Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=102.5-105° C.). The reaction was monitored by tlc (Rf=0.25 in 50% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([CH3:46])[C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:40]3[CH:39]=[C:38]([CH:42]([CH3:46])[C:43]([OH:45])=[O:44])[CH:37]=[CH:36][CH:41]=3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(C(=O)O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)C(=O)O)c3)cc12

Procedure:
To a mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (0.84 g, 1.7 mmol) and 2-(3-Bromo-phenyl)-propionic acid (0.39 g, 1.7 mmol) in a 20 mL microwave reaction flask was added THF (6 mL), acetonitrile (6 mL), and sodium carbonate (1 N in water, 6 mL, 6 mmol). The resulting suspension was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (62 mg, 76 mmol) was added and the purging was continued for another minute. The flask was sealed and was irradiated in a microwave reactor to 90° C. for 10 minutes. The reaction mixture was adjusted to pH 4 using 1 N hydrochloric acid, extracted with ethyl acetate (10 mL×3). The combine organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-propionic acid as a off white solid (497 mg, 58%). MS: m/z 504 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Cc1ccc(CO)nc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(CCl)nc1
Yield: 73 %

Procedure:
Thionyl chloride (30 ml) was added to (5-methylpyridin-2-yl)methanol (3.0 g, 24.3 mmol) at 20° C. under nitrogen. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC). The reaction mixture was concentrated under reduced pressure upon which it was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 6% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 2-(chloromethyl)-5-methylpyridine (2.5 g, 73%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 4.6 (s, 2H), 2.3 (s, 3H). MS: [M+H]+: m/z=142.2.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:16]=O.Cl>CN(C=O)C>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][C:11](=[CH2:16])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: C=O
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Agent: Cl
Solvent: CN(C)C=O
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Accordingly, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one was synthesized from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one using a formaldehyde reagent (paraformaldehyde), a mineral acid (HCl), and an ammonium salt (ammonium chloride) in an aprotic solvent (DMF). The ammonium salt appears to have had a positive impact on the rate of the reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH2:34][CH2:35][CH:36]=1)CCC>O1CCOCC1.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:32]2[O:33][CH2:34][CH2:35][CH:36]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1SCCc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1C1=CCCO1
Temperature: 100 °C
Yield: 8.5 %

Procedure:
To a stirred solution of 290 mg (0.72 mmol) trifluoromethanesulfonic acid 2-amino-5-cyano-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-4-yl ester in 10 ml dioxane and 2 ml DMF under argon at room temperature were added 283 mg (0.79 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 50 mg (0.07 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 1 h, then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate then 5/95 methanol/ethyl acetate) followed by trituration in ether afforded 20 mg (9%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a light brown crystalline solid. ES-MS m/e (%): 348 (M+Na+, 30), 326 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][NH2:23])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: NN
Reactant: Clc1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Solvent: O
Solvent: CCO
Product: NNc1nc(Cl)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
2,4-Dichloro-5,6-diphenylpyrimidine (2.0 g, 6.6 mmol) (synthesized according to the procedure described in example 7) was treated with hydrazine hydrate (0.73 g, 14.6 mmol) in ethanol (10 ml) under stirring for 5 hours at room temperature. The reaction mixture was poured onto ice-water mixture. The solid thus separated was extracted with diethylether. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.64 g, 32.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=1.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:20]([O:19][C:18](=[O:24])[NH:17][C:13]1[CH:12]=[C:11]([CH2:10][S:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[NH:1][S:34]([C:26]2[O:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)(=[O:35])=[O:36])[CH:16]=[CH:15][N:14]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1cc(CSc2ccc(Cl)cc2N)ccn1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)ccn1
Yield: 55.6 %

