Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].CO[C:12]1[CH2:17][CH:16]=[C:15]([CH3:18])[CH2:14][CH:13]=1.II>O1CCCC1.ClC1C=CC=CC=1.C(O)(=O)C.CCCCCC.C(OC)(C)(C)C.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: Nc1c(F)cccc1Cl
Reactant: COC1=CCC(C)=CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: II
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of 3.91 g 2-chloro-6-fluoro-aniline in 4 ml of tetrahydrofuran and 35 ml of chlorobenzene is cooled down to −40 to −45° C. At this temperature, 5.09 g of titanium-tetrachloride is added to the solution, followed by the addition of 5.0 g of 1-Methoxy-4-methylcyclohexa-1,4-diene. The reaction mixture is allowed to warm up to approx. −35° C. and stirred for 2 hours at this temperature. A solution of 10.18 g of iodine in 20 ml of tetrahydrofuran and 2.3 ml of acetic acid is then added drop-wise to the reaction mixture and the temperature was allowed to warm up to 0° C. The mixture was stirred for 1 hour at 0° C. and 16 hours at 25° C. Then 3.4 g of iodine is added to the reaction mixture and stirring is continued for additional 24 hours at 25° C. The reaction is finally quenched by pouring the reaction mixture onto a mixture of 250 ml of aeq. Sodium bisulfite (38-40%) and 400 ml of saturated aeq. sodium carbonate. The aqueous phase is extracted with ethyl acetate (1×200 ml and 2×100 ml), the ethyl acetate phases are unified and washed with 100 ml of water. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow viscous liquid. The liquid was dissolved in hexane/t-butyl-methylether and the solution was filtered over silica gel to obtain, after evaporation of the solvent, 4.33 g of crude product. The product can be used directly in the next step. Alternatively, it can be purified e.g. by column chromatography on silica gel with hexane/t-butyl-methylether (9:1) as eluent to yield pure N-(2′-chloro-6′-fluoro-phenyl)-4-methylaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:17])[C:13]([NH2:16])([CH3:15])[CH3:14])=[N:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:17])[C:13]([NH:16][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([F:31])=[CH:33][CH:34]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)N)nc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-Amino-2-methyl-propionylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (249 mg, 0.748 mmol), triethylamine (300 uL. 2.16 mmol) and 4-fluorobenzoyl chloride (135 uL, 1.13 mmol) in dichloromethane (3 mL) was stirred at RT for 2 h and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 456.1 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(COC)OC>[C:31]1([S:37]([N:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.08 h
Yield: 125.9 %

Procedure:
To a stirred solution of 7.0 g (0.02 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole in 50 ml glyme at 0° was added 3.4 g (0.03 mole) of potassium t-butoxide. The mixture was stirred at 0° for five minutes, then a solution of 5.3 g (0.03 mole) of benzenesulfonyl chloride in 50 ml glyme was added dropwise. The mixture was stirred at 0° for one hour, then at room temperature overnight. The mixture was poured onto ice water and the crude solid product was collected and washed with water and hexane to give 12.4 g of tan solid. The product was purified by chromatography on silica gel, eluting with toluene, to give 7.2 g, white crystals, mp 171.5°-172.5° (from methylcyclohexane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([N:14]3C(=O)C4=CC=CC=C4C3=O)[C:10]([CH3:25])=[N:9]2)=[CH:6][CH:7]=1.C(O)C.O.NN>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([NH2:14])[C:10]([CH3:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2ccc(Cl)nn2)c(C)c1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2ccc(Cl)nn2)c(C)c1N

Procedure:
A mixture of 3.54 g (0.01 moles) of 3-chloro-6-(3,5-dimethyl-4-phthalimido-1-pyrazolyl)-pyridazine, 40 ml of ethanol and 1.08 g (0.01 moles) of 98% hydrazine hydrate is heated to reflux for 3 hours and the mixture is poured into 100 ml of water. After cooling the precipitated crystals are filtered, washed with water, triturated with 10 ml of hot ethanol, filtered and dried. Yield: 1.8 g (81%); m.p. 165°-168° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28])=[N+:31]=[N-:32]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)cc(OC)c1OC
Temperature: 45 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
A mixture of 506.1 mg (1.2 mmol) of 7-chloro-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile and 390.0 mg (6.0 mmol) of sodium azide in 10.0 mL of DMSO is heated at 40-50° C. for 5 hours, and then at room temperature for 15 hours. The mixture is poured into ice water and extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. Removal of the solvent yields 493.4 mg (97.7%) of 7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile as a yellow solid which is used in the next reaction without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.Br[C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37]>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CNC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure of Example 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and 2-bromo-2,N-dimethyl-propionamide in cesium carbonate and DMF were reacted at 80° C. to give 464 isolated as a white solid (33 mg, 17%). LCMS: RT=7.62 min, [M+H]+=467. 1H NMR δ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.17 Hz), 8.06 (1H, s), 7.63 (1H, s), 7.16 (1H, dd, J=8.20, 1.82 Hz), 6.96 (1H, s), 5.83-5.73 (1H, m), 4.32 (2H, t, J=5.01 Hz), 3.53 (2H, s), 3.39 (2H, t, J=5.02 Hz), 2.58 (3H, d, J=4.63 Hz), 1.50 (6H, d, J=6.59 Hz), 1.06 (6H, s). 3 Protons obscured by water peak
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 7 h
Yield: 75 %

