Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:12](=[O:14])[O:11][C:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:4]1[C:13]2[C:12](=[O:14])[O:11][C:10]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1oc(-c2c(F)cccc2F)nc2cccc([N+](=O)[O-])c12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1cccc2nc(-c3c(F)cccc3F)oc(=O)c12

Procedure:
5-Nitro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.4 g) was dissolved in acetic acid (30 mL) under N2, PtO2 (20 mg) was added and the mixture was hydrogenated with H2 gas. Reaction time 1 day. The reaction mixture was filtered through Hyflo®, which was rinsed afterwards with ethyl acetate. The combined organic phases were evaporated to dryness and subsequently treated three times with toluene followed by evaporation. The resulting mixture was dissolved in THF and precipitated with hexane giving a crude product which was purified on a silicagel column using dichloromethane as eluent. One fraction was collected (51 mg), identified as 5-amino-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one, LC-MS 275 M+1, ELS purity 100%, mp. 197 C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:21]3[N:25](COCC[Si](C)(C)C)[C:24]4[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=4[N:22]=3)[C:9](=[O:20])[N:10](COCC[Si](C)(C)C)[N:11]=2)=[CH:2]1>ClCCl.FC(F)(F)C(O)=O.C(S)(S)C>[NH:25]1[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=[C:21]1[C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccsc2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccsc2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30 mg of 6-thiophen-3-yl-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanyl -ethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one is dissolved in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml), 18 μl of ethanedithiol are added, and the resulting solution is stirred at room temperature for 18 hours. After the solvent has been distilled off, the crude product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=O.N1C=C[CH:12]=[CH:11][C:10]=1[CH:15]=[O:16]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[CH:12][CH:11]=[CH:10][CH:15]=[O:16]
Reactant: O=Cc1ccccn1
Reactant: O=Cc1cnccn1
Product: O=CC=CC=Cc1cnccn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 2-pyrazinecarboxaldehyde for the 2-pyridinecarboxaldehyde of Reference Example 5. MS 161 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:34]2[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:33]=2[F:32])[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cc(F)c(F)cc1F
Yield: 75.9 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2,4,5-trifluorophenylboronic acid (0.088 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.080 g (76%) of the title compound.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].C1COCC1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([O:27][C:28]3[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:24]2)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([O:27][C:28]3[C:29]4=[N:34][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:30]4[CH:31]=[CH:32][CH:33]=3)=[CH:24]2)=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ccc2ccc(Oc3cccnc3N)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ccc(OC3=CC=CN4CCS(=O)(=O)N=C34)cc2c1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a mixture of sodium hydride (60%, 375 mg), 2-chloroethanesulfonyl chloride (612 mg) and dehydrated THF (15 mL) was added a mixture of 3-[(7-methoxynaphthalen-2-yl)oxy]pyridin-2-amine (500 mg) and dehydrated THF (15 mL) at room temperature. The reaction mixture was stirred for 2 hr, water was added, and THF was evaporated under reduced pressure. The resulting precipitate was washed with water and diisopropyl ether to give the title compound (348 mg) as a pale-brown solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a pale-brown solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCO.O.[NH2:16][NH2:17]>>[C:5]1([CH2:4][C:3]([NH:16][NH2:17])=[O:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1ccccc1

Procedure:
Phenyl-acetic acid methyl ester (5 g, 33.3 mmol) was dissolved in hydrazine hydrate (25 mL) and EtOH (50 mL) and the reaction was heated in a sealed tube to 80° C. overnight. After cooling the reaction was concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=O)[CH3:19]>>[CH3:19][C:18]1[CH:1]=[C:2]2[N:7]([CH:17]=1)[CH:6]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:4]=[CH:3]2
Reactant: CC(=O)CCl
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cn1
Product: Cc1cc2ccc(NC(=O)OC(C)(C)C)cn2c1
Yield: 31 %

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation III using the Tschitschibabin reaction, starting with 5.79 g of tert-butyl (6-methylpyridin-3-yl)carbamate [described in J. Med. Chem.; (2000), 43, 5017-5029] and chloroacetone. 1.96 g of a pasty residue are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:12]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=2[F:35])=[C:13]([F:26])[C:14]2[N:15]([C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:18][N:19]=2)[CH:16]=1)=[O:10]>CO.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:12]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=2[F:35])=[C:13]([F:26])[C:14]2[N:15]([C:17]([C:20]#[CH:21])=[CH:18][N:19]=2)[CH:16]=1)=[O:10]
Reactant: COC(=O)c1cn2c(C#C[Si](C)(C)C)cnc2c(F)c1Nc1ccc(C)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2c(F)c(Nc3ccc(C)cc3F)c(C(=O)OC)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Potassium carbonate (70 mg, 0.51 mmol) was added to a solution of 8-fluoro-7-(2-fluoro-4-methyl-phenylamino)-3-trimethylsilanylethynylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester in MeOH (5 mL) and stirred at room temperature for two hours. The mixture was diluted with ethyl acetate, washed with brine (2×), dried over Na2SO4 and concentrated to a brown residue. Flash column chromatography (dichloromethane to 80:1 dichloromethane/MeOH) provided the desired product (16 mg, 65%) as a yellow liquid. MS APCI (+) m/z 342 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].B(O)O>O1CCCC1.O.C(OCC)(=O)C.C1(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)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 13.7 %

