Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[N:20]12[CH2:30][CH2:29][CH2:28][N:27]=[C:26]1[CH2:25]CCC[CH2:21]2.N12CC(CC1)NCC2>C(#N)C>[N:20]12[CH2:21][CH:28]([CH2:29][CH2:30]1)[N:27]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:26][CH2:25]2
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: C1CN2CCC(C2)N1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN4CCC3C4)c(F)c21
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of 0.81 g (3 mmole) 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 0.46 g (3 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml acetonitrile was added 0.37 g (3.3 mmole) 1,4-diazabicyclo[3.2.1]octane and the mixture stirred at reflux 51/2 hours. After standing overnight at room temperature a yellowish solid was filtered, washed with acetonitrile and ether and dried in vacuo to afford 0.22 g product, mp decomposed above 233° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 13 (367 mg, 0.82 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (226 mg, 0.98 mmol) using Method D to give the title compound.
Reaction SMILES: [OH-].[Al+3].[Li+].[OH-].[OH-].[OH-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2([OH:24])[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]2([OH:24])[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:12][CH:13]=1
Reactant: OC1(C#Cc2ccc(Br)cc2)CN2CCC1CC2
Agent: [Al+3]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(C=Cc2ccc(Br)cc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1M solution of lithium aluminium hydroxide in tetrahydrofuran (3.0 ml) was added dropwise over 15 minutes to a stirred suspension of 3-[2-(4-bromophenyl)ethynyl]-3-hydroxyquinuclidine (918 mgs) in dry tetrahydrofuran (20 ml) at ambient temperature, under an atmosphere of argon. A complete solution formed as the addition progressed. The mixture was then stirred for 2 days at ambient temperature. A 2.0M solution of sodium hydroxide was then added dropwise to destroy the complex. The mixture was evaporated to dryness and the residue was purified by flash column chromatography on silica gel using 10% methanol in dichloromethane containing 1% ammonia (density, 0.88 g/cm3) to give [3-[2-(4-bromophenyl)-ethenyl]-3-hydroxyquinuclidine which was further purified by crystallisation from ethanol (210 mg) m.p. 218°-219° C.; NMR: 1.25(1H,m), 1.5(1H,m), 1.69(2H,m), 2.0(1H,m), 2.7(5H,m), 2.9(1H,d), 4.8(1H,s), 6.58(1H,d), 6.68(1H,d) and 7.42(4H,m).
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.CO.C(O)=O>>[N:12]1[C:11]2[CH2:17][CH2:18][NH:8][CH2:9][C:10]=2[C:15](=[O:16])[NH:14][CH:13]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=CO
Product: O=c1[nH]cnc2c1CNCC2
Temperature: 60 °C

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 2, 18.0 g, 0.0738 mol), triethylamine (48 mL, 0.34 mol) Palladium hydroxide (10 g, 0.07 mol) in methanol (242 mL, 5.91 mol) was heated to 60° C. Formic acid (7.6 mL, 0.20 mol) was added dropwise to the mixture over a 15 minute period. The mixture was heated at 65° C. for three hours, allowed to cool, and filtered over Celite. The filtrate was concentrated under reduced vacuum to yield the title compound as a yellow solid which was used directly in the next reaction. (9.62 g, 77.6%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:45])[NH:24][C@@H:25]([CH2:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH2:26][N:27]([CH3:37])[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:37][N:27]([CH2:26][C@@H:25]([NH:24][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C@H:8]([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH2:18]1)=[O:45])[CH2:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCOCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCOCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A 50 mL flask was charged with methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (100 mg, 0.15 mmol) and Pd(OH)2 (20 mg) dissolved in MeOH (5 mL) under H2. After stirring for 0.5 hr, the mixture was filtered, evaporated to give crude methyl 2-((R)—((R)-1-((S)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (20 