Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].C([O-])C.[Na+].N[C:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[CH:12][C:13]#[N:14].Cl>C(O)C.O>[NH2:14][C:13]1[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[NH:5][C:3](=[S:4])[N:2]=1
Reactant: N#CC=C(N)c1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(Cl)cc2Cl)[nH]c(=S)n1

Procedure:
16.51 g (718.08 mmol) of sodium are dissolved in 353 ml of ethanol, and 40.996 g (538.56 mmol) of thiourea are added to the sodium ethanolate solution prepared in this way, followed by 76.5 g (359.04 mmol) of 3-amino-3-(2,4-dichlorophenyl)acrylonitrile. The mixture is heated under reflux for 18 h and, after cooling, 500 ml of water are added. The mixture is neutralized with 1M hydrochloric acid, and the precipitate which has separated out is filtered off with suction. The latter is washed with water, suspended in THF and again filtered off with suction. It is washed with 300 ml of petroleum ether and then dried under high vacuum. 67.5 g (55% of theory) of the product are obtained as a solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1.[Cl:22][C:23]1[CH:36]=[C:35]([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:34]([Cl:43])=[CH:33][C:24]=1[O:25][C@H:26]1[CH2:29][C@H:28]([CH2:30][NH:31][CH3:32])[CH2:27]1>C1COCC1>[Cl:22][C:23]1[CH:36]=[C:35]([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:34]([Cl:43])=[CH:33][C:24]=1[O:25][C@H:26]1[CH2:27][C@H:28]([CH2:30][N:31]([CH3:32])[C:19]([CH:16]2[CH2:15][CH2:14][O:13][CH2:18][CH2:17]2)=[O:21])[CH2:29]1
Reactant: O=C(O)C1CCOCC1
Reactant: CNC[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1)C(=O)C1CCOCC1

Procedure:
CDI (71 mg, 0.43 mmol) was added to a solution of tetrahydropyran-4-yl-carboxylic acid CAS 5337-03-1 (57 mg, 0.43 mmol) in THF (2 ml) at RT under stirring, the mixture was stirred at RT for 1 h. Example 381, ({trans-3-[2,5-dichloro-4-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (100 mg, 0.29 mmol) was added to the mixture and the solution was stirred at RT for 20 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 5 g, hexane/CHCl3 20:80→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.20 mL) was added, and the reaction mixture was evaporated to dryness. The obtained crystals were washed with ether and dried in vacuo to give the title compound (70 mg, 50% yield). LC/MS data: 455.1 (M+H) (calculated for C23H32Cl2N2O3 455.43). 1H NMR-data (DMSO-d6): 10.64 (br. s, 1H, NH+); 7.88-8.09 (m, 1H, Ar—H); 7.00-7.13 (m, 1H, Ar—H); 4.88-5.37 (m, 1H), 4.32-4.44 (m, 2H); 3.79-3.91 (m, 2H); 3.33-3.56 (m, 6H); 2.98-3.15 (m, 4H); 2.76-2.93 (m, 2H); 2.56-2.65 (m, 1H); 2.10-2.33 (m, 4H); 1.81-2.07 (m, 4H); 1.46-1.69 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([NH:17][C@@H:18]([C:21]3[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)[CH2:19][OH:20])=[N:13][C:12]=12)=[O:7].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C(#N)C>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:18]([C:21]4[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)[CH2:19][O:20][C:35]3=[O:36])=[N:13][C:12]=12)=[O:7]
Reactant: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)NCCCCl)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ncc(F)cc1[C@H]1COC(=O)N1c1ccn2ncc(C(=O)NCCCCl)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of (S)-N-(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) in ACN (2 mL) was added CDI (35 mg, 0.21 mmol). The solution was stirred at ambient temperature for 16 hours then partitioned between saturated NH4Cl solution (20 mL) and EtOAc (10 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 1% MeOH/DCM to afford (S)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (37 mg, 58% yield) as a white solid. MS (apci) m/z=449.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1cc(F)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 88.5 %

Procedure:
To 2-(ethyloxy)-4-fluoro-1-nitrobenzene (Example 116, step A) (3.0 g, 16.2 mmol) in 60 mL of dioxane was added, piperazine (4.19 g, 48.61 mmol). The mixture was heated to 120° C. 72 h. The mixture was purified by flash chromatography to give the title compound of step A (3.6 g, 14.33 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=9.34 Hz, 1H), 6.40 (dd, J=9.34, 2.56 Hz, 1H), 6.30 (d, J=2.56 Hz, 1H), 4.13 (q, J=6.96 Hz, 2H), 3.30-3.33 (m, 4H), 2.95-3.02 (m, 4H), 1.48 (t, J=6.96 Hz, 3H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:8]=[CH:7][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(Nc2cc(NC3CCCCC3)ncn2)c1
Temperature: 200 °C
Yield: 71 %

