Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[N:3][CH:4]=2)[O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120 mg) in dry DCM (3 ml) and triethylamine (1.5 equiv., 114 uL) was added acetic anhydride (1.1 equiv., 57 ul) and the reaction mixture was stirred at room temperature overnight. Dichloromethane/brine extraction and purification on silica gave 66 mg of N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:29]([CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C)c(OC)c3)CC2)ccc1Cl
Yield: 69 %

Procedure:
The title compound (29 mg, 69%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methoxy-4-methylbenzoic acid. MS: 417.4 (MH+).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][NH:3]1.O=P(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:18][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccccc2)c[nH]c1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(-c2ccccc2)cnc1Cl
Temperature: 25 °C

Procedure:
2-Oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2.50 g, 12.7 mmol) was added to a suspension of POCl3 (1.5 ml) and PCl5 (7.35 g) at room temperature. The suspension was then stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and added cautiously to iced water. The solution was then adjusted to pH 11 with sodium carbonate and the resulting white solid was filtered, washed with water, then dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].[OH-].[NH4+]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(O)cc1Cl

Procedure:
A solution of 1.6 g (8 mmol) of (2-chloro-4-methoxyphenyl)acetic acid, prepared according to Preparation 3, in 13 ml of hydrobromic acid (in 48% aqueous solution) is refluxed for two hours. After cooling, ammonium hydroxide is added until the pH is basic, and the mixture is extracted with methylene chloride. The water is evaporated from the aqueous phase and the residue is washed several times with ethanol to give the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:13]([CH2:19][C:20]#[N:21])(=O)[C:14]([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:13]1[CH:19]=[C:20]([NH2:21])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)[N:2]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
Methyl 4-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(NC(C)C)(C)C.C([Li])CCC.[C:23](=[O:25])=[O:24]>>[Cl:1][C:2]1[C:7]([C:23]([OH:25])=[O:24])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CSc1nc(Cl)c(C(=O)O)c(Cl)n1

Procedure:
Methyl iodide can be added to a solution of 2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione and aqueous sodium hydroxide to provide 2-(methylthio)pyrimidine-4,6-diol. The reaction is typically performed in a solvent such as but not limited to ethanol, and may require the use of heat. Addition of phosphorus oxychloride to 2-(methylthio)pyrimidine-4,6-diol will provide 4,6-dichloro-2-(methylthio)pyrimidine. The reaction is typically done at elevated temperature without an additional solvent. 4,6-Dichloro-2-(methylthio)pyrimidine can be added to a mixture of diisopropylamine and n-butyl lithium, followed by the addition of dry carbon dioxide gas to provide 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid. The reaction is typically performed at reduced temperature in a solvent such as but not limited to tetrahydrofuran. A mixture of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid and thionyl chloride can be refluxed together and concentrated, followed by the addition of aqueous ammonia at reduced temperature in a solvent such as but not limited to tetrahydrofuran to provide 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxamide. A compound of formula (1A) wherein B, R2, R3, and m are as described herein, can be reacted with 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxamide in the presence of a base such as but not limited to N,N-diisopropylethylamine to provide compounds of formula (4). The reaction typically requires the use of heat and a solvent such as but not limited to 1,4-dioxane. Compounds of formula (5) can be prepared by reacting compounds of formula (4) with hydrazine hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to 1,4-dioxane. Methyl orthoformate can be reacted with compounds of formula (5) to provide compounds of formula (6). The reaction may require the use of heat. Compounds of formula (7), which are representative of the compounds of Formula (I), can be prepared by reacting compounds of formula (6) with an organozinc compound of formula (2A), wherein Z, A, R1, and n are as described herein and XA is a halide. The reaction typically involves the use of heat and a nickel or palladium catalyst such as but not limited to bis(triphenylphosphine)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) in a solvent such as but not limited to N-methylpyrrolidone, tetrahydrofuran, or mixtures thereof.
Reaction SMILES: [Br:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH:3]1Br.N12CCCC1=NCCC2.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH:3]=1
Reactant: NC(=O)N1c2ccccc2C(Br)C(Br)c2ccccc21
Agent: C1CN=C2CCCN2C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1c2ccccc2C=C(Br)c2ccccc21
Reaction time: 2 h

Procedure:
With cooling at 5°-10° C, 12 g (app. 0.03 mole) of the crude 10,11-dibromo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide obtained according to (a) are suspended in 35 ml of dimethyl formamide. With stirring, 10 g (app. 0.08 mole) of 1,5-diazabicyclo[4.3.0]non-5-ene are added dropwise at 5°-10° C. Stirring is continued for 2 hours at 25° C and a new precipitate forms. The reaction mixture is then heated for 10 minutes to 90°-100° C and, after it has cooled, poured onto a mixture of water and ice and the organic phase is dissolved in ethyl acetate. The aqueous phase is then separated and the organic phase is washed with water, dried over calcium chloride and evaporated in a water jet vacuum. The residue is crystallised from 30 ml of acetonitrile to yield light green 10-bromo-5-H-dibenz[b,f]azepine-5-carboxamide of m.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[NH:28][CH:29]=[N:30][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:33].[BH4-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[NH:28][CH:29]=[N:30][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH2:21]2)=[O:15])(=[O:10])=[O:11])=[CH:4][C:3]=1[Cl:33]
Reactant: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(=O)CC2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(O)CC2)cc1Cl
Reaction time: 12 h