mg, 21%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C@@H:28]([NH2:30])[CH3:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([OH:7])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[N:30]2[CH:28]([C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH3:29])=[CH:17][CH:18]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-chlorobenzoyl)benzoic acid (5 g, 19.2 mmol, 1 equiv.) in dry THF (20 mL) was added under nitrogen atmosphere thionylchloride (3.0 mL, 38.3 mmol, 2 equiv.) and 3 drops of anhydrous DMF. The reaction mixture was stirred for 4 h at room temperature and concentrated in vacuo. The resulting pale yellow oil was taken up in dry THF (20 mL), and (S)-4-chloro-α-methylbenzylamine (2.43 g, 15.6 mmol, 1.1 equiv.) and DIPEA (3.49 mL, 21.1 mmol, 1.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and the solvents were removed in vacuo. The residue was taken up in EtOAc (100 mL), filtered, and the filtrate washed with water (3×50 mL) and brine (1×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a solid, which was recrystallised (EtOAc/Petrol) as a white crystalline powder (3.10 g, 55%). 1H NMR (300 MHz, CDCl3): Mixture of two diastereoisomers: 7.74-7.09 (m, 13H, Ar—H and OH), 4.52 and 4.45 (q, J=6.9 Hz, 1H, CH*), 1.75 and 1.48 (d, J=7.2 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3): Mixture of two diastereoisomers: 166.94, 166.43, 149.17, 149.11, 142.01, 141.51, 139.65, 139.33, 133.24, 133.14, 132.90, 131.76, 131.60, 131.54, 131.47, 129.79, 129.71, 129.52, 128.67, 128.62, 128.26, 127.88, 127.84, 123.13, 122.74, 122.70, 91.19, 90.94, 51.22, 50.46, 20.21, 18.24. FTIR: 3103 (OH), 1665 (C═O) cm−1. m/z (ES): 398 [M+H]+. Anal.: calc. for C22H17Cl2NO2+0.3 H2O: C, 65.45; H, 4.40; N, 3.47. Found: C, 65.00; H, 4.30; N, 3.60.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[C:4]([F:14])[CH:3]=1.[CH:15]([O:17]CCO)=[CH2:16].C(=O)([O-])[O-].[K+].[K+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:14][C:4]1[CH:3]=[C:2]([C:15](=[O:17])[CH3:16])[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=1
Reactant: COCCCOc1cc(F)cc(Br)c1
Reactant: C=COCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COCCCOc1cc(F)cc(C(C)=O)c1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
1-Bromo-3-fluoro-5-(3-methoxypropoxy)benzene (4.0 g) was added to water (30.4 mL), and then thereto were added ethylene glycol monovinyl ether (6.8 mL), potassium carbonate (2.52 g), 1,3-bis(diphenylphosphino)propane (125 mg) and palladium acetate (34 mg), and the mixture was heated to stir at 90° C. for 22 hours. After cooling, thereto was added concentrated hydrochloric acid (7.2 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and then dried over magnesium sulfate. After concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1→2/1) to give 1-[3-fluoro-5-(3-methoxypropoxy)phenyl]ethanone [REx(19-2)] (1.03 g) as a yellow oil.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:22][N:23]1[CH2:27][CH2:26][C:25]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:28][CH:29]=O)[CH2:24]1.C([BH3-])#N.[Na+].O1CCCC1.[OH-].[K+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].ClCCl.CO.C(OCC)(=O)C.ClCCl>[Cl:38][C:33]1[CH:32]=[C:31]([C:25]2([CH2:28][CH2:29][N:11]3[CH2:10][CH2:9][C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]3)[CH2:26][CH2:27][N:23]([CH2:22][C:21]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:24]2)[CH:36]=[CH:35][C:34]=1[Cl:37]
Reactant: COc1cc(CN2CCC(CC=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 4-phenyl-piperidine-4-carboxylic acid-amide hydrochloride (0.5 g, 2.1 mmol), 1-(3,4,5-trimethoxybenzyl)-3-(3,4-dichloro-phenyl)-3-(2-oxo-ethyl)-pyrrolidine (0.23 g, 0.53 mmol), and titanium(IV) isopropoxide (0.2 g, 0.7 mmol) in methanol (5 mL). Add a solution of sodium cyanoborohydride in tetrahydrofuran (0.9 mL, 1M, 0.9 mmol). After 18 hours, a precipitate had formed. Filter, rinse with methanol and dichloromethane, and evaporate the filtrate to give a residue. Combine residue with dichloromethane and an aqueous 2M solution of potassium hydroxide. Separate the layers, extract the aqueous layer with dichloromethane, combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, dichloromethane/methanol/concentrated ammonia (196/4/0.2), dichloromethane/methanol/concentrated ammonia (242/8/0.4), and then dichloromethane/methanol/concentrated ammonia (238/12/0.6) to give the title compound. Elemental Analysis calculated for C34H43 Cl2N3O4.0.4 H2O: C 64.52; H 6.64; N 6.64. Found C 64.15; H 6.33; N 6.67.