Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:38])=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]4=[N:21][C:20]=3[C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31](OC)=[O:32])[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[F:40][C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:42]=1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:40][C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:42]=1[NH:43][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][CH:37]=[C:28]([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[C:19]=2[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:39])[C:7]=3[CH3:38])[N:18]=2)[CH:29]=1
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3C)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)cccc1OCCN(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
To a solution of methyl 3-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}-2-methylphenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzoate (60.0 mg, 0.115 mmol) and 2,6-difluoroaniline (0.0350 mL, 0.345 mmol) in THF (5 mL) was added sodium bis(trimethylsilyl)amide (0.46 mL, 0.460 mmol, 1.0 M solution in THF), and the reaction mixture was stirred for 5 min at rt. The mixture was quenched with saturated NaHCO3, diluted with DCM, and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 70 mg (98% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=6.6 Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 8.20 (d, J=5.3 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.42 (t, 2H), 7.12-7.28 (m, J=8.0, 8.0 Hz, 3H), 7.03 (d, J=7.5 Hz, 1H), 6.87 (d, 2H), 6.48 (d, J=5.3 Hz, 1H), 4.07 (t, J=5.8 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.22 (s, 6H), 2.07 (s, 3H). MS (APCI+) m/z 620 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:20]=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1C
Product: Clc1ccc2c(c1)c(-c1ccccc1)cc1nncn12

Procedure:
In the manner given in Example 2, 6-chloro-4-phenyl-2-hydrazinoquinoline and triethyl orthoformate are refluxed in xylene to give 7-chloro-5-phenyl-s-triazolo[4,3-a]quinoline of melting point 265°-266.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH:19](O)=O.C=O.N>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCCNC1CCc2c(cccc2NC(C)=O)C1
Reactant: O=CO
Agent: C=O
Agent: N
Solvent: ClCCl
Solvent: O
Product: CCCN(C)C1CCc2c(cccc2NC(C)=O)C1

Procedure:
2.46 g (0.010 mol) of 5-acetylamino-2-n-propylamino-tetraline (Example 4.1.1) are heated with 2.34 g (0.050 mol) of formic acid and 2.2 ml of 30% formalin solution (0.022 mol of formaldehyde) for 30 minutes over a boiling water bath. The reaction mixture is shaken with 50 ml of water, 50 ml of methylene chloride and 2 ml of conc. ammonia. The aqueous phase separated off is extracted twice more with 15 ml of methylene chloride. The combined methylene chloride extract are washed with 20 ml of water, dried with sodium sulphate and concentrated by evaporation, after removal of the drying agent, in a rotary evaporator, finally at 80° C. under a total water jet vacuum. The residue is crystallised from 5 ml of acetone and 20 ml of petroleum ether. The title compound is obtained in a yield of 1.80 g (69.2% of theory) and with a melting point of 78° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C)nc1Cl
Reaction time: 5 h

Procedure:
To a suspension of 2-chloro-6-methylnicotinic acid (5.3 g, 30.8 mmol) in dichloromethane (100 ml) at 0° C. were added DMF (1 ml) and oxalyl chloride (3.2 ml, 36.9 mmol). The mixture was allowed to warmn to room temperature and stirred for 5 h. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (50 ml) and methanol (50 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a brown oil; yield 5.70 g (100%).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH2:21][CH3:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:1][CH3:2])=[O:17])=[C:14]([CH2:21][CH3:22])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1CC

