2:11][C:10]1[O:5][C:4]([CH2:6][CH3:7])=[C:3]([CH2:2][CH3:1])[N:9]=1
Reactant: N#CN
Reactant: CCC(=O)C(O)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1nc(N)oc1CC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 29.7 %

Procedure:
Propioin (1.03 g, 8.87 mmol) was dissolved in ethanol (15 mL). Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (dichloromethane:methanol=9:1) to give the title compound (369.2 mg, 29.7%) as a yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Cl:29])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[ClH:29].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate (1662 g, 5.52 mol) in dimethylformamide (10.9 L) is added 3-picolyl chloride hydrochloride (947.3 g, 5.77 mol) followed by powdered potassium carbonate (2409.9 g, 17.36 mol). The reaction mixture is stirred at room temperature for 2 days. At that time, additional quantities of 3-picolyl chloride hydrochloride (95 g) and powdered potassium carbonate (241 g) are added, and the reaction is stirred for 3 more days. The solids are then filtered away, the crude product is poured into water (22 L), and the pH is adjusted to pH=8 with 6N sodium hydroxide. This solution is extracted well with toluene (4×10 L), the combined organic layers are washed with water (2×12 L), and then with 6N hydrochloric acid (3×1600 mL). This aqueous layer is then re-adjusted to pH=8 with 6N sodium hydroxide, extracted with toluene (4×10 L), dried (Na2SO4), and the solvent is evaporated. The oil obtained is re-dissolved in ethyl acetate (12 L), cooled to 5° C., and to this is added methanolic HCl (834 mL). After stirring for 2 hours, the precipitated product is collected by filtration to give methyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoate hydrochloride.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7](OC)=[O:8])[CH:2]=[CH2:3].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([NH:16][NH2:17])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: C=CCc1cc(C(=O)NN)ccc1C

Procedure:
A solution of methyl 3-allyl-4-methylbenzoate (2.84 g, 15 mmol) and hydrazine hydrate (2.1 mL, 37.5 mmol) in ethanol (5 mL) was heated to 100° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water, and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 3-allyl-4-methyl-benzoic acid hydrazide as a white solid. (Yield 2.80 g, 98.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:20][CH3:21])[C@@H:13]([CH2:18]O)[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>O1CCOCC1>[CH2:20]([N:12]([S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:10])=[O:11])[C:13](=[CH2:18])[C:14]([OH:16])=[O:15])[CH3:21]
Reactant: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 80 °C
Yield: 43.5 %

Procedure:
A solution of 3G (2.8 g, 7.9 mmol) in dioxane (30 mL) was added with 20% NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 5 h. The organic solvent was removed under reduced pressure and the aqueous phase acidified with 10% HCl and extracted with CH2Cl2 (3×30 mL). The recombined organic phases were anhydrified using Na2SO4, evaporated under reduced pressure and then the resulting residue purified by flash chromatography (100% EtOAc) to obtain 4G as white solid (1 g, 44% yield). 1HNMR (DMSO, 200 MHz) δ 1.07 (t, 3H), 3.42 (q, 2H), 5.78 (s, 1H), 6.36 (s, 1H), 7.67 (m, 2H), 7.87 (m, 1H), 13.02 (bs, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][CH:12]([C:14]([OH:16])=O)[CH3:13])[CH:2]=1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH2:24][CH2:25][CH3:26])[NH2:22]>>[CH3:18][O:19][C:20](=[O:27])[C@@H:21]([NH:22][C:14](=[O:16])[CH:12]([CH3:13])[NH:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: CC(Nc1cnc2ccccc2c1)C(=O)O
Agent: Cl
Product: CCCC[C@H](NC(=O)C(C)Nc1cnc2ccccc2c1)C(=O)OC

Procedure:
Using General Procedure G, followed by hydrolysis set forth in General Procedure C, N-(quinolin-3-yl)-D,L-alanine was prepared. This compound was then coupled to L-norleucine methyl ester hydrochloride (Sigma) using General Procedure D to provide for the title compound as an oil. The latter reaction was monitored by tlc (Rf=0.76 in 10% methanol/methylene chloride and 0.07 in 1:1 EtOAc:Hexanes and the product was purified by flash chromatography using 10% methanol/methylene chloride as the eluent.
Reaction SMILES: [C:1]([P:5]([CH2:10][C:11](=[CH2:22])[CH2:12]P1C2CCCC1CCC2)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C(PC(C)(C)C)(C)(C)C.[Cl:32]CC(CCl)=C>C(#N)C>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:10][C:11]([CH2:12][Cl:32])=[CH2:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CCl)CCl
Reactant: C=C(CP1C2CCCC1CCC2)CP(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)PC(C)(C)C
Solvent: CC#N
Product: C=C(CCl)CP(C(C)(C)C)C(C)(C)C
Temperature: 60 °C
Yield: 40 %