Procedure:
410 mg (0.8 mMol) of 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(piperidin-4-on-1-yl]-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide are dissolved in 8 ml of absolute dimethylformamide, mixed with 100 mg (2.6 mMol) of sodium borohydride and left to stand for 12 hours at ambient temperature. Then the reaction mixture is poured into water and extracted 3 times with ethyl acetate. The organic phase is washed twice with water, dried with sodium sulphate and evaporated down. The residue is purified over a silica gel column, the evaporated eluate is triturated with ether and suction filtered.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)(=O)C.[OH-].[Na+].Cl>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1ccc(OC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(O)cc1[N+](=O)[O-]

Procedure:
A mixture of 61 g. (0.29 m.) of 4-methoxy-3-nitrophenyl acetate (part B) and 34.68 g. (0.87 g. (0.87 m.) of NaOH in 500 ml. of H2O was stirred and heated on a steam bath for 2 hours. The reaction solution was acidified with 87 ml. of conc. HCl, keeping the temperature below 20°C. The acid solution was extracted three times using a total of 1500 ml. of benzene. The combined benzene extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 33 g. m.p. 78°-80°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C>CN(C)C=O.C1COCC1.C(Cl)Cl>[CH:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9]1
Reactant: O=C(O)c1ccc(OCCC2CC2)cc1
Reactant: NCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 96.2 %

Procedure:
Oxalyl chloride (8.64 mL, 99.0 mmol) and one drop of N,N-dimethylformamide (DMF) were added to a methylene chloride (30 mL) solution of 4-(2-cyclopropylethoxy)benzoic acid (9.28 g, 45.0 mmol) prepared in Example 1 (1a), under ice-cooling. The mixture was stirred at room temperature for 1.75 hours, and then the solvent was evaporated. Then, the obtained residue was suspended in THF (3 mL). This suspension was dropwise added to a 50% THF aqueous solution (120 mL) of glycine (4.41 g, 58.7 mmol) and triethylamine (15.7 mL, 112 mmol) under ice-cooling. The resulting mixture was stirred at room temperature for 1.5 hours, and the solvents (mainly THF) were evaporated. Then, 10% hydrochloric acid (40 mL) was added to the residue under ice-cooling. The resulting precipitate was collected by filtration, washed with water, and dried by heating under reduced pressure to give 11.4 g of the title compound (powder, yield: 97%).
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:19]=2[C:20](O)=[O:21])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[C:19]=2[C:20]([NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:21])[CH2:17][CH2:16]1
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Product: O=C(N[C@@H]1CCCC[C@@H]1N1CCCC1)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=449.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-cyclopropyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate AN).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](Cl)=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)(O)[O-].[Na+].C([O-])(=O)C.CCCCCC>O1CCCC1.C(OCC)C.C(OCC)C.CCCCCC.C(OCC)(=O)C.CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:28](=[O:29])[CH2:27][C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (S)-4-benzyl-2-oxazolidinone (2.6 g, 34 mmol) and tetrahydrofuran (80 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of n-butyl lithium (13.5 mL, 2.5 M, 27 mmol). After 15 minutes, slowly add a solution of 3,4-dichlorophenylacetyl chloride (9.4 g, 44 mmol) in tetrahydrofuran (20 mL). After 20 minutes, warm to ambient temperature. After 2 hours, dilute the reaction mixture with diethyl ether and add a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with a saturated ammonium chloride solution and then water. Dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 5% ethyl acetate/hexane, 10% ethyl acetate/hexane, and 15% ethyl acetate/hexane. Combine the product containing fraction to give a residue. Rechromatograph the residue on silica gel eluting sequentially with 5% ethyl is acetate/hexane, 10% ethyl acetate/hexane, 15% ethyl acetate/hexane, and 20% ethyl acetate/hexane to give a residue. Recrytallize from diethyl ether/hexane to give (S)-4-benzyl-3-(3,4-dichlorophenyl)acetyl-2-oxazolidinone: mp; 70.5-71.5° C. Rf=0.75 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([NH:47]C(OC(C)(C)C)=O)[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C@H:41]([CH2:43][CH3:44])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[ClH:55]>C(#N)C>[ClH:55].[CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]([NH2:47])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C@H:41]([CH2:43][CH3:44])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:19][CH:20]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1

Procedure:
Under a nitrogen atmosphere, 317 mg (0.43 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane in 15 ml of acetonitrile and 15 ml of 2N HCl are stirred at 50° C. for 20 hours and worked up analogously to Example 25h to form the title compound: HPLC20-100 : tRet =14.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(OCC)(=O)CC(O)=O.[CH2:23]([NH2:25])[CH3:24].BrC1C=CC([C@H](N)C)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:25][CH2:23][CH3:24])=[O:11])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Agent: CCOC(=O)CC(=O)O
Agent: C[C@@H](N)c1ccc(Br)cc1
Product: CCNC(=O)C(C)(C)c1ccc(Br)cc1
Yield: 82 %

