Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:42]=[CH:43][CH:44]=1)[C:15]([NH:17][C:18]1[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:25][C:19]=1[O:20][CH2:21][C:22]([OH:24])=O)=[O:16].Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:42]=[CH:43][CH:44]=1)[C:15]([NH:17][C:18]1[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)(=[O:33])=[O:34])[CH:26]=[CH:25][C:19]=1[O:20][CH2:21][C:22]([NH:50][C:48](=[O:49])[CH2:47][NH2:46])=[O:24])=[O:16]
Reactant: NCC(N)=O
Reactant: O=C(O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc3ccccc3s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: NCC(=O)NC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
Under ice-cooling, triethylamine (220 μl) was added to a mixture of 2-[3-(2-benzothiazolylmethoxy)benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid (400 mg, 0.62 mmol), glycine amide hydrochloride (86 mg), 1-hydroxybenzotriazole (125 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (130 mg) and N,N-dimethylformamide (10 ml), and the mixture prepared was stirred at room temperature for 12 hours. Water and ethyl acetate were added to the reaction solution. The insoluble solid material formed was collected by filtration, washed with ethyl acetate, water, 1 N hydrochloric acid, water, ether, 1 N sodium hydroxide aqueous solution, water and ether in that order and then dried under reduced pressure. Acetonitrile (13 ml) was added to the resulting solid material, and the mixture was heated under reflux for 5 minutes with stirring and then cooled. The crystals formed were collected by filtration to give N-[[2-[3-(2-benzothiazolylmethoxy)benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy]acetyl]glycine amide (170 mg, 0.24 mmol, 39%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:39]=[CH:38][C:10]3[N:11]([C:14]4[S:18][C:17]([C:19]([NH2:21])=[O:20])=[C:16]([O:22][CH:23]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]6[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]6)[CH:26]=5)[CH3:24])[CH:15]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[C:40](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CO>[CH3:40][N:35]1[CH2:34][CH2:33][CH:32]([O:31][C:27]2[CH:26]=[C:25]([CH:23]([O:22][C:16]3[CH:15]=[C:14]([N:11]4[C:10]5[CH:38]=[CH:39][C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)=[CH:8][C:9]=5[N:13]=[CH:12]4)[S:18][C:17]=3[C:19]([NH2:21])=[O:20])[CH3:24])[CH:30]=[CH:29][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CC(=O)O
Reactant: CC(Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCNCC2)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCN(C)CC2)c1
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
(+/−)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[3-(4-piperidinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (0.108 g, 0.199 mmol) was dissolved in 9 mL of DCM and 4.5 mL of MeOH with stirring. Acetic acid solution (0.24 mL, 1.0M in DCM, 0.24 mmol) and formaldehyde solution (0.030 mL, 37% in water, 0.40 mmol) were added. Sodium triacetoxyborohydride (0.0633 g, 0.299 mmol) was added in a single portion. The reaction was stirred for 1.5 h and poured into 1N aqueous NaOH solution. The mixture was extracted three times with 4:1 DCM/i-PrOH. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was triturated with 1:1 ether/hexanes, filtered, and washed with hexanes. The solid was dried and collected to afford 0.099 g (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.17 (s, 1H), 7.93 (m, 1H), 7.90 (s, 1H), 7.75 (br s, 1H), 7.55 (dd, J=8.6, 1.5 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.26 (dd, J=7.9, 7.9 Hz, 1H), 7.12-7.07 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 6.85 (dd, J=7.9, 2.2 Hz, 1H), 5.69 (q, J=6.4 Hz, 1H), 4.30 (m, 1H), 3.84 (s, 3H), 2.57-2.43 (m, 2H), 2.09 (s, 3H), 2.10-2.00 (m, 2H), 1.88-1.78 (m, 2H), 1.67 (d, J=8.4 Hz, 3H), 1.60-1.47 (m, 2H). MS (ESI): 557 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Al](C)C.[CH3:23][S:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](OC)=[O:36])=[CH:30][CH:29]=1)(=[O:26])=[O:25]>>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][N:13]([C:35](=[O:36])[CH2:34][C:31]4[CH:30]=[CH:29][C:28]([NH:27][S:24]([CH3:23])(=[O:25])=[O:26])=[CH:33][CH:32]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Reactant: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1
Agent: C[Al](C)C