Procedure:
FIG. 1: 9-(2-{[di(tert-butyl)phosphino]methyl}-2-propenyl)-9-phosphabicyclo[3.3.1]nonane A mixture of di-tert-butylphoshine (5 g, 34.1 mmol) and 3-chloro-2-chloromethyl-1-propene (14.04 g, 69 mmol) was dissolved in degassed acetonitrile (70 ml) and heated to 60° C. for 16 hours. The solvent was removed in vacuo and the product was suspended in hexane (50 ml). After filtration the product was washed with hexane (2 times 40 ml). The white solid salt was neutralized in a mixture of toluene (50 ml) and water (30 ml) with HNEt2 (5 ml) under reflux conditions. The toluene layer was separated, washed with water (2 times 30 ml) and removed in vacuo, to yield 3.14 g (40%) of di(tert-butyl)[2-(chloromethyl)-2-propenyl]phosphine. The product could be characterized by showing a distinct resonance signals in 31P NMR at δ=+21.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[NH3:13].C(OCC)(=O)C.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 4-bromo-2-chlorobenzenesulfonyl chloride (2.50 g, 8.45 mmol) in THF (25 ml) was added a solution of ammonia (25%, 6.3 ml, 84.5 mmol). The reaction mixture was stirred for 4 h at RT. Ethyl acetate (70 ml) and water (50 mL) were added. The organic phase was separated and washed with hydrochloric acid (1 M, 50 ml) and brine (2×30 ml) and dried over sodium sulfate. After evaporation the product was obtained as a white solid (2.05 g, 90%) which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([CH:21]=1)[C:9]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)=[O:10])([O-])=O.O.NN>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([CH:21]=1)[C:9]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)=[O:10]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1cc([N+](=O)[O-])ccc1O
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Yield: 74.1 %

Procedure:
A suspension of 6 g of 5-nitro-2-hydroxy-N-(1H-indol-4-yl)-benzamide of Example 50, 600 ml of methanol and 15 ml of 64% hydrazine hydrate and 6 g of Raney nickel was refluxed for two hours and filtered. The filtrate was evaporated to dryness under pressure at 50° C. and the residue was taken up in a 1-1 mixture of chloroform and methanol. The mixture was filtered and the crystalline product was dried to obtain 4 g of 5-amino-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at >260° C.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[OH-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>O.[Cl-].[Na+].O>[Na+:1].[Cl:13][C:4]1[CH:5]=[C:6]([S:9]([O-:12])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=1[O:2][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: O=S(=O)([O-])c1ccc(O)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
4-hydroxy-3-chlorobenzenesulfonic acid sodium salt (11.53 g, 50.0 mmol) and sodium hydroxide (2.00 g, 50.0 mmol) were dissolved in distilled water (50 mL) and the solution cooled to 0° C. Methane sulfonyl chloride (4.25 mL, 55.0 mmol) was added dropwise with stirring and the mixture then allowed to warm to room temp. and left for 2 h. Brine (20 mL) was added and the solution left to stand for 1 h with the formation of white crystalline solid. The solids were filtered, recrystallised (brine), and dried under vacuum to give the title compound as a white crystalline solid (9.40 g, 61%),
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Agent: Cl
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-chlorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 291, 293 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[CH2:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc2cn[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2cn[nH]c2c1
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
To a solution of 6-vinyl-1H-indazole (350 mg, 2.42 mmol) in MeOH (24 ml) was added 10% Pd on carbon (wet, 443 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) for 2.5 h then filtered over Celite, rinsing with EtOAc. The filtrate was concentrated to afford 305 mg (86%) of 6-ethyl-1H-indazole as a white semi-solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.32 (s, 1H), 7.06 (d, J=8.3 Hz, 1H), 2.80 (q, J=7.6 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:25])[CH3:24].[H-].[Na+]>O1CCOCC1>[CH2:23]([O:25][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)[CH3:24]
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccnc(Cl)n2)cc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 0 °C

Procedure:
25 mg (0.08 mmol) N-(1-(4-((2-chloropyrimidin-4-yl)ethynyl)phenyl)propan-2-yl)acetamide (170) in 1.0 mL dioxane are added to 9.3 μl (0.16 mmol) ethanol in 0.5 ml dioxane and cooled down to 0° C. 10 mg (0.24 mmol) NaH are added and the mixture is stirred at r.t. over night. The reaction is quenched with water and the solvent is evaporated in vacuo. The residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:8]([C:7]1[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1-n1cccn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and powdered potassium carbonate (2 g) in DMF (10 mL) was stirred vigorously at room temperature for 4 days. The mixture was diluted with water, causing precipitation of a solid, which was filtered and dried, affording 670 mg (63%) of 3-nitro-2-(pyrazol-1-yl)pyridine. 1 H NMR (CDCl3) δ6.51 (m, 1), 7.37 (dd, 1 J=5, 8), 7.76 (m, 1) 8.03 (dd, 1, J=2, 8), 8.40 (m, 1), 8.60 (dd, 1, J=2, 5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example J18) (180 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (206 mg).