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:9]([CH:11]1[O:13][CH2:12]1)[Cl:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:13][CH:11]([CH2:9][Cl:10])[CH2:12][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1CC(O)CCl

Procedure:
2-Nitroimidazole (1 molar equivalent) in acetone was mixed with epichlorohydrin (1.1 molar equivalent) and potassium carbonate (0.001 molar equivalent). The mixture was refluxed overnight and taken to dryness in vacuo to give 1-(2-hydroxy-3-chloropropyl)-2-nitroimidazole. 1-(2-Hydroxy-3-chloropropyl)-2-nitroimidazole is taken up in ethyl acetate and mixed with an equal volume of 10% aqueous sodium hydroxide with vigorous stirring for 1 hour at room temperature. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and taken to dryness to give 1-(2,3-epoxypropyl)-2-nitroimidazole. 1-(2,3-epoxypropyl)-2-nitroimidazole (1 molar equivalent) dissolved in acetone was mixed with N′-1,1,1,3,3,3-hexafluoroisopropylpiperazine (1.1 molar equivalent) and the solution refluxed overnight. The reaction solution was taken to dryness in vacuo to give 1-(2-hydroxy-3-(N′-1,1,1,3,3,3-hexafluoroisopropylpiperazino)-2-nitroimidazole (XVI) that was recrystallized from ethanol. The chemical intermediate, N′-1,1,1,3,3,3-hexafluoroisopropylpiperazine, was prepared by heating 1,1,1,3,3,3-hexafluoroisopropyl bromide (1.0 molar equivalent) and piperazine (1.1 molar equivalent) at reflux in ethanol overnight. The chemical intermediate 1,1,1,3,3,3-hexafluoroisopropyl bromide was prepared by reacting commercially available 1,1,1,3,3,3-hexafluoroisopropyl alcohol (1 molar equivalent) with phosphorus tribromide (0.33 molar equivalent) in ethyl ether overnight at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.NC1C=CC([I:29])=CC=1NC1C=CN=C(N)N=1>>[I:29][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: Nc1nccc(Nc2cc(I)ccc2N)n1
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(I)cc32)n1

Procedure:
The title compound was prepared by procedure described for 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine, by replacing 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine with 4-N-(2-amino-5-iodophenyl)pyrimidine-2,4-diamine: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 7.01 (1H, d, J=5.1 Hz), 7.22 (2H, s), 7.77-7.69 (3H, m), 8.58 (1H, d, J=5.0 Hz), 11.97 (1H, s); LC-MS: m/z=+454/456/458 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[CH3:26][S:27]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:29])=[O:28]
Reactant: Cc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)cc1
Temperature: 0 °C
Yield: 34.8 %

Procedure:
10 g (42 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(4-methylphenyl)-acetonitrile are dissolved in 80 ml of THF and cooled in an ice bath. After adding 8.8 ml (63 mmol) of triethylamine to the solution, 3.6 ml (47 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 4.6 g (35%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-(4-methylphenyl)-acetonitrile are obtained in the form of yellow crystals having a melting point of 139-141° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34](Br)=[CH:35][CH:36]=1)(=[O:31])=[O:30]>>[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:35][CH:36]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.53) (165 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 72%). MS (ISP) 587.1 [(M+H)+]; mp 174° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[C:10]=3[N:9]=2)[CH2:6][CH2:5][N:4]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][C:32]=2[C:39]([F:42])([F:41])[F:40])[CH2:3]1>O=[Mn]=O>[CH3:1][CH:2]1[N:7]([C:8]2[NH:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[CH:15][C:14]([C:27]([F:29])([F:30])[F:28])=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][N:4]([C:31]2[N:36]=[CH:35][C:34]([CH:37]=[O:38])=[CH:33][C:32]=2[C:39]([F:42])([F:40])[F:41])[CH2:3]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1c1nc2c(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)cc2[nH]1