Product: CS(=O)(=O)Nc1ccc(CC(=O)N2CCOc3ccc(-n4ccnc4)cc3OCC2)cc1

Procedure:
In a manner similar to preparation 7, react 9-(1H-imidazol-1-yl)-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, trimethylaluminum, and 4-[(methylsulfonyl)amino]benzeneacetic acid, methyl ester to obtain the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>S(Cl)(Cl)=O.C(Cl)Cl>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acridine-9-carboxylic acid (1 g, 4.1 mmol) was suspended in thionyl chloride (5 mL) and the reaction mixture was refluxed for 3 hours. The solvent was removed under reduced pressure leaving a yellow solid which was dissolved in methylene chloride and pyridine (350 μL) under argon. This solution was cooled in an ice bath and a solution of phenol (0.78 g, 8.2 mmol) in methylene chloride was added dropwise. The reaction mixture was stirred overnight at room temperature. After evaporation of solvent, the residue was redissolved in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to obtain a crudematerial which was chromatographed on silica gel (30% ethyl acetate/hexane)to yield the pure product as a yellow solid. 1H NMR (CDCl3) δ7.35-7.57 (m, 5H), 7.63-8.37 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]1[CH:16]=[N:15][CH:14]=[C:13]([C@H:17]2[NH:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:22]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:13]2[CH:14]=[N:15][CH:16]=[CH:11][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: c1cncc([C@@H]2CCCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(Br)n1)N1CCCCC1c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
After 6-bromopicolinic acid (565 mg, 2.80 mmol) was suspended in acetonitrile (25 ml), anabasine (499 mg, 3.07 mmol), N,N-diisopropylethylamine (0.73 ml, 4.20 mmol), and HBTU (1.27 g, 3.36 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 255 mg of white solid (26%).
Reaction SMILES: Cl.C1COCC1.CC1(C)[O:32][CH2:31][C:11]2([CH2:14][C:13]([C:20]3[N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:23]4=[N:22][N:21]=3)([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH2:12]2)[CH2:10][O:9]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[N:22]1[N:21]=[C:20]([C:13]2([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][C:11]([CH2:31][OH:32])([CH2:10][OH:9])[CH2:14]2)[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:23]=12
Reactant: CC1(C)OCC2(CO1)CC(c1cccs1)(c1nnc3n1CCCCCC3)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OCC1(CO)CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
1M Hydrochloric acid was added to a THF (10 ml) solution of 3-[7,7-dimethyl-2-(2-thienyl)-6,8-dioxaspiro[3,5]non-2-yl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2270 mg) and the whole was stirred at room temperature for 30 minutes. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=9:1) to obtain 1862 mg of [3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocin-3-yl)-3-(2-thienyl)cyclobutane-1,1-diyl]dimethanol (colorless solid).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH2:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=3)[N:7]=2)[CH2:3]1.[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][CH:2]2[CH2:10][CH2:9][C:8]3[C:4](=[CH:5][N:6]([C:11]4[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=4)[N:7]=3)[CH2:3]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(-n2cc3c(n2)CCC(N)C3)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(-n2cc3c(n2)CCC(NC(=O)c2nc(Cl)c(CC)[nH]2)C3)nc1C
Yield: 75.1 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(5-amino-4,5,6,7-tetrahydro-2H-indazol-2-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (243a) (127 mg, 0.42 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (72 mg, 0.42 mmol), WSC hydrochloride (239 mg, 1.25 mmol), 1-hydroxybenzotriazole (56 mg, 0.42 mmol) and N-methylmorpholine (0.09 mL, 0.83 mmol), to obtain 146 mg of the title compound as a pale yellow solid (76%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[C:26]([OH:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:4]=1)[CH3:2].CI.[C:35]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:35][N:27]1[C:28]([CH3:31])=[CH:29][CH:30]=[C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[C:26]1=[O:32]
Reactant: CCc1nn(Cc2ccc(C)nc2O)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(C)n(C)c2=O)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.8 %

