Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1.[C:21]([O:25][C:26]([NH:28][C:29]([NH2:31])=[NH:30])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:31]=[C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[NH:30][CH:15]=3)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(=O)CBr)c2s1
Solvent: CC#N
Product: COC(=O)Nc1nc2c(OC)ccc(-c3c[nH]c(NC(=O)OC(C)(C)C)n3)c2s1
Yield: 17 %

Procedure:
0.25 g of (7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (0.0007 Mol) and 0.33 g of tert-butoxycarbonylguanidine (0.0021 Mol) were heated to reflux in acetonitril (3 ml) for 3 hrs. After evaporation of the solvent the residue was triturated with water (10 ml) and filtered. The filtrate was evaporated and the residue subjected to column chromatography (silicagel, ethyl-acetate/hexanes 1:1) to yield the title compound as a white solid (17%); F.p.: 255-265° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: Cc1cncc(Br)c1
Reactant: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methyl-benzoic acid ethyl ester and 3-bromo-5-methyl-pyridine
Reaction SMILES: Cl[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@@H:30]2[CH2:32][C@H:27]1[CH2:28][NH:29]2)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(CC)CC>CC#N>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]2[CH2:32][CH:27]1[CH2:28][N:29]2[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: ClCc1ccc(Cc2nc3ccccc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-chloromethyl-benzyl)-benzothiazole (1.0 g, 3.7 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.9 g, 4.4 mmol) in CH3CN (36 mL) was added Et3N (0.77 mL, 5.5 mmol) and the resulting solution was stirred at rt for 24 h. The reaction mixture was then concentrated and the crude residue was then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (200 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 10% CH3OH in CH2Cl2) afforded the title compound as clear oil (0.88 g, 55%). MS (ESI): mass calcd. for C25H29N3O2S, 435.59; m/z found, 436.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 8.01 (d, J=8.2 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.37-7.34 (m, 5H), 4.44 (s, 2H), 4.40 (br s, 0.5H), 4.25 (br s, 0.5H), 3.75-3.75 (m, 2H), 3.64-3.44 (m, 2H), 3.17 (t, J=11.3 Hz, 1H), 2.90 (dd, J=25.2, 9.5 Hz, 1H), 2.74 (d, J=9.6 Hz, 0.5H), 2.55 (d, J=9.4 Hz, 0.5H), 1.88-1.86 (br m, 1H), 1.73-1.65 (br m, 1H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine (15.3 mg, 0.035 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.07 mmol, 2 eq.) and triethylamine (0.015 mL, 0.11 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 16 mg (89%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-2.02 (m, 4 H) 2.77 (s, 3 H) 2.98-3.19 (m, 2 H) 3.31 (br. s., 1 H) 3.71 (d, J=10.55 Hz, 1 H) 4.56 (br. s., 1 H) 6.01 (d, J=7.54 Hz, 1 H) 6.97-7.56 (m, 8 H) 8.37 (s, 1 H), [M+H]+ 517.4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>ClCCl.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:10]=2)[C:6]([CH3:14])([CH3:13])[C:7]1=[O:12]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-amino-1,3,3-trimethylindolin-2-one (W. von der Saal et al., J. Med. Chem. 1989, 32(7), 1481-1491; 500 mg, 2.63 mmol) in dry dichloromethane (13 ml) were added triethylamine (798 mg, 1.1 ml, 7.88 mmol) and isonicotinoyl chloride hydrochloride (724 mg, 3.94 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, water and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1 M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as brown solid (661 mg).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[N-:9]=[N+:10]=[N-:11].[Na+].[N-]=[N+]=[N-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O.CN(C)C=O>[N:9]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC[C@H](CCl)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CNC(=O)O1