Procedure:
71 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 29 mg of cyclohexylamine and 84 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using PE:EtOAc 1:1. N4-(3-Chlorophenyl)-N6-cyclohexylpyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[NH2:17].Cl>CO.[OH-].[Na+]>[NH2:17][CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: NO
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1CCN(C(=O)c2ccccc2)CC1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
N-Benzoyl-4-piperidone (45.92 g, 226 mmol) was converted to the oxime by treatment with HONH2.HCl (237 mmol, 16.49 g) in 90 ml of methanol and 90.4 ml of 2.5N NaOH. After stirring overnight, the reaction was concentrated under reduced pressure and three times treated with toluene and reconcentrated to remove the last traces of water. The resulting oxime (57 g) was dissolved in 1L of methanol, treated with 226 ml of 1N HCl and 4 g of PtO2. The mixture was then hydrogenated in a Paar apparatus at 50 psi. After 16.75 h, the catalyst was filtered and the methanol was concentrated in vacuo. Water (100 ml) was then added to the aqueous phase that was then extracted with 7×700 ml of CH2Cl2. The aqueous phase was made basic with 2.5N NaOH and extracted with 5×100 ml of CH2Cl2. The pooled extracts were concentrated in vacuo affording 18.17 g (88.9 mmol, 39% overall yield) of 4-amino-1-benzoylpiperidine as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19]O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].[I-:21]>>[I:21][CH2:19][C@@H:17]1[CH2:18][C@@H:16]1[CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)[CH2:11][CH2:12]1
Reactant: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Reactant: [I-]
Product: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CI)CC2)nc1

Procedure:
The product of step B was converted to the iodide using the conditions outlined for intermediate 8, step A.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:29])[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28])#[CH:21]>>[F:19][C:18]1[C:2]([C:21]#[C:20][C:22]2([OH:29])[CH2:26][CH2:25][N:24]([CH3:27])[C:23]2=[O:28])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC1(O)CCN(C)C1=O
Product: CN1CCC(O)(C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)C1=O
Yield: 30 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (WO2009/158011A 1) to give the titled compound (34.8 mg, 30%).
Reaction SMILES: C[CH:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:4]=2[O:3]1.CC1(C)C(=O)N(C)C2C=CC(C(=O)C(C)CC(OC)=O)=CC=2O1>>[CH3:9][N:6]1[C:5]2[CH:10]=[CH:11][C:12]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:4]=2[O:3][CH2:2][C:7]1=[O:8]
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)OC(C)C(=O)N2C
Agent: COC(=O)CC(C)C(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2C
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2C

Procedure:
The following compounds were made by the above procedure, using the appropriate starting materials: methyl 4-(3,4-dihydro-2,4-dimethyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyrate (oil); and methyl 4-(3,4-dihydro-2,2,4-trimethyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyrate (oil).
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=CC=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([CH3:36])[CH:27]=[CH:26][C:25]([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])=[CH:24][CH:23]=1.C(C1CCCCC1)C#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH3:36])=[CH:27][CH:26]=2)[CH:14]=[C:13]([CH2:12][CH:11]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[O:35]1)[CH3:33]
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCC1CCCCC1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(C)cc2)C=C(CC2CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]|SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylcyclohexane (73.2 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-tolyl-6-(cyclohexylmethyl)-1,2-oxaphosphorin 2-oxide (66.5 mg, 64%) which is a title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Ic1ccc(-n2cccn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cccn3)cc2)cc1
Yield: 64.3 %