Procedure:
A mixture of N-(3-ethyl-1-((2-hydroxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (18.3 mg, 0.0429 mmol) and methyl iodide (2.68 μL, 0.0429 mmol) with K2CO3 (17.8 mg, 0.129 mmol) in DMF (3 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was extracted 3 times with EtOAc. The organic phases were combined and washed with brine. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (10:1 DCM/MeOH) to provide the final product (6 mg). MS (ES+APCI) m/z=441 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1ccccc1)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
The procedure of the process of P. Quitt et al. (Helv. Chim. Acta, 46, 327 (1963)) was followed. A 16.5 g quantity (0.1 mole) of Phe was dissolved in 50 ml of 2N aqueous NaOH solution, 10.1 ml of benzaldehyde was added to the solution with ice-cooling, and the mixture was stirred for about 10 minutes to obtain a uniform reaction mixture. To the mixture was added 1.14 g of NaBH4 in small portions at a temperature of up to 15° C., and the mixture was stirred for 30 minutes. The above procedure was repeated 3 times with use of benzaldehyde and NaBH4, each in one-half the above amount. The reaction mixture was stirred for 2 hours and then washed with ether. The aqueous layer was neutralized with 1N HCl with ice-cooling, and the resulting precipitate was filtered off and dried. The product was recrystallized from a mixture of 50 ml of dimethylformamide (DMF) and 200 ml of methanol to obtain 20.73 g of Nα -benzyl-phenylalanine (BzPhe), yeild 81.2%. M.p. 250°-253° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23]OS([O-])=O.[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.9 %

Procedure:
190 g (0.59 mmole) of 1′-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4′-piperidine]-2-oxide [prepared as described in Preparation 4(a)] were dissolved in 30 ml of methanol, and 10 ml of an aqueous solution containing 270 mg (1.77 mmole) of Oxone (trade mark) were added. The reaction mixture was stirred at room temperature for 5 days, after which it was poured into water and then extracted twice with chloroform. The organic extract was separated and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by thin-layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 175 mg (yield 88%) of the title compound as white crystals.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[Cl:9][CH2:10][C:11](Cl)=[O:12].O>ClCCl.N1C=CC=CC=1>[Cl:9][CH2:10][C:11]([C:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2)=[O:12]
Reactant: O=C1NC2C=CC1C2
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C1NC2(C(=O)CCl)C=CC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
10.1 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in a mixture of dichloromethane (10 ml), pyridine (8.4 ml) and 0.22 g of 4-N,N-dimethylaminopyridine at 10° C. under nitrogen. 13.5 g of chloroacetyl chloride were added dropwise over the course of 1 h. The temperature rose to 44° C. The mixture was stirred for a further 2 h at room temperature. 100 ml of water were added to the solution. After phase separation, the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulphate and completely evaporated. The residue was boiled in 100 ml of diisopropyl ether under reflux in the presence of 1 g of active charcoal for 10 minutes. After hot filtration, the filtrate was cooled to room temperature, and the solid was filtered and dried. 10.35 g of title compound were obtained. The yield was 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: Cc1nnc2c(NC(=O)OC(C)(C)C)cc(Cl)nn12
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(Cl)nn3c(C)nnc23)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 112.5 using tert-butyl (6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)carbamate (Step 112.4) and 4-methoxybenzylchloride at 80° C. for 1 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 10-25%). tR: 5.35 min (HPLC 1); tR: 1.19 min (LC-MS 2); ESI-MS: 404 [M+H]+ (LC-MS 2); Rf=0.74 (hexane/EtOAc 1:1) Step 126.2: tert-butyl (6-(4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-6-oxopyrrolo[3,4-c]pyrazol-5
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].[CH2:9](OS(C1C=CC(C)=CC=1)(=O)=O)[CH:10]([CH3:12])[CH3:11]>C(OCC)C>[CH2:9]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7])[CH:10]([CH3:12])[CH3:11]
Reactant: Cc1ccsc1Br