Procedure:
1-Benzylpiperazine (2.8 ml; 16 mmol) and potassium carbonate (2.3 g; 17 mmol) were added to a solution of 1-chloro-4-nitrobenzene (2.0 g; 13 mmol) in dimethylformamide (0.5 ml), and the mixture was stirred for 7 hours in a bath controlled at 100° C. Water was added to the reaction mixture to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 2.9 g (yield: 76%) of 4-(4-benzyl-1-piperazinyl)-1-nitrobenzene as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.[CH:35]([N:38](CC)[CH:39](C)C)(C)C.Cl.CN(C)CCCN=C=NCC.CNC>CN(C=O)C.C1COCC1>[CH3:35][N:38]([CH3:39])[C:15](=[O:17])[CH2:14][O:13][C:7]1[N:6]=[C:5]2[S:4][C:3]([C:18](=[O:23])[NH:19][CH:20]3[CH2:21][CH2:22]3)=[C:2]([NH2:1])[C:10]2=[C:9]([CH3:11])[C:8]=1[Cl:12]
Reactant: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCC(=O)N(C)C)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.200 g, 0.562 mmol) in a 1:1 mixture of THF:DMF (1.5 ml each) are added 1-hydroxybenzotriazole hydrate (0.099 g, 0.731 mmol), N,N-diisopropylethylamine (0.109 g, 0.843 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.162 g, 0.843 mmol), and dimethylamine (2.0 M in MeOH)(0.85 ml, 1.69 mmol). The resulting solution is stirred at room temperature for 24 hours, then at 50° C. for 24 hours. The reaction is cooled to room temperature and quenched by the addition of water. The mixture is partitioned between water and EtOAc (40 ml each), and the layers are shaken and separated. The aqueous layer is acidified to pH 3 with 1 N HCl and then extracted with EtOAc (40 ml). The combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (100% EtOAc) to give the title compound as a white solid (0.040 g, 19%). Mass (m/z): 383.2 (M++1), 381.2 (M+−1).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:18]=[CH:19][C:12]=12>C1COCC1.CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[C:13]2=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])=[C:12]2[CH:19]=[N:18]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: O=C1NCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1NCC[C@@H]1Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
Sodium hydride (60% in oil) (0.435 g, 10.88 mmol) was added to (S)-3-hydroxypyrrolidin-2-one (CAS no. 34368-52-0) (1 g, 9.89 mmol) in THF (50 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (4.01 g, 15.13 mmol) in DMF (25 mL) was added and the resulting mixture was stirred at r.t. for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4) and evaporated (3.8 g). The crude product was purified by flash silica chromatography, eluting with 0-50% MeOH in ethyl acetate to afford the product (0.810 g, 24.8%). 1H NMR (400 MHz, CDCl3) δ 2.30-2.42 (1H, m), 2.81-2.91 (1H, m), 3.45-3.64 (2H, m), 6.05 (1H, t), 6.44 (1H, s), 7.42-7.51 (2H, m), 7.51-7.56 (1H, m), 7.57-7.66 (1H, m), 8.33 (1H, s), 8.60 (1H, s); m/z (ES+) (M+H)+=330.27; HPLC tR=1.61 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([C:4]4[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: COc1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 8 h
Yield: 32 %