Procedure:
5-(R)-Chloromethyloxazolidine-2-one (prepared according to [Danielmeier et al. Efficient Pathways to (R)- and (S)-hydroxymethyl-2-oxazolidinone and some derivatives. Tetrahedron: Asymmetry. 1995, vol. 6, pp. 1181-1190] (5 mmol) is reacted with sodium azide (7-10 mmol) in acetone (ca. 40-50 mL) at r.t. for ca. 24 h (until the reaction is completed). Solids are filtered off, and supernatant evaporated under vacuum to afford the product which is immediately used for the next step. Optionally, the synthesis is performed in dry N,N-dimethylformamide under inert atmosphere with sodium azide (5-10 mmol) or tetrabutylammonium azide (5-10 mmol), and the resulting solution of the crude 5-(S)-azidomethyloxazolidine-2-one is employed for the next step without solvent removal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42]O)=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C(Cl)(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=3)[N:9]=[C:10]([CH2:41][CH2:42][N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(CCO)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(CCN3CCN(C)CC3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 0.16 mmol; prepared as in Example 8, Step C), DIEA (0.057 mL, 0.33 mmol), and chloroform (5 mL), cooled in an ice bath under N2 was added methanesulfonyl chloride (0.0189 mL, 0.244 mmol). The reaction was allowed to warm to room temperature slowly as the ice melted. The solution was stirred for 30 minutes at room temperature. A portion of the reaction mixture (1.25 mL) was transferred to a second flask and concentrated in vacuo. To the residue was added 1-methylpiperazine (0.023 mL, 0.20 mmol). The neat reaction mixture was heated to 100° C. for 1 hour. The crude was partitioned between DCM (2 mL) and a 1:1 saturated aqueous NaHCO3/water mixture (2 mL). The phases were separated, and the organic phase was dried (Na2SO4) and loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. Yield: 4 mg, 12%. 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.36 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.26 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 6.18 (d, J=6 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H), 3.29 (m, 2H), 2.93 (m, 2H), 2.5-2.8 (m, 8H), 2.42 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:37][O:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-[7-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.5 mg, 0.0413 mmol) HCl salt, methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol) in DMSO (0.5 mL) was stirred at RT for 1 h. The mixture was diluted with DMSO, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=569.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].CO>N1CCCCC1.C(Cl)Cl>[C:13]([C:15](=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)C(C#N)=Cc1ccc(NC(C)=O)cc1

Procedure:
A mixture of p-acetamidobenzaldehyde (4.08 g, 0.025 m), methyl cyanoacetate (2.50 g, 0.026 m), methanol (75 ml) and piperidine (10 drops) is heated and stirred at reflux for 0.5 hour. The reaction mixture is cooled and the pale yellow solid collected by filtration and dried in air. Recrystallization of the product from 50/50 isopropanol/toluene (by volume) gives 4.5 g of pure UV absorber product by mass spectrum analysis which has an absorption maximum at 346 nm in methylene chloride.
Reaction SMILES: [Cl:1]C1C=CC(C(O)=O)=CN=1.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21](C(F)(F)F)=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21]([Cl:1])=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I

Procedure:
The title product was prepared from 6-chloronicotinic acid in the same manner as in the preparation of (4-iodo-6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:17])([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:16])[NH:14][CH3:15])[CH2:9][CH2:8]1)[C:3]([OH:5])=O.[NH2:18][CH2:19][C:20]([N:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][O:32][C:33]2[C:41]3[N:40]=[C:39]([O:42][CH3:43])[N:38]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:37]=3[CH:36]=[CH:35][CH:34]=2)[C:25]=1[Cl:51])[CH3:23])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:51][C:25]1[C:26]([CH2:31][O:32][C:33]2[C:41]3[N:40]=[C:39]([O:42][CH3:43])[N:38]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:37]=3[CH:36]=[CH:35][CH:34]=2)=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[N:22]([CH3:23])[C:20](=[O:21])[CH2:19][NH:18][C:3](=[O:5])[C:2]([F:1])([F:17])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([NH:14][CH3:15])=[O:16])[CH2:9][CH2:8]1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CNC(=O)N1CCN(CC(F)(F)C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Agent: F[B-](F)(F)F
Product: CNC(=O)N1CCN(CC(F)(F)C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CC1

Procedure:
2,2-difluoro-3-(4-(methylcarbamoyl)piperazin-1-yl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide are coupling using TBTU as described for compound 1 to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-2,2-difluoro-3-oxopropyl)-N-methylpiperazine-1-carboxamide. LCMS (APCI) 733 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:12]([C:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][C:2]([CH3:1])([CH3:15])[CH2:11][C:10]=2[N:9]=1)=[O:14])([CH3:21])[CH3:20]
Reactant: CC1(C)CCc2ccc(C(=O)O)nc2C1
Reactant: CC(C)(N)CO
Product: CC1(C)CCc2ccc(C(=O)NC(C)(C)CO)nc2C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid (Example 143 d) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, LC-MS (UV peak area/EIC) 99.7%, 277.1910(M+H)+.
Reaction SMILES: Br[C:2]1[CH2:3][CH2:4][CH2:5][O:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH2:3][CH2:4][CH2:5][O:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: BrC1=COCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Clc1ccc(C2=COCCC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
A mixture of 5-bromo-3,4-dihydro-2H-pyran (1.0 g, 6.13 mmol), (4-chlorophenyl)boronic acid (1.05 g, 6.74 mmol), potassium carbonate (2.5 g, 18.4 mmol), Pd(dppf)C12 (449 mg, 0.613 mmol), and ethanol/water (2/2 mL) in toluene (10 mL) was stirred at 100° C. for 12 hours. The mixture was filtered, and the filtrate was evaporated and purified by silica gel chromatography to give the title compound (700 mg, 58.8%) as orange solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.25 (d, 2 H), 7.20 (d, 2 H) 6.90 (s, 1 H), 4.03 (t, 2 H), 2.37 (t, 2 H), 2.02 (m, 2 H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH:31]([CH3:33])[CH3:32]>>[CH:31]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)([CH3:33])[CH3:32]
Reactant: CC(C)Br
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: CC(C)Oc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromo-propane following the procedure of Example 478: MS (ESI) m/z 436.
Reaction SMILES: [OH-].[Na+].O.NN.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[CH3:16])[N:10]=1)(=O)[CH3:7]>C(O)COCCO>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[N:10]=1)[CH3:7]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCc1cccc(CC)n1
Temperature: 120 °C
Yield: 58.3 %