Procedure:
A mixture of 5.00 g 2,4-dichloro-5-fluoropyrimidine, 4.683 g p-chlorophenylboronic acid, 1.730 g tetrakistriphenylphosphino palladium and 8.278 g potassium carbonate in 125 ml tetrahydrofurane and 125 ml water was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The phases were separated and the organic phase was washed with brine dried over sodium sulfate and evaporated. The solid residue was triturated in ca 60 ml methanol for 30 min. The solids were collected by filtration to yield 5.2 g of an off white solid (contains some boronic acid which gives a start spot). The mother liquor was evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=8:2 to 1:1 to yield 1.0 g of the product as white solid. Both crops were combined and dissolved in ca 50 ml dichloromethane and filtered over ca 50 g silica gel with dichloromethane to remove a polar start spot. The filtrate was concentrated under aspirator vacuum whereby precipitation occurred. The solid was collected by filtration to yield 5.76 g of the title compound as white crystals. MS (EI): 230.1 and 228.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:41])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].CO.Cl>O.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:41])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (1.1 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water (20 mL) and 1 N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.9 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 74.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:36][N:37]([CH3:42])[S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:36][N:37]([CH3:42])[S:38]([N:12]1[CH2:11][C:10]2[N:6]([C:7]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[N:8][N:9]=2)[C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:13]1)(=[O:40])=[O:39]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.251 mmol) in dichloromethane (0.6 ml) was added dimethyl sulfamoyl chloride (0.27 ml, 0.251 mmol) at room temperature. Stirring for 20 h was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (39 mg, 61%) as white solid. MS m/e: 505 ([M+H]+)
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH2:13])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:12]2)=[N:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1(c2ccc(Br)cn2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1(c2ccc(Br)cn2)CC1
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Commercially available 1-(5-bromopyridin-2-yl)cyclopropanamine dihydrochloric acid salt (494 mg, 1.73 mmol) is dissolved in CH2Cl2 (11.5 mL, 0.15M) and had 3.1 eq. of triethylamine (543 mg, 5.36 mmol) added to it. 1.1 eq. of methanesulfonyl chloride (218 mg, 1.9 mmol) is then added and the mixture stirred for 16 hours. Dichloromethane (20 mL) is added and washed with NaHCO3 (sat, aq). The solvent is evaporated to give the title compound (310 mg): m/z (Cl) 293 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:23]([O:22][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:27])=[O:3])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C=Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C=CC(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid ethyl ester (2.7 g, 7.2 mmol) obtained in Example 8(1) was dissolved in ethanol (40 ml), and a 4M sodium hydroxide aqueous solution (3.6 ml) was added thereto. The mixture was refluxed under heat for 12 hours. The reaction mixture was cooled to room temperature, and water (40 ml) was added thereto. The mixture was neutralized with 10% citric acid aqueous solution, and the precipitate was collected by filtration, thereby obtaining 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid (1.9 g, 77%) as a white solid.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:29])[NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(#N)C>[CH:1]1([NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[O:13])=[CH:27][CH:28]=2)=[O:29])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NC3CCC3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)NC1CCC1

Procedure:
tert-Butyl 4-(4-(3-cyclobutylureido)benzoyl)piperazine-1-carboxylate (48.7 mmol, 19.6 g) was dissolved in a mixture of dichloromethane (125 ml) and acetonitrile (10 mL). After complete dissolution, trifluoroacetic acid (269 mmol, 20 mL, 30.7 g) was added over 10 minutes. The reaction was stirred until no trace of starting material remained. The reaction was neutralised with sodium hydrogen carbonate, filtered and concentrated under vacuum to generate a white solid. The desired product was isolated by continuous extraction of this material using soxhlet apparatus with dichloromethane as elutant. The organic phase was concentrated under vacuum to yield the title compound as a white powder (14.34 g). MS (ESI) m/z 303.5[M+H]+
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>C(O)C>[OH:27][CH2:26][CH:25]([NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7])[CH2:28][OH:29]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Reactant: NC(CO)CO
Solvent: CCO
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NC(CO)CO)c(O)c2c1
Yield: 114.3 %

