Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:26][CH2:25]2.O[Li].O.O.Cl>CCO.C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([OH:34])=[O:33])[CH2:26][CH2:25]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(N5CCOCC5)cc4)oc3C)ccc21
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(N3CCOCC3)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Ethyl [(1S)-5-(2-{5-methyl-2-[4-(4-morpholinyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (0.058 g, 0.12 mmol) was dissolved in EtOH (1 mL), and LiOH.H2O (0.025 g, 0.6 mmol) was added. Water (1 mL) was added, followed by THF was added until the cloudy solution became clear. The resulting mixture was stirred overnight at rt. HCl (2 N) was added to adjust the pH to 2, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried, filtered and evaporated. The residue was purified by preparative HPLC to obtain [(1S)-5-(2-{5-methyl-2-[4-(4-morpholinyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1 H-inden-1-yl]acetic acid (0.038 g, 0.08 mmol) in 70% yield. 1H NMR ((CDCl3) δ 1.8 (m, 1H), 2.4 (m, 3H), 3.0 (t, 2H), 3.3 (m, 4H), 3.5 (m, 1H), 3.9 (m, 4H), 4.2 (t, 2H), 6.7 (m, 1H), 6.8 (s, 1H), 6.9 (d, 2H), 7.1 (d, 1H), 7.9 (d, 2H); MS (ES) 463 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[O:31]1C[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])O.[Na+].C(Cl)(=O)C=C>O>[C:32]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:31])[CH:33]=[CH2:34]
Reactant: C1CCOC1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CC(=O)Oc1ccccc1C=Cc1ccc(N(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
At first, 14.9 g of the 2-hydroxy-4′-(N,N-bis(4-methylphenyl)amino)stilbene, 100 ml of tetrahydrofuran and 21.5 g of a 12% sodium hydrogen carbonate solution were put in a reaction vessel having a stirrer, a thermometer and a dropping funnel. Under a nitrogen gas flow, 5.17 g of acrylic acid chloride was dropped therein over 30 min at 5° C., and the reaction was further performed for 3 hours at the same temperature. The reaction liquid was put in water, and the mixture was subjected to extraction with toluene, condensation and column-refinement with a silica gel to prepare a crude product. The crude product was then recrystallized with ethanol. Thus, 13.5 g of a yellow needle-form crystal 4′-(N,N-bis(4-methylphenyl)amino)stilbene-2-yl acrylate (compound No. 105 listed before) having a boiling point of 104.1 to 105.2° C. was prepared at a yield of 79.8%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].N1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:4]([O:3][CH3:1])=[O:5])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 162 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7E) (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an ice/water bath as methyl chlorofomate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight at room temperature, the reaction mixture was washed twice with a 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 5-10% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 601 (M++1); 1H NMR (coalescing mixture of conformers, CDCl3) δ 0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1-2.3 (bm, 1H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H).
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.CN(C)C=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>O1CCCC1.CN(C)C1C=CN=CC=1>[OH:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:2]2[N:3]=[C:4]3[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]4[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=4)[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:41]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Reactant: OC1CCCNC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(N4CCCC(O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 68.4 %

Procedure:
The 2-hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (1.00 g, 3.19 mmol) obtained in (E) was dissolved in anhydrous tetrahydrofuran (15.0 ml) and anhydrous dimethylformamide (15.0 ml), added with 4-dimethylaminopyridine (585 mg, 4.79 mmol) and p-toluenesulfonyl chloride (730 mg, 3.83 mmol), and then the mixture was stirred at room temperature for 50 minutes. Subsequently, the reaction solution was added with 3-hydroxypiperidine (646 mg, 6.38 mmol) and stirred at room temperature for 16 hours, and then added with 3-hydroxypiperidine (968 mg, 9.57 mmol) and stirred at 60° C. for 1.5 hours. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5→100:10, v/v) to obtain the title compound (865 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]CC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(CCc2ccccc2OCc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CCc1cccc(Cl)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
The whole of this benzyl 2-[2-(3-chlorophenyl)ethyl]phenyl ether was dissolved in 50 ml of methylene chloride, and 17 ml of a 1M solution of boron tribromide in methylene chloride were added to the solution, whilst ice-cooling. The mixture was then allowed to stand at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.80 g (yield 99%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1CCc2cc(N)c(OC)cc2CC1=O
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1=O