Procedure:
A mixture of NaOH (14.7 g, 0.37 mol), hydrazine monohydrate (15 mL) and 2,6-diacetylpyridine (6 g, 36.8 mmol) suspended in diethylene glycol (27 mL) was cautiously heated to 120° C. for 16 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were washed with 1 N NaOH, dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, J=7.8 Hz, 3H), 2.80 (d, J=7.8 Hz, 2H), 6.97 (d, J=2.0 Hz, 2H), 7.51 (t, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:11].[C:12]1(=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13]1.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([NH:7][C:12]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13]2)=[CH:8][C:9]=1[CH3:10]
Reactant: COc1c(C)cc(N)cc1C
Reactant: CCOC(=O)C=C1CCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(Nc2cc(C)c(OC)c(C)c2)CCC1
Yield: 10.4 %

Procedure:
To a solution of 4-methoxy-3,5-dimethylaniline (5 g) and ethyl 2-cyclobutylideneacetate (10 g) in 6 mL toluene, under nitrogen was added by syringe 1mL HCl (4M in dioxane). After refluxing the solution for 3 days, the mixture was concentrated, water was added, and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude compound was purified by column chromatography (10% ethyl acetate/hexane), giving ethyl 2-(1-(4-methoxy-3,5-dimethylphenylamino)-cyclobutyl)acetate (1 g) as a while solid. 1H-NMR (300 MHz, CDCl3) δ=6.21 (s, 2H), 4.10(q, 2H), 3.67 (s, 3H), 2.90 (s, 2H), 2.33 (m, 2H), 2.19 (m, 8H), 1.95 (m, 2H), 1.24 (t, J =6.9 Hz, 3H) ppm. MS: m/z 293 (100, M+H)+
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=1)[CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Temperature: 120 °C
Reaction time: 6 h

Procedure:
0.771 g (24 mmol) of sodium hydride at 75% by weight in liquid petroleum jelly is added to a solution of 5.03 g (24 mmol) of 5-chloro-3-methoxycarbonyl-1H-indole in 120 cm3 of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere. After the reaction mixture has been stirred for 0.5 hour at a temperature in the region of 40° C., 3.94 g (24 mmol) of 4-chloroquinoline are added. After stirring for 6 hours at a temperature in the region of 120° C., the reaction mixture is cooled to a temperature in the region of 20° C. and then poured into 400 cm3 of water and extracted with 500 cm3 of ethyl acetate. The organic phase is washed three times with 250 cm3 of water, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica gel (eluent: dichloromethane). After the fractions containing the expected product have been concentrated to dryness under reduced pressure, 2.5 g of 5-chloro-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-indole are obtained in the form of a sticky beige-colored solid, which is used in the following step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]#[N:30]>CN(C)C=O>[C:29]([CH2:28][N:12]1[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11]1)#[N:30]
Reactant: N#CCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
To the solution of 55.0 g of 4-diphenylmethoxy-piperidine in 250 ml of dimethylformamide, 32.0 g of anhydrous potassium carbonate are added while stirring, followed by the dropwise addition of the solution of 17.2 g of chloroacetonitrile in 25 ml of dimethylformamide and the suspension is stirred overnight at room temperature. It is concentrated, partitioned between water and diethyl ether, the organic phase washed with saturated aqueous sodium chloride, dried and evaporated. The residue is recrystallized from ethanol, to yield the 1-cyanomethyl-4-diphenylmethoxypiperidine melting at 78°-80°.