Procedure:
Ethyl iodide (0.268 mL) was added to a suspension of 4-benzyloxy-2-ethylbenzoic acid (0.572 g) and potassium carbonate (0.617 g) in N,N-dimethylformamide (5.6 mL) at room temperature with stirring. The mixture was stirred at 50° C. for 1.5 hrs and at room temperature for 13 hrs, and then water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium chloride and brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.635 g).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([C:26]#[N:27])([CH:23]3[CH2:25][CH2:24]3)[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:33].C1C([N+]([O-])=O)=CC=C([Cl-][C:44]([O-])=[O:45])C=1.[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>ClCCl>[C:26]([C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:31]=[CH:32][C:2]([NH:1][C:44]([NH:51][CH2:50][CH:47]4[CH2:49][CH2:48]4)=[O:45])=[C:3]([F:33])[CH:4]=3)[CH2:13][CH2:12]2)[CH:16]=1)([CH:23]1[CH2:25][CH2:24]1)[CH3:22])#[N:27]
Reactant: NCC1CC1
Reactant: CC(C#N)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C1CC1
Solvent: ClCCl
Product: CC(C#N)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)c(F)c3)CC2)c1)C1CC1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)—N-(1-cyano-1-cyclopropyl-ethyl)benzamide (49 mg, 0.109 mmol) was stirred In dichloromethane at room temperature. 4-Nitrophenylchloroformate (22 mg, 0.109 mmol) was added and the reaction mixture stirred for 30 minutes. Cyclopropylmethylamine (23 mg, 0.327 mmol) was added and the reaction allowed to stir for 30 minutes at room temperature. The reaction was concentrated under reduced pressure and the resulting residue purified by silica column chromatography to afford the title compound (25 mg). MS (ESI) m/z 547.5 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:18]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1c[nH]c2ccccc12
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ccccc13)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indole-3-carboxaldehyde to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([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)=CC=1>[F:9][C:10]1[CH:11]=[C:12]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cnc(-c2cccc(F)c2)s1
Temperature: 120 °C
Yield: 54 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (0.6 g, 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. Na2CO3. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120° C. for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One chromatography (using 6% ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]+ 208.02. found 208.0.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:31][CH:30]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCOc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCC)cc2)cc1
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In tetrahydrofuran were dissolved 1.0 g of p-octyloxybenzoic acid chloride and 800 mg of p-hexyloxyphenol, and 500 mg of triethylamine was added to the solution and reaction was carried out with stirring overnight. The precipitate was removed by filtration, and the filtrate was concentrated, purified by using a silica gel column and recrystallized from ethanol to obtain 800 mg of 4-hexyloxyphenyl 4-octyloxybenzoate. The phase transition temperatures of the so-obtained compounds are as follows. ##STR142##
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:35])[F:37])=[CH:31][CH:32]=4)[N:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)Oc1ccc(-c2cccc(CCl)n2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
A solution of 37 mg (0.17 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 2-Chloromethyl-6-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diethylether. The residue was dried at 40° C. to give 15 mg (18%) of the title compound as white powder.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11]>CC#N>[C:1]([NH:5][C:10]([NH:9][CH2:8][CH2:7][Cl:6])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NCCCl
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A solution of t-butylamine (6.00 g, 82 mmol) in MeCN (120 mL) was treated with 2-chloroethylisocyanate (9.00 g, 85 mmol), stirred at RT for 1 h, and the resulting solid was collected via filtration to afford 1-(tert-butyl)-3-(2-chloroethyl)urea (12.2 g, 83%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 5.89 (t, J=5.9 Hz, 1 H), 5.82 (s, 1 H), 3.53 (t, J=6.2 Hz, 2 H), 3.24 (q, J=6.1 Hz, 2 H), 1.19 (s, 9 H); MS (ESI) m/z: 179.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]([OH:9])[C:7]([CH3:10])=[CH:6][C:5](=[O:11])[C:4]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([CH:34](Br)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:8]([O:9][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:7]([CH3:10])=[CH:6][C:5](=[O:11])[C:4]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2c(CO)n(O)c(C)cc2=O)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(CO)n(OC(c3ccccc3)c3ccccc3)c(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 300 mg of 6-hydroxymethyl-5-p-methoxybenzyloxy-2-methyl-1-hydroxy-4-pyridone in 10 ml of dimethylformamide were successively added 213 mg of potassium carbonate and 423 mg of diphenylmethyl bromide. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction liquid was concentrated and the concentrate was added to 20 ml of water and 40 ml of dichloromethane. The organic phase was washed with 20 ml of water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:9]CC)=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41]Br>CC1C=CC=CC=1C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH2:41][P:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:9])([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOP(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: BrCc1ccc2ccccc2c1-c1c(CBr)ccc2ccccc12
Solvent: Cc1ccccc1C
Product: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccc(F)cc2)c2ccc(F)cc2)ccc2ccccc12)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 135 °C