Procedure:
Followed the same procedure as that of step 1 in Example 133 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (147 mg, 0.5 mmol) and 1-(4-iodo-phenyl)-1H-pyrazole (203 mg, 0.75 mmol) to afford the title product (140 mg, 60% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:18]21[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCCC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), cyclohexanone (2.0 mL, 1.9 g, 19 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred overnight at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 30 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. The solid was triturated with DMF/dichloromethane, then the precipitate was collected by filtration to afford the title compound (0.0738 g, 56%) as a yellow solid:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[CH2:14][N:13]([CH3:17])[C:12]2=[O:18])[CH:5]=1.[Li]>O1CCCC1.O>[CH3:17][N:13]1[CH2:14][C:15](=[O:16])[N:11]([CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:19])=[O:2])[C:12]1=[O:18]
Reactant: COC(=O)c1cccc(CN2C(=O)CN(C)C2=O)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC(=O)N(Cc2cccc(C(=O)O)c2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3-Methyl-2,5-dioxo-imidazolidin-1-ylmethyl)benzoic acid methyl ester (100 mg, 0.381 mmol) in THF/water (2/1, 2 mL) is added lithium hydroxyde monohydrate (24 mg, 0.572 mmol) and the reaction is stirred at rt during 16 h before quenching with water and ethylacetate. The separated aqueous phase is acidified to pH 2 with an aqueous 1N HCl solution, extracted with ethylacetate and the organic phase is dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1([F:36])[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:21]=3)=[CH:16][C:14]=2[NH2:15])[CH2:8]1>N1C=CC=CC=1>[F:36][C:7]1([F:6])[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:33])([F:34])[F:35])[N:21]=3)=[CH:16][C:14]=2[NH:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]1
Reactant: Nc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCC(F)(F)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Methanesulfonylchloride (29.23 mg; 0.26 mmol; 0.6 eq.) was added to a solution of Example 41 (75 mg; 0.43 mmol; 1 eq.) in pyridine (1 mL) and the resulting solution was stirred at room temperature for 36 hours then concentrated in vacuo. The residue was purified by column chromatography (c-hexane/ethyl acetate, 70/30) followed by crystallization from ethyl acetate/n-pentane to afford the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:27]([CH3:29])[CH3:28]>CN(C)C=O>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=2)[N:7]([CH:27]([CH3:29])[CH3:28])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2cc(C(F)(F)F)ccc12)C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-trifluoromethyl-1H-indol-3-yl)-ethanone (1.0 g, 3.56 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was treated with potassium carbonate (1.22 g, 8.89 mmol). The resulting mixture was stirred at 25° C. for 10 min. At this time, the reaction was treated with 2-iodopropane (0.53 mL, 5.34 mmol). The reaction was heated at 65° C. for 4 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (75 mL) and ethyl acetate (75 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (1×25 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2,2,2-trifluoro-1-(1-isopropyl-6-trifluoromethyl-1H-indol-3-yl)-ethanone (850 mg, 74%) as a pale orange solid: mp 92-93° C.; EI-HRMS m/e calcd for C14H11F6NO (M+) 323.0745, found 323.0739.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([S:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)(=[O:27])=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.25 g, 1.0 mmol), 4-fluorobenzenesulfonyl chloride (0.23 g, 1.2 mmol), and triethylamine (349 μL, 2.5 mmol) are stirred at room temp. for 15 h. The reaction mixture is diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([OH:25])=O)[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:67][NH2:68]>C(OCC)(=O)C.ClCCl>[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([NH:67][NH2:68])=[O:25])[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:38]([F:40])([F:39])[F:41])[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NNC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 53; 1.6 g, 2.35 mmol), triethylamine (1 ml, 7.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (910 mg, 4.7 mmol), 4-N,N-dimethylaminopyridine (20 mg, 0.16 mmol), dichloromethane (15 ml) and hydrazine (1M solution in THF, 5 ml, 5 mmol) was stirred at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO , water and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (1 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:10])=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH:18]=1.[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].[K+]>>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:11][C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[C:3]([C:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH:18]=2)[CH:4]=1)=[O:10]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN(C)CCNC(=O)Cc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Agent: [K+]
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1

Procedure:
The title compound was prepared from 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-N-(2-dimethylamino-ethyl)-acetamide (as prepared in the previous step) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)) according to the procedure in Example 1, step (f). Mass spectrum (ESI, m/z): Calcd. for C31H46N6O3Si, 579.3 (M+H). found 579.3.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([C:10](=O)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:3][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Temperature: 60 °C

Procedure:
Hydrazine monohydrate (2.16 mL) is added to a solution of 1,3-diphenylpropane-1,3-dione (10.0 g) in ethanol (100 mL) and the mixture is heated to 60° C. for 2.5 h forming a white precipitate over this time. Ethanol is removed in vacuo and the residue is taken up in ethyl acetate. The resulting suspension is filtered to give 3,5-diphenyl-1H-pyrazole, 22 (3.44 g) as a white powder. The filtrate is washed with water (2×100 mL), dried over magnesium sulfate and concentrated to give further 3,5-diphenyl-1H-pyrazole, 22 (5.90 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(F)(F)F)c1C
Yield: 89 %

Procedure:
To a solution of 2-methyl-3-trifluoromethyl-benzoic acid (Apollo, 1 g, 4.90 mmol) in methanol (20 mL) was added concentrated sulfuric acid (0.5 mL) and the resulting mixture was heated to reflux overnight. The cooled reaction mixture was concentrated and diluted with water (25 mL) and a saturated sodium bicarbonate solution (25 mL). The mixture was extracted with ethyl acetate (50 mL), the organic phases combined, washed with water and dried over magnesium sulfate. The mixture was filtered and evaporated to give 2-methyl-3-trifluoromethyl-benzoic acid methyl ester (0.95 g, 4.35 mmol, 89%); 1H NMR (300 MHz, CDCl3) δ ppm 2.65 (s, 3H), 3.94 (s, 3H), 7.35 (t, J=7.85 Hz, 1H), 7.72-8.01 (m, 2H).