Procedure:
The title compound was prepared as described in Step 1 of Example A(39), where 2-(4-bromophenyl)-2-methyl propionic acid was substituted for ethyl hydrogen malonate and ethyl amine was substituted for (R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 82%. 1H NMR (CDCl3) δ: 1.01 (t, J=5.3 Hz, 3H), 1.55 (s, 6H),), 3.2 (q, J=7.0, 5.3, 2H), 5.15 (brs, 1H), 7.22-7.26 (m, 2H), 7.46-7.50 (m, 2H).
Reaction SMILES: CC(O[C:6](=O)[N:7]([CH2:9][CH2:10][C@@H:11]([O:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=1[C:27]#[N:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(C)C.Cl.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>O1CCOCC1.C(O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[Cl:25][C:23]1[C:22]([F:26])=[CH:21][C:20]([C:27]#[N:28])=[C:19]([O:18][C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH:7][CH3:6])[CH:24]=1
Reactant: CN(CC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CNCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccccc1

Procedure:
[(3R)-3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-phenylpropyl]methyl carbamic acid 1,1-dimethylethyl ester (220 mg, 0.525 mmol) was stirred in a 4N solution of hydrogen chloride in dioxan (20 ml) for 20 minutes. The hydrochloride salt was,applied to a silica gel column and eluted with 10% 7N ammonia in methanol/dichloromethane. The free base was then converted into an oxalate salt with 1 equivalent of oxalic acid in ethanol. The title compound was obtained as a colourless solid (175 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (4.55 g, 29 mmol) in DMF (30 mL) was added K2CO3 (4.8 g, 34.9 mmol) followed by Mel (2.7 mL, 43.6 mmol), and the mixture was stirred at room temperature for 16 hours. Following concentration in vacuo, the residual was taken up in ethyl acetate, washed with H2O, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with ethyl acetate/hexanes 1/5 afforded 2-chloro-3-methoxybenzaldehyde 3a (4.68 g, 94%) as a colorless oil, which solidified upon standing. GCMS (EI) m/z 170, 172 (M+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:30]>C(Cl)Cl>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:30].[ClH:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](N)C1CCCCC1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Suspend Boc-(L)-Chg-(L)-Pal-NH2 (1.27 g, 3.12 mmol) in methylene chloride (50 mL), and add chlorhydric acid (10 mL, 4M in dioxane). After 30 minutes, evaporate dioxane and methylene chloride, dissolve the solid in methanol and precipitate the product by addition of ether (200 mL) and filter to give H-(L)-Chg-(L)-Pal-NH2.2HCl (1.12 g, 95%).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)O)ccc32)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4)ccc32)c1

Procedure:
The carboxylic acid (Example 28 ) (0.25 g) was stirred at room temperature in dichloromethane (3 ml) with benzene sulphonamide (0.10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g) and 4-dimethylaminopyridine (0.02 g) for 144 hours. The reaction mixture was diluted with chloroform and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by preparative reverse-phase HPLC (1 inch LP1-ODS column), eluting with 75:25:0.1 methanol:water:acetic acid, gave N-{1-[3-(isobutoxycarbonylamino)benzyl]indol-5-ylcarbonyl}benzene sulphonamide.
Reaction SMILES: C[Li].[CH3:3][C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1.[CH3:9][C:10]([CH3:12])=O>>[CH3:3][C:4]1[CH:8]=[CH:7][C:6](=[C:10]([CH3:12])[CH3:9])[CH:5]=1
Reactant: CC(C)=O
Reactant: CC1=CC=CC1
Agent: [Li]C
Product: CC1=CC(=C(C)C)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
150 ml of methylcyclopentadiene dimer was fractionally distilled from 100 ml of mineral oil and at 62° C. and collected at 0° C. 500 mmol of methyl lithium (1.4M; diethylether) were added, dropwise, to a mixture of 500 mmol of freshly distilled methylcyclopentadiene and 137 ml of dry acetone at 0° C. The solution was stirred for 1 hour at 25° C. 8 g (85% yield) of 3,6,6-trimethylfulvene were recovered from the organic layer by vacuum distillation after an extraction with 100 ml of saturated, aqueous NH4Cl and drying over MgSO4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.CC(N(C)C)=O.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:15]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[CH:3][CH:4]=3)[NH:24][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
300 mg (0.89 mmol) of 6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (see Stage 19.5), dissolved in 20 ml of abs. THF and 2 ml (3.56 mmol) of DMA are treated with 0.29 ml of ethyl isocyanate (FLUKA) with exclusion of moisture and heated under reflux until starting material is no longer present in the TLC (24 h). The reaction mixture is evaporated to dryness in vacuo and the crude product is chromatographed on silica gel, ethyl acetate/methanol being used as the eluent. Fractions which contain the desired product are combined and evaporated to dryness. The residue is dissolved in a little THF. The target compound is precipitated/crystallized by addition of n-hexane. Colorless crystals of 4-(3-chloroanilino)-6-(4-[N3-ethylureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine are obtained; m.p.>290° C., FAB-MS: (M+H)+=407.