Procedure:
While stirring under nitrogen, 10.70 g (0.04 mol) of ethyl bis(4-fluorophenyl)phosphinite are added dropwise to a solution of 8.80 g (0.02 mol) of 2,2'-bis(bromo-methyl)-1,1'-binaphthyl in 40 ml of o-xylene, which solution has been heated to 135° C. After the end of the addition, the mixture is heated under reflux for a further 1.5 hours. After cooling to room temperature, the precipitated crystals are filtered off with suction and washed with xylene. This gives 14.1 g (94 %) of colorless crystals having a melting point of 211°-214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[CH2:13]([O:15][C:16](OCC)([O:22]CC)[C:17](OCC)=O)[CH3:14]>>[CH2:13]([O:15][C:16]([C:17]1[S:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[N:1]=1)=[O:22])[CH3:14]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Product: CCOC(=O)c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 2-amino-4-trifluoromethyl-benzenethiol (0.7 g) was added ethyl triethoxyacetate (3 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 460 mg of 5-trifluoromethyl-benzothiazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18](O)=[O:19])=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.O[NH:24][C:25]([C:27]1[S:28][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:30][CH:31]=1)=[NH:26]>>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:19][N:26]=[C:25]([C:27]5[S:28][C:29]([S:32]([NH2:33])(=[O:35])=[O:34])=[CH:30][CH:31]=5)[N:24]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)s1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (heptane/diethyl ether) as an off-white solid (179 mg, 83%). MS (ISP) 492.2 [(M+H)+]; mp 280° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)[O:3][C:4]=2[CH:10]=1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Reactant: Clc1ccc2nc(Cl)oc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OC1CCN(c2nc3ccc(Cl)cc3o2)CC1)c1ccccn1

Procedure:
Compound 22 is prepared using synthesis method 3 using intermediates 2f and 6a (yield: 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Br:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][Br:22])=[CH:27][CH:28]=2)=[O:9])[CH:10]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(CCCBr)cc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 5-bromo-2-chlorobenzoic acid (2.31 g, 9.80 mmol) and oxalyl chloride (1.41 g, 11.11 mmol) in CH2Cl2 (30 mL) was added 0.05 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred overnight and then the volatiles were removed under reduced pressure. The resulting crude 5-bromo-2-chlorobenzoyl chloride was dissolved in dichloromethane (30 mL), and the solution was cooled to 0˜5° C. Then AlCl3 (1.31 g, 9.8 mmol) was added in portions, the mixture was stirred for 30 min, and (3-bromopropyl)benzene (1.50 g, 6.53 mmol) in dichloromethane (4 mL) was added. The reaction solution was warmed to room temperature and stirred for 4 h. The reaction was quenched by pouring into ice water. The suspension was diluted with water and extracted 3× with CH2Cl2. The combined organic extracts were washed 2× with 1N HCl, 1× with water, 2× with 1M NaOH, and 2× with brine, and then dried over Na2SO4. After removal of the volatiles, the crude product was purified by column chromatography (eluent EA:PE=1:20) to obtain intermediate DD (2.4 g) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.68˜7.66 (d, 2H), 7.50˜7.47 (dd, 1H), 7.42 (d, 1H), 7.28˜7.19 (m, 3H), 3.33 (t, J=6.8 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.17˜2.10 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: COc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 65 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[4-(2-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 24) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (83.8 mg, 65%); ES+-HRMS m/e calcd for C26H33N5O5 [M+H+] 496.2555 found 496.2552. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.21-1.74 (m, 8H), 1.91 (m, 1H), 2.27 (m, 1H), 3.80 (s, 3H), 3.89 (s, 2H), 4.68 (s, 1H), 5.45 (dd, J=4.2, J=11.2 Hz, 1H), 5.56 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.00-7.11 (m, 1H), 7.20-7.31 (m, 2H), 7.31-7.41 (m, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]([CH3:62])[CH3:61])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]([CH3:62])[CH3:61])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (10 mg) and triethylamine (6 μL) are dissolved in dichloromethane (1 mL), treated with isopropyl chloroformate (28 μL, 1 M solution in toluene) and stirred for 12 hours at room temperature. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is used directly in the next step. LC (method 5): tR=1.27 min.