Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][C:11]1[CH:12]=[C:13]([OH:19])[C:14](=[CH:16][C:17]=1[CH3:18])[OH:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][C:11]1[C:17]([CH3:18])=[CH:16][C:14]2[O:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O:19][C:13]=2[CH:12]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: Cc1cc(O)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2cc(C)c(C)cc2O1
Temperature: 30 °C

Procedure:
86 g of ethyl 2,3-dibromopropionate was added, over a 15-minute period, to a stirred mixture of 41 g of 6A, 97 g of potassium carbonate and 300 ml of acetone. The temperature of the mixture rose to 60° C. The mixture was refluxed for 19 hours, cooled to 30° C. and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was recrystallized from hexane to give 6, mp: 71°-72° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[N:18][CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CCO>[CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[N:18][CH:19]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a solution of mixture of ethyl (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (227 mg) in EtOH (2 mL) was added 1N sodium hydroxide solution (1.3 mL) at ambient temperature and the mixture was allowed to stand for 18 hrs. The reaction mixture was adjusted to pH 6.0 with 1 mol/L hydrochloric acid and evaporated in vacuo. The residue was dissolved in a mixture of chloroform and MeOH (5-1) and the precipitate was filtered off. The filtrate was concentrated in vacuo to give (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (209 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]CC)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH3:15]>>[NH2:1][C:2]1[C:3]([C:10]([NH2:15])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N
Reactant: CCOC(=O)c1nccc(C#N)c1N
Product: N#Cc1ccnc(C(N)=O)c1N
Temperature: 100 °C
Yield: 94 %

Procedure:
A mixture of liquid ammonia (30 ml) and ethyl 3-amino-4-cyanopyridine-2-carboxylate (Preparation 11; 2.8 g, 0.0147 mol) was heated at 100° C. in an autoclave for 18 hours. The ammonia was allowed to evaporate and the resulting product crystallized from ethyl acetate to give the title compound as an off-white solid (2.2 g, 94%), m.p. >310° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29]O.CS([Cl:35])(=O)=O.O>CN(C)C=O>[Cl:35][CH2:29][C:3]1[C:4]([CH3:28])=[CH:5][CH:6]=[C:7]([N:8]([C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)[CH3:27])[C:2]=1[CH3:1]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2,6-dimethyl-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl) cinnamoylglycyl]amino]benzene (2.00 g) in N,N-dimethylformamide (100 ml) was added methanesulfonyl chloride (784 mg) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature and overnight at ambient temperature. To the mixture was added water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was pulverized with diethyl ether to give 1-chloromethyl-2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzene (2.00 g) as white powder.
Reaction SMILES: [F:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[C:20]1(C)[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[F:1][CH:2]([C:7]([O:9][CH2:10][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C:3]([O:5][CH2:6][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: COC(=O)C(F)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C(F)C(=O)OCc1ccccc1
Yield: 81 %

Procedure:
A 3-neck, 5-L round-bottom flask equipped with a vacuum distillation head, a thermometer, and a magnetic stir bar was charged with dimethyl fluoromalonate (339 g assayed at 83% purity by VPC, 1.88 mol), benzyl alcohol (935 mL, 9.04 mol), toluene (846 mL), and p-toluenesulfonic acid monohydrate (21.5 g, 0.113 mol). The mixture was heated under vacuum (10-15 inches of Hg) until all of the toluene had distilled, then at 28-29 inches of Hg (water aspirator vacuum), the reaction temperature being maintained at 100° to 115° C. The progress of the reaction was monitored by 19F NMR. After a total of 7 hours, the heat was removed, and the mixture was allowed to cool, with continued stirring. When the temperature had lowered to 75° C., isopropanol (450 mL) was added. When the temperature had lowered to 55° C., hexane (1 L) was added. The product crystallized out and the mixture was placed in the freezer overnight. The product was filtered, washed with hexane (2×1 L), sucked dry, and dried overnight in vacuo. The yield was 452 g (96% pure by weight). A second crop of 29 g was obtained from the combined filtrates and washings, for a total yield of 81%.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][C:5]3[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=3)=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N#Cc1cccc(Oc2ccccc2Br)n1
Product: N#Cc1cccc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-(2-bromophenoxy)picolinonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 383.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=1.4, 2H), 7.99 (dd, J=8.5, 7.4, 1H), 7.71-7.67 (m, 1H), 7.56 (dd, J=7.6, 1.7, 1H), 7.55-7.46 (m, 2H), 7.42-7.37 (m, 1H), 7.35-7.25 (m, 4H), 6.85 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](Cl)(C)C.[C:19](#[N:22])[CH:20]=[CH2:21].Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH2:20][C:19]#[N:22])=[O:13]
Reactant: C=CC#N
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCCP(=O)(O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.44 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.68 ml), trimethyl silylchloride (0.61 ml) and acrylonitrile (0.17 ml) and the reaction mixture was stirred at room temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a highly crystalline solid 0.5 gm (90% yield), m.p. 80°-82° C.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C@@H:9]2[C:14]3[CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:24])([CH3:23])[C@H:10]2[OH:25])[CH2:7][CH2:6][S:5]1)#[N:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:25][C@H:10]1[C@H:9]([N:8]2[CH2:7][CH2:6][S:5][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH3:23])[CH3:24])(=[O:28])[CH3:27]
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](N2CCSC2=NC#N)c2cc(S(C)(=O)=O)ccc2OC1(C)C
Reaction time: 8 h