Reactant: Cc1ccc(S(=O)(=O)OCC(C)C)cc1
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccsc1CC(C)C
Yield: 48 %

Procedure:
A part of a solution containing 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) in dry diethyl ether is added drop-wise to a suspension of magnesium (308 mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether until the mixture starts to reflux. The remaining solution is added dropwise. A solution of toluene-4-sulfonic acid isobutyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether is added dropwise at room temp., then the mixture is further refluxed for two hours. After cooling to room temp., the mixture is quenched with sat. ammonium chloride solution and extracted with tert. butylmethylether. The combined organic extracts are washed with water, brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated to give a yellow oil. After Kugelrohr-distillation, 630 mg of the title compound is obtained as a colorless oil. GC-MS (EI): M=154
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.6 g, 12.0 mmol) was added to a THF solution (15 mL) containing 6-(3-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (2.5 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(3-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 70% yield.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7](OCC)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[NH2:15][NH2:16]>C(O)C>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([NH:15][NH2:16])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: CCOC(=O)c1ccc(C#N)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a 250 mL round bottom flask charged with ethyl 4-cyanobenzoate (16.85 g, 96.2 mmol) in 95% ethanol (75 mL) was added hydrazine mono-hydrate (18.2 mL, 64% solution, 240 mmol). This mixture was heated to reflux for a period of 4.5 h, then allowed to cool to room temperature over a 16 h period. The solvent was removed under reduced pressure and the yellow residue was taken up in ice-cold water (150 mL). The light yellow solid was filtered off and washed with additional cold water (50 mL). The solid was then dried under high vacuum to yield the title compound as a light yellow solid (13.98 g, 90%). 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.05 (br s, 1H), 7.95 (AA′XX′, J=8.5 Hz, 4H), 4.61 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23](C)C(Cl)=O.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:22]#[N:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(Cl)c3)n2)cc1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
500 mg (1.67 mmol) of N-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine are suspended in 5 ml of acetonitrile, and 0.42 ml (4.5 mmol) of dimethylcarbamoyl chloride and 0.56 ml (4.5 mmol) of trimethylsilyl cyanide are added. After stirring for 14 hours at 60°, the reaction mixture is cooled to RT and the reaction product is isolated by filtration and washed with diethyl ether. Recrystallisation from tetrahydrofuran gives N-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine in the form of yellow crystals; m.p. 221°-222°, Rf =0.6 (hexane:ethyl acetate=1:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:5](N1C2C=CC=CC=2N=N1)=[O:6].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:5]([C:4]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:2]([Cl:1])[C:3]=2[OH:20])=[O:6])[CH2:23][CH2:22]1
Reactant: O=C(c1cc(Cl)cc(Cl)c1O)n1nnc2ccccc21
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)cc(Cl)c1O)C1CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
N-(3,5-Dichloro-2-hydroxybenzoyl)benzotriazole (prepared according to Katritizky et al., Synthesis 2007, 20, 3141-3146, which is expressly incorporated by reference herein; 2.0 g, 6.5 mmol) was stirred in dry THF (25 mL), cooled to −30° C., treated in portions with cyclopropylmagnesium bromide (0.5 M in THF; 28 mL, 14 mmol) and stirred at −30° C. for 30 min. The cooling bath was removed and the mixture was allowed to warm to 25° C. and stir for 3 h. The reaction was quenched by addition of 10 mL satd NH4Cl, and shaken with EtOAc (50 mL) plus 20% citric acid solution (30 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (450 mg): 1H NMR (400 MHz, CDCl3) δ 13.03 (s, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 2.70-2.54 (m, 1H), 1.41-1.32 (m, 2H), 1.24-1.15 (m, 2H); EIMS m/z 230.