Procedure:
Following General Procedure B, the title compound (555 mg, 56%) was prepared from tert-butyl (4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate (667 mg, 1.827 mmol) and benzofuran-2-sulfonyl chloride (396 mg, 1.827 mmol) in pyridine (10 ml).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([Sn:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)C>[CH2:2]([Sn:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCBr
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
In a three-necked flask, a solution of 1-bromobutane (34.25 g, 250 mmol) in diethyl oxide was added on magnesium (7.3 g, 300 mmol) covered with dry diethyl oxide. When the addition was completed, the mixture was refluxed during one hour. This solution was then added to triphenyltin chloride (42.6 g, 110 mmol) in 150 mL of diethyl oxide and refluxed for 3 hours. The mixture was hydrolysed with a minimum of water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated. Crystallization of the crude product in methanol gave a white solid (32.3 g, 93 mmol).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[N:11]2)=[O:6].Cl>C(O)C>[F:24][C:20]1[CH:19]=[C:18]([C:8]2[C:7]([C:5]([OH:6])=[O:4])=[C:15]3[N:10]([N:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14]3)[N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1c(-c2cccc(F)c2)nn2nc(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(C(=O)O)c(-c3cccc(F)c3)nn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
2N sodium hydroxide (50 ml) was added to a solution of 2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylic acid methyl ester (2.3 g) in absolute ethanol (50 ml) and the resulting mixture heated to reflux for three hours. The cooled reaction mixture was poured slowly into a stirred solution of 2N hydrochloric acid (300 ml). The resulting suspension was stirred at ambient temperature for 1 hour then filtered and the filter cake washed with water and dried in vacuo at 60° to give the title compound as an off-white solid (2.0 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N+:6]([O-:29])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ncc(Cl)cc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Cl)c[n+]3[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine (8.5 g, 27.7 mmol) in CH2Cl2 (150 mL) in an ice bath was added m-chloroperbenzoic acid (85%, 8.4 g, 41.6 mmol). The mixture was stirred at RT for two h. The reaction mixture was quenched by saturated sodium thiosulphate solution. The organic layer was washed with saturated NaHCO3 solution and water, dried (Na2SO4) filtered, and concentrated under reduced pressure to afford 8.75 g (90%) of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-4-oxide as a yellow solid. MS (ESI): m/z=323.0 [M+1]+.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:27][CH:26]([OH:28])[CH2:25]2)[CH:19]=1)N.C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:28][CH:26]1[CH2:27][N:24]([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:16]3[C:4](=[O:15])[C:5]([N:10]4[CH:14]=[CH:13][N:12]=[N:11]4)=[CH:6][NH:7]3)[CH:19]=2)[CH2:25]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1cc(N2CC(O)C2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CC(O)C2)ncn1
Temperature: 25 °C

Procedure:
348 mg (1.7 mmol) of the compound from Example 3A and 300 mg (1.7 mmol) of the compound from Example 11A are initially introduced into a mixture of 6 ml THF and 6 ml ethanol. 63 mg (0.3 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is reacted in a single mode microwave (CEM Explorer) at 130° C. for 1.5 h. The mixture is allowed to cool to RT, a further 50 mg of the compound from Example 3A and a spatula-tip of p-toluenesulfonic acid monohydrate are added and the mixture is heated at 150° C. for 1 h. It is allowed to cool to room temperature and is decanted off from the solid and the solid is washed several times with THF (solid batch 1). The supernatant decanted off and the wash solution are combined, the mixture is concentrated and 5 ml ethanol and 5 ml THF and a spatula-tip of p-toluenesulfonic acid monohydrate are added to the residue obtained. The mixture is reacted again in a single mode microwave (CEM Explorer) at 150° C. for 2 h. It is allowed to cool to RT and the solid formed is filtered off (solid batch 2). The filtrate is concentrated, 3 ml DMSO are added to the residue and purification is carried out by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated. The residue is dissolved in ethanol, a little THF is added and the mixture is concentrated, with formation of a precipitate. The solid is filtered off and washed with THF (solid batch 3). The three solid batches obtained are combined and the mixture is dried under a high vacuum.
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=O.[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([C:33]#[N:34])[NH:29][C:28]=1[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[C:46]([C:54]([O:56]C)=[O:55])[CH:45]=2)[CH2:40][CH2:39]1)=[O:36]>>[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([C:33]#[N:34])[NH:29][C:28]=1[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[C:46]([C:54]([OH:56])=[O:55])[CH:45]=2)[CH2:40][CH2:39]1)=[O:36]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C#N)c(Cl)c3Cl)CC2)c2ccccc2n1
Agent: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Product: N#Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc4ccccc34)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared by an analogous procedure to Intermediate 3 starting with methyl 4-(4-{[(3,4-dichloro-5-cyano-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)quinoline-2-carboxylate (Example 273) and following the work-up procedure of Example 272.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH:45]1[C:50]#[N:51]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:47]2[CH2:48][CH2:49][NH:44][CH:45]([C:50]#[N:51])[CH2:46]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: N#CC1CNCCN1
Reactant: COc1cc(Cl)c(Cl)cc1NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a mixture of 2-(4,5-dichloro-2-methoxyphenylamino)acetic acid (260 mg, 1.04 mmol), EDCI (273 mg, 1.43 mmol), HOBt (194 mg, 1.43 mmol) and Et3N (288 mg 2.85 mmol) in DCM (10 mL) at 0° C., piperazine-2-carbonitrile was added. The resulting mixture was stirred at RT for 8 h. The mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (108 mg, 30% yield).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[C:9]3[C:14]([NH:15][C:16](=[O:17])[C:7]2=[CH:6][N:5]=1)=[CH:13][C:12]([C:18]([OH:20])=O)=[CH:11][CH:10]=3)([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][CH3:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:1]([C:4]1[N:8]2[C:9]3[C:14]([NH:15][C:16](=[O:17])[C:7]2=[CH:6][N:5]=1)=[CH:13][C:12]([C:18]([N:23]([CH3:24])[CH3:22])=[O:20])=[CH:11][CH:10]=3)([CH3:2])[CH3:3]
Reactant: CC(C)c1ncc2c(=O)[nH]c3cc(C(=O)O)ccc3n12
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ncc2c(=O)[nH]c3cc(C(=O)N(C)C)ccc3n12
Reaction time: 18.5 h