Agent: O=[Mn]=O
Product: CC1CN(c2ncc(C=O)cc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
(6-{(3R)-3-Methyl-4-[6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-piperazin-1-yl}-5-trifluoromethyl-pyridin-3-yl)-methanol (422 mg, 0.7 mmol, Example 189c) reacted with MnO2 (1.22 g, 14 mmol, Aldrich) under the conditions of Example 154a to give the title compound as a white solid. MS ESI, pos. ion m/e: 602 (M+1).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:32]=[CH:31][C:13]([CH2:14][N:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH3:16])=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:32]=[CH:31][C:13]([CH2:14][N:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH3:16])=[CH:12][CH:11]=1
Reactant: CN(Cc1ccc(F)cc1)C1CCN(c2ccc(C=O)cc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N2CCC(N(C)Cc3ccc(F)cc3)CC2)cc1
Yield: 50.2 %

Procedure:
2.6 g (7.9 mmol) of the amine from Example 25 were reduced with 2.8 g (23.7 mmol) of triethylsilane and 9.0 g of trifluoroacetic acid in a similar manner to Example 14. 1.7 g of 4-(N-(4-fluorobenzyl)-N-methylamino)-1-(4-tolyl)piperidine fumarate were obtained. Melting point 146° C.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:31]>C1(C)C=CC=CC=1>[Ti+4:31].[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2]
Reactant: CCP(=O)(O)CC(C)CO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCP(=O)([O-])CC(C)CO
Yield: 91 %

Procedure:
166 g (1 mol) of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid (produced as in Example 13) and 85 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 161 g (91% of theory) of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid titanium salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C(C)C([O-])=O.[Na+].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32](Br)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]
Reactant: CC(C(=O)[O-])c1nccs1
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 2-(2-thiazolyl)propionate (148 mg) is introduced into DMF (5 ml), and 2-(1-benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 8A; 171 mg), HATU (291 mg) and 4-methylmorpholine (194 mg) are added. The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated and the residue is purified by preparative HPLC. 101 mg (36% of theory) of product are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O[Si](C)(C)C)[C:10]#[N:11].C(N(S(F)(F)[F:23])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:23])[C:10]#[N:11]
Reactant: C[Si](C)(C)OC(C#N)c1ccc(Cl)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC(F)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-2-(trimethylsilyloxy)acetonitrile (1.57 g, 5.73 mmol) in dichloromethane (20 ml) under argon at −78° C. was added (diethylamino)sulfur trifluoride (1.51 ml, 11.5 mmol) dropwise over 15 minutes. The reaction was stirred at this temperature for 20 minutes, then warmed to 0° C. and allowed to stir for an additional 30 minutes. The reaction was poured onto a mixture of ice water and saturated sodium bicarbonate and allowed to stir for 30 minutes. The mixture was extracted with ether twice, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 1.05 g of the title compound (89% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][N:12]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=3)[CH2:11][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:31][CH:32]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(Cc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CS(=O)(=O)N(Cc1ccncc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 15 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 2H) 8.2 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (d, 2H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 4.4 (s, 2H) 4.3 (s, 2H) 3.6 (m, 2H) 2.9 (m, 5H).