Procedure:
3-(Methyloxy)-2-pyridinecarboxylic acid (available from Milestone Pharm Tech, 123 mg, 0.81 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (306 mg, 0.81 mmol) and DIPEA (0.422 ml) were stirred in DMF (2 ml) for 30 mins under nitrogen. Then 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.40 mmol) was added and the reaction was stirred overnight. The reaction was loaded onto an aminopropyl column and left for 3 h, before eluting with 10% MeOH in DCM. Appropriate fractions were combined and evaporated under vacuum. The residue was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (49 mg).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]1>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][NH:38][CH2:37][CH:34]4[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:27]([F:30])([F:28])[F:29])=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: NCC1CCNCC1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CNCC2CCNCC2)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and C-piperidin-4-yl-methylamine according to the procedure of Example 66. MS (ESI) m/z 504.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]Cl>ClC1C=CC=CC=1Cl>[F:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([N:8]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2c(N)cccc2F)CC(C)(C)C1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2c(F)cccc2N2CCNCC2)CC(C)(C)C1
Temperature: 200 °C
Yield: 26.8 %

Procedure:
To a solution of 3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (623 mg, 2.52 mmol) produced in Example (97c) in 1,2-dichlorobenzene (7 mL) was added bis(2-chloroethyl)amine hydrochloride (560 mg, 3.14 mmol), followed by reflux for 5 hours at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was circulated into the reactor several times to remove the hydrogen chloride gas. After cooling the reaction mixture to room temperature, ethyl acetate, tetrahydrofuran, methanol, saturated aqueous solution of sodium carbonate and water were added for partition between oil and water. The aqueous layer was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 214 mg of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(OC(=O)[NH:12][CH:13]([CH2:16][C:17]#[N:18])[CH2:14][CH3:15])(C)(C)C>O1CCCC1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH2:12][C@H:13]([CH2:14][CH3:15])[CH2:16][C:17]#[N:18]
Reactant: CCC(CC#N)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CC[C@@H](N)CC#N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Methane sulfonic acid (71 g) was added to a solution of (1-cyanomethyl-propyl)-carbamic acid tert-butyl ester in tetrahydrofuran (530 mL). The reaction mixture was heated to 40° C. for approximately 30 minutes. The temperature was raised to 45° C. and stirred for approximately one hour. The temperature was raised again to 65° C. and the reaction mixture was stirred for five hours. The mixture was allowed to cool to ambient temperature. The resulting solids were isolated by filtration to afford the title compound (41.53 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.N#N>CN(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.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 59.5 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (5.00 g, 11.1 mmol), TMS-acetylene (7.90 mL, 55.5 mmol) and triethylamine (4.64 mL, 33.3 mmol) in DMF (56 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (1.28 g, 1.11 mmol) and CuI (106 mg, 0.56 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) to afford (2-methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol, 59% yield). LCMS-ESI+: calc'd for C25H35N4O3Si: 467.3 (M+H+). Found: 467.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:12]=[C:11]([F:28])[C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C(O)C>[F:28][C:11]1[CH:12]=[C:13]([S:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH:14]=[C:2]([F:1])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1c(F)cc(SCCNS(=O)(=O)c2ccccc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1c(F)cc(SCCNS(=O)(=O)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 2,6-difluoro-4-[2-(phenylsulfonylamino)ethylthio]phenoxyacetate (1.5 g) and ethanol (12 ml) was added 10% sodium hydroxide (3 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was made acidic with 3% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave 2,6-difluoro-4-[2-(phenylsulfonylamino)ethylthio]phenoxyacetic acid (Compound No. 67) (1.3 g).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=O.COC1C=CC(/[CH:39]=[C:40]2/[C:41]([NH:43][C:44]([S:46]/2)=[NH:45])=[O:42])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:45][C:44]1[S:46]/[C:40](=[CH:39]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH:16]([C:17]([F:20])([F:18])[F:19])[C:21]([F:22])([F:23])[F:24])/[C:41](=[O:42])[N:43]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OC(C(F)(F)F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1OC(C(F)(F)F)C(F)(F)F

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-quinoline-3-carbonitrile (example 45b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 447 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[N:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH:14]2[CH:21]3[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[C:3]1=[O:24]>CO.[C].[Pd]>[CH3:1][C:2]1([CH3:25])[N:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH:14]2[CH:21]3[CH2:20][CH:19]4[CH2:18][CH:17]([CH2:16][CH:15]2[CH2:23]4)[CH2:22]3)[C:3]1=[O:24]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1/C=C/c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 5.2 %

Procedure:
A solution of 4,4-dimethyl-1-[(E)-2-phenylethenyl]-2-(adamantan-2-yl)-1,2-diazetidin-3-one (38.4 mg, 0.103 mmol) prepared in Example 265 in methanol (2 mL) was added with 10% palladium carbon (catalyst amount), and the resultant was stirred at room temperature for 40 minutes under a hydrogen atmosphere. The reaction solution was filtered using celite, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (1.80 mg, 5.20%) was obtained as a white crystalline powder.