Procedure:
A mixture of 1-isopropyl-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-7-carboxyic acid as synthesized in above Example 8, 271 mg, dimethylamine hydrochloride 90 mg, 1-hydroxybenzotriazole 230 mg, 4-dimethylaminopyridine 24 mg, pyridine 6.8 mL and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 288 mg was stirred for 18.5 hours in nitrogen atmosphere. After distilling the solvent off, 25 mL of water was added to the residue and heated under reflux. Cooling the reaction liquid off, the precipitated crystals were recovered by filtration and washed successively with water, hexane and then with diethyl ether. Drying the crystals by heating under reduced pressure, 235 mg of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[Cl:14])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:4][C:5]1[C:6]([Cl:14])=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(N)c1Cl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 278A (2 g, 10.35 mmol) in ethyl acetate (60 ml) added tin(II) chloride dihydrate (8.18 g, 36.2 mmol), and the mixture was heated at 65° C. overnight. The reaction mixture was cooled to room temperature, diluted with 100 mL ethyl acetate, and 1M aqueous Na2CO3 was added until precipitation stopped. The solid was filtered through a pad of diatomaceous earth. The filter pad was suspended in ethyl acetate, stirred for a few minutes, and rinsed with ethyl acetate. The filtrate was washed with saturated aqueous Na2CO3, water, and brine, dried over MgSO4, filtered, and concentrated. Chromatography was performed with an Analogix 280 with an SF 40-80 column, 0% to 5% methanol/dichloromethane gradient over 30 minutes to provide the title compound. MS (DCI+) m/z 164.1 (M+H)+.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([N:5]1[CH:9]=[C:8]([CH3:10])[CH:7]=[N:6]1)[CH3:4].[OH-].[Na+]>ClCCCl>[Cl:1][C:9]1[N:5]([CH2:3][CH3:4])[N:6]=[CH:7][C:8]=1[CH3:10]
Reactant: ClCl
Reactant: CCn1cc(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCn1ncc(C)c1Cl
Yield: 56.2 %

Procedure:
167.7 g (2.36 mol) of chlorine were passed into a solution of 165 g (1.5 mol) of 1-ethyl-4-methylpyrazole and 625 g of 1,2-dichloroethane over the course of 2 h. The temperature rose to 60° C. and could be kept at 60° C. by cooling with ice. While cooling, the resulting reaction solution was neutralized at 25° C. with 533.9 g (2.0 mol) of 15% strength aqueous sodium hydroxide solution. After phase separation, the organic phase was distilled to afford 122.1 g (0.843 mol) of 5-chloro-1-ethyl-4-methylpyrazole of boiling point (200) 118° C. and a purity of 99.8% (GC) and 109.1 g (0.61 mol) of 3,5-dichloro-1-ethyl-4-methylpyrazole of boiling point (200) 154° C. and a purity of 99.6%. This corresponds to a yield of 96.6% of theory based on 1-ethyl-4-methylpyrazole.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.[N:42]([Sn](CCCC)(CCCC)CCCC)=[N+:43]=[N-:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[N:42]=[N:43][NH:44][N:17]=2)[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC#N)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1nn[nH]n1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 100 °C

Procedure:
To a solution of (S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetonitrile (0.1 mmol) in toluene (6 mL), add azidotributyltin (0.1 mmol) and heat at 100° C. After heating for 14 h, cool to room temperature and dilute with ethyl acetate (20 mL). Wash the reaction with concentrated sodium fluoride (2×20 mL), dry the organic phase over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0.5-5%), to afford the title compound as a colorless foam. MS (ES+): 633 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:17]I>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][N:13]([CH3:17])[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNC2
Solvent: CC(C)=O
Product: CN1CCn2c(nc3cc(Br)ccc3c2=O)C1
Yield: 62.2 %

Procedure:
A solution of 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (200 mg, 0.71 mmol, 1 equiv) and MeI (101 mg, 0.71 mmol, 1 equiv) in acetone (35 mL) was stirred at room temperature for 2 h. Then the reaction mixture was then concentrated and purified by column chromatography to give 130 mg of the desired product. MS (ESI): 294/296 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C.O>O1CCCC1>[C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]2[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)(=[O:34])[CH3:33]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(N)cc23)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of tert-butyl [6-amino-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.21 g, 0.5 mmol) in tetrahydrofuran (10 ml) were added acetyl chloride (0.04 ml, 0.6 mmol) and triethylamine (0.08 ml, 0.6 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-(acetylamino)-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.19 g, yield 83%) as white crystals.