Procedure:
0.035 gm of 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 0.088 g of 2-amino-propane-1,3-diol were dissolved in 1 ml of ethanol and the mixture was refluxed for 24 h. The reaction mixture was concentrated and the residue was dissolved in 10 ml of ethyl acetate. The ethyl acetate solution was extracted with 5 ml of aqueous 1M HCl and water, dried (sodium sulfate) and concentrated to give 0.042 g of a white solid: MS-(+)-ion: 355.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[CH:16]([O-])([O-])OCC>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH:16]=[N:15][N:14]=2)[N:13]=1
Reactant: NNc1ncc(-c2ccccc2Cl)nn1
Reactant: CCOC([O-])[O-]
Product: Clc1ccccc1-c1cnc2nncn2n1

Procedure:
A mixture of 4.45 g. of 6-(o-chlorophenyl)-3-hydrazino--1,2,4-triazine and 50 ml. of ethyl orthoformate is refluxed for 4 hours and then cooled, giving the desired product as yellow crystals, m.p. 145°-148° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:16][C:17](=[O:31])[CH:18]([NH2:30])[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:32]([C@H:35]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36](O)=[O:37])(=[S:34])[CH3:33].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.CCCCCC.ClCCl>[CH2:22]([NH:21][C:19](=[O:20])[CH:18]([NH:30][C:36](=[O:37])[C@@H:35]([C:32](=[S:34])[CH3:33])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:17]([NH:16][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: CC(=S)[C@H](CCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(=S)[C@@H](CCc1ccccc1)C(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reaction time: 18 h
Yield: 92 %

Procedure:
Combine N,N′-diphenethyl-2-aminomalonamide trifluoroacetic acid salt (0.50 g, 1.0 mmol) and dichloromethane (15 mL). Add (R)-2-thioacetyl-4-phenylbutyric acid (0.545 g, 1.0 mmol), N-methylmorpholine (0.22 mL, 2.0 mmol), and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloric acid salt (0.23 g, 1.2 mmol), and 1-hydroxybenztriazole hydrate (0.16 g, 1.2 mmol). After 18 hours, evaporate the reaction mixture in vacuo, dilute the concentrated reaction mixture with ethyl acetate, extract with an aqueous 5% sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Extract each aqueous layer with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/2 ethyl acetate/hexane to give the title compound (92%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]=[C:17]3[C:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16]3)=[N:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.CO>O1CCOCC1>[N:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:18]=[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 2-(4-cyanophenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 10) (150 mg, 0.443 mmol) was dissolved in 1,4-dioxan (ml) and 4M hydrogen chloride in 1,4-dioxan (3 ml) added. The mixture was stirred at room temperature for 2 hours. Methanol was added and the mixture purified on 10 g SCX column, eluting initially with methanol, than with 2M ammonia in methanol. Evaporation of the basic fractions gave the title compound (D11). MS (ES+) m/e 239 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:12])=[CH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl.C(OCC)(=O)C.C(OCC)C.[I-].[Zn+2].[I-]>[Br:1][C:2]1[C:11]2[CH:10]([CH3:12])[C:9](=[O:32])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CC1=CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1C(=O)CCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of Example 132A (170 mg, 0.43 mmol) in CH2Cl2 (5 mL) at 0° C. was treated with mCPBA (136 mg, 0.47 mmol), warmed to room temperature, stirred for 2 hours, diluted with ethyl acetate, washed with NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in toluene (5 mL), treated with activated-zinc iodide (37 mg, 0.12 mmol), heated to reflux for 1 hour, diluted with diethyl ether, washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (140 mg, 79% yield). MS (ESI) m/e 410 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.73 (m, 2H), 7.4 (m, 2H), 7.24 (d, 1H), 7.0 (d, 1H), 3.6 (q, 1H), 3.15 (m, 1H), 2.93 (m, 1H), 2.59 (m, 1H), 2.41 (m, 1H), 1.2 (d, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([Br:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[Br:20][C:16]1[N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][C:7]3[C:21]([Cl:24])=[CH:22][CH:23]=[C:5]([N:4]([C:1](=[O:3])[CH3:2])[CH3:29])[C:6]=3[Cl:25])[C:11]2=[N:18][C:17]=1[CH3:19]
Reactant: CI
Reactant: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 58.9 %

Procedure:
To a solution of 8-(3-acetylamino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (222 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (24 mg, 60% oil dispersion) in one portion at ambient temperature. The mixture was stirred for half an hour at the same temperature and iodomethane (142 mg) was added thereto. After stirring for half an hour, the mixture was poured into water. The separated oil was extracted with ethyl acetate. The extracts were washed with water, dried, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 3-bromo-8-[2,6-dichloro-3-(N-acetyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (135 mg) as a solid.