Procedure:
The title compound was prepared from 7-Amino-3-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a tan solid (0.060 g, 65%). MP: 222-233° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.16 (d, 1H, J=8.6 Hz), 8.08 (s, 1H), 8.02 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 6.61 (s, 1H), 6.57 (d, 1H, J=2.5 Hz), 6.55-6.51 (m, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.84-3.80 (m, 2H), 3.70-3.64 (m, 2H), 3.48 (q, 2H, J=7.2 Hz), 3.25-3.17 (m, 4H), 3.03-2.97 (m, 2H), 2.65-2.57 (m, 4H), 2.38 (s, 3H), 1.17 (t, 3H, J=7.1 Hz). MS: 566 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C@H:12]([CH3:18])[CH2:13][CH2:14][N:15]=[N+]=[N-])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C@H:12]([CH3:18])[CH2:13][CH2:14][NH2:15])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C[C@H](CCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCN)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzenesulfonamide (0.144 g, 3.59 mmol) in THF (35 mL) was added lithium aluminum hydride (7.16 mL, 1 M in THF) at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to stir at 0° C. for 1 h w and subsequently treated by successive dropwise addition of 0.272 mL of water, 0.272 mL of 15% sodium hydroxide solution, and 0.816 mL of water. The mixture was concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 1.12 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzenesulfonamide as a light brown oil in 97% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([CH:20]1[CH2:22][CH2:21]1)[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:24][C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([NH:32][C@:33]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:35][C@H:34]2[CH:36]=[CH2:37])=[O:31])[CH2:26]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([CH:20]1[CH2:22][CH2:21]1)[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:28]1[CH2:29][C@H:25]([OH:24])[CH2:26][C@H:27]1[C:30]([NH:32][C@:33]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:35][C@H:34]1[CH:36]=[CH2:37])=[O:31])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C1CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN1CCOCC1
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A solution of 2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoic acid (1.47 g, 4.71 mmoL) in 20 mL of DCM was treated sequentially with ethyl 1(R)-[4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate hydrochloride (prepared in example 5) (1.44 g, 4.71 mmoL), N-methyl morpholine (1.80 mL, 16.34 mmoL), and HATU (2.14 g, 5.53 mmoL). The reaction mixture was stirred at rt under N2 for 3 h, and then concentrated in vacuo. The residue was dissolved in water and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 1.55 g (58%) of ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate as a white foam:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].CS([C:18]1[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)(=O)=O.O>CN(C)C=O>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:20]=[N:19][C:18]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[N:23][CH:22]=1
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxypiperidine (6.18 g, 61 mmol), and potassium carbonate (11.0 g, 80 mmol) in N,N dimethylformamide (150 mL) was added 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (12.3 g, 54 mmol) and stirred at room temperature for 18 h. To the reaction mixture was added 300 mL of water and the heterogeneous mixture was stirred for an additional 10 minutes. The white solid was filtered and washed with water to afford the desired product.
Reaction SMILES: C([BH3-])#N.[Na+].C([O:7][C:8](=O)[C:9]([CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][C:20]=1[Cl:34])([CH2:15][CH:16]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.Cl.Cl.[N:38]1[C:42]2[CH2:43][CH2:44][CH:45]([NH2:47])[CH2:46][C:41]=2[NH:40][CH:39]=1.C(O)(=O)C>CO>[CH2:13]([O:12][C:10]([C:9]1([CH2:18][C:19]2[C:20]([Cl:34])=[CH:21][C:22]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][C:24]=2[Cl:25])[CH2:15][CH2:16][N:47]([CH:45]2[CH2:44][CH2:43][C:42]3[N:38]=[CH:39][NH:40][C:41]=3[CH2:46]2)[C:8]1=[O:7])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(CC=O)(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)OCC
Reactant: NC1CCc2nc[nH]c2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN(C2CCc3nc[nH]c3C2)C1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
Add sodium cyanoborohydride (3.6 g, 57.4 mmol) portion wise to a solution of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethyl ester (6.7 g, 14.4 mmol) (Preparation 10) and 4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylamine dihydrochloride salt (6.0 g, 28.7 mmol) (Preparation 1) in 70 ml of Methanol. After 3 h, add 4 ml of acetic acid and warm to 60° C. for 16 h. Most of the Methanol is removed via rotovap. Quench the resulting mixture with saturated bicarbonate and extract with ethyl acetate. Dry extracts over sodium sulfate, concentrate, and purify by normal phase column chromatography (0-10% methanol in ethyl acetate) to afford 3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid ethyl ester as a white solid (3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[C:42](=[O:43])[C:41]4[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:39]3=[O:48])[CH:24]=2)[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2cn(CCCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
The product of step e) (0.034 g, 0.080 mmol), N-(4-bromobutyl)phthalimide (0.028 g, 0.10 mmol) and sodium hydride (95%, 0.0024 g, 0.10 mmol) was dissolved in dry DMF (0.5 ml). After stirring at room temperature for 1.5 hour HPLC shows complete reaction. The reaction was quenched by addition of aqueous acetic acid (1 M, 2 ml) and ethyl acetate (2 ml). The phases were separated and the organic phase washed with water (1×2 ml). Solvent removal followed by chromatographic purification on silica, eluting with heptane—ethyl acetate (20:80), furnished the sub-title product (0.019 g, 38%) as a slightly brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[C:4]=2[N:3]=[N:2]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[CH:23][N:24]([CH3:26])[CH3:25])[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[C:4]=2[N:3]=[N:2]1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1cccc2[nH]nnc12)c1ccc(Cl)cc1Cl
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cccc2[nH]nnc12

Procedure