Procedure:
A mixture of trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (5.5 g) and acetic anhydride (25 ml) in pyridine (50 ml) was allowed to stand at room temperature overnight. The mixture was concentrated to give a residue of trans-3-acetoxy-4-[2-(cyanoimino)thiazolidin-3-yl]-3,4-dihydro-6-mesyl-2,2-dimethyl-2H-1-benzopyran, which was washed with diisopropyl ether and dried in vacuo. To a suspension of this residue in toluene (21 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (10.5 ml), and the mixture was stirred at 100° C. for 1 hour. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate as an eluent to afford 4-(2-cyanoiminothiazolidin-3-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran as a white solid. Recrystallization from 50% aqueous acetonitrile gave the pure product (1.44 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH3:21][C:22]1[N:23]([CH2:27][CH2:28]C)[CH:24]=[CH:25][N:26]=1.C1C=CC2N([OH:39])N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][C:22]1[N:23]([CH2:27][C:28]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:39])[CH:24]=[CH:25][N:26]=1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: On1nnc2ccccc21
Reactant: CCCn1ccnc1C
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nccn1CC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 61 mg 3-(2-methyl-1H-imidazol-1-yl)propan acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The reaction mixture is quenched with 3 ml water and 5 ml dichloromethane. The organic phase is separated, the water phase extracted with dichloromethane. The combined organic phases are dried and evaporated. 315 ml of yellow oil is obtained, which is further purified by preparative HPLC-methods.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][O:12][CH2:11][C@H:9]([NH2:8])[CH3:10])=[CH:19][CH:18]=1
Reactant: C[C@H](COCc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)COCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
Dissolve (R)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)-propane (2.18 g, 7.7 mmol) in DCM (50 mL), add trifluoroacetic acid (25 mL), and stir at 0° C. for 20 min. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (1.2 g, 85%). MS (ES+) m/z: 184 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:23])[C:15]2([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34](F)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:23])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:34]4[C:35]([O:37][CH3:38])=[C:36]5[C:31]([C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28][N:27]5[CH:24]5[CH2:26][CH2:25]5)=[CH:32][C:33]=4[F:40])[CH2:19]3)[CH2:16][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1(C2CCNC2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 75 °C
Yield: 55 %

Procedure:
A solution of 4-[methyl-(1-pyrrolidin-3-yl-cyclopropyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) in acetonitrile (30.0 mL) was added 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (98 mg, 0.33 mmol) and DBU (0.23 mL, 1.53 mmol). The suspension was heated to 75° C. overnight. The reaction mixture was partitioned between ethyl acetate and 5% citric acid. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% methanol in dichloromethane) to give the title compound as a yellow solid (102 mg, 62%). ESI MS m/z 599.3 (M+H+).
Reaction SMILES: [H][H].C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][C:41](=[NH:43])[NH2:42])=[CH:35][CH:34]=2)=[O:31])[CH2:26][CH2:25]1)=O)C1C=CC=CC=1>C(OCC)C>[NH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([CH:39]=[CH:40][C:41](=[NH:42])[NH2:43])=[CH:37][CH:38]=2)=[O:31])[CH2:26][CH2:25]1
Reactant: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CNC(=O)OCc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CN)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 9 ml of a 30% hydrogen bromideacetic acid mixture and 18 ml of glacial acetic acid, was added 2.7 g of 4-(β-amidinoethenyl)phenyl trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylate methanesulfonate. After stirring the mixture for one hour at room temperature, anhydrous ethyl ether was added to wash out a white solid substance. The solid substance was recrystallized from ethanol to obtain 1.1 g of a white powder of 4-(β-amidinoethenyl)phenyl trans-4-aminomethylcyclohexane carboxylate dihydrobromide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.BrC[C:23]([O:25][CH2:26][CH3:27])=[O:24].[ClH:28].C(O)C>CN(C)C=O>[ClH:28].[N:8]1([CH2:6][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (50 ml) was dissolved 1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition of triethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained. The resulting substance was dissolved in a saturated hydrochloric acid—ethanol solution (10 ml) and the resulting solution was concentrated under reduced pressure. The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2O)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: N#Cc1ccc2c(c1)C(O)CCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(C#N)cc21

Procedure:
To a suspension of 7-cyano-1,2,3,4-tetrahydro-naphthalen-1-ol (0.298 g, 1.72 mmol) and isopropyl 4-imidazolecarboxylate (0.185 g, 1.204 mmol), which can be prepared as described in Example 1, in THF (10 mL) at 0° C. is added triphenylphosphine (0.451 g, 1.72 mmol), followed by diisopropyl azodicarboxylate (94%, 0.369 g, 1.72 mmol). After 1 hour the mixture is diluted with ethyl acetate and washed with water. The organic phase is dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(7-cyano-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 310.1 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(7-cyano-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.36 (d, J=6.1 Hz, 3 H), 1.39 (d, J=6.3 Hz, 3 H), 1.90-1.98 (m, 2 H), 2.29-2.33 (m, 2 H), 2.97 (dt, J=17.7, 6.3 Hz, 1 H), 3.12 (dd, J=17.7, 6.8 Hz, 1 H), 5.21 (sept, J=6.3 Hz, 1 H), 6.35 (t, J=6.3 Hz, 1 H), 7.25 (s, 1 H), 7.45 (d, J=8.1 Hz, 1 H), 7.59 (s, 1 H), 7.62 (dd, J=8.1, 1.5 Hz, 1 H), 7.78 (d, J=1.5 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[C:19]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=[C:15]3N=N2)=[N:6][CH:7]=1.[OH-:29].[NH4+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[C:15]([OH:29])=[CH:20][C:19]([CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1cc(Br)cnc1CCCCn1nnc2cc(Cc3cccnc3)cnc21
Agent: [NH4+]
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1O
Reaction time: 0.67 h

Procedure:
A mixture of 3-[4-(5-bromo-3-methylpyrid-2-yl)butyl]-6-(pyrid-3-ylmethyl)-3H-1,2,3-triazolo[5,4-b]-pyridine (0.6 g) and polyphosphoric acid (ca. 6 g) was heated with stirring at 190°-200° C. for 40 minutes. The cooled residue was dissolved in aqueous ammonium hydroxide to give a solution of ca. pH 8 and extracted with chloroform (4×30 ml). The combined chloroform extracts were dried over magnesium sulphate, concentrated in vacuo and the residue was chromatographed on silica eluted with 7.5% v/v methanol in chloroform and then crystallised under ether to give the title compound (0.12 g), m.p. 164°-166° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([OH:25])=O)[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:32]([O:34][C:35](=[O:45])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:33].C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH2:32]([O:34][C:35](=[O:45])[CH2:36][N:37]([C:23](=[O:25])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:33]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.5 h

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-L-valine (1.0 g) was dissolved in a mixed solvent of dichloromethane (10 mL) and DMF (0.1 mL), and to the solution oxalyl chloride (374 mg) was added dropwise at 0° C. The mixture was stirred for 30 minutes and added dropwise into a solution of N-(benzyl)glycine ethyl ester (587 mg) and triethylamine (477 mg) in dichloromethane (10 mL) at 0° C. The resultant mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to obtain the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.C([C:14]1([CH:22]([CH3:26])C([O-])=O)[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]1[CH3:21])C.Cl>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[C:15]([CH3:21])[C:14]([CH2:22][CH2:26][C:8]([O:10][CH2:5][CH3:6])=[O:9])=[CH:19][C:18]=1[C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:10])=[O:11]
Reactant: CCC1(C(C)C(=O)[O-])C=CC(Cl)=CC1C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)c(Cl)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 166.9 %

Procedure:
Aluminum chloride (5.87 g; 0.044 mole) was added portionwise (5 minutes) to a mixture of succinic anhydride (1.1 g; 0.011 mole) and 1-ethyl-4-chloro-2-methylphenylpropionate (2.27 g; 0.01 mole) in CH2Cl2 (20 ml) with cooling (ice bath). The reaction mixture was stirred at room temperature for 24 hours, poured into ice and 10 ml concentrated HCl and extracted with ether. The ether solution was dried and evaporated to give a yellow brown oil, which was purified by flash column chromatography (silica gel and 2% HOAc-10% acetone-90% CH2Cl2) to give the product as a yellow oil (3.0 g; 92% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20](N)=[C:19](Cl)[N:18]=[C:17](C)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:25][NH2:26].C([N:29]([CH2:32]C)CC)C>C(O)C>[CH3:25][NH:26][C:17]1[N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH:20]=[C:19]([NH:29][CH3:32])[N:18]=1
Reactant: Cc1nc(Cl)c(N)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Reactant: CCN(CC)CC
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NC)n1
Temperature: 140 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
0.47 g (0.0013 mol) of 4-tert-butyl-N-(6-chloro-2-methyl-amino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.3 g (0.019 mol) of methylamine hydrochloride and 4.7 ml (0.034 mol) of triethylamine and stirred in an autoclave at 140° C. for 18 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and the insoluble constituents were filtered off under suction. The filtered cake was recrystallized in methanol/diethyl ether. There was obtained 0.15 g (33%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-4-tert-butyl-benzenesulfonamide as white crystals; m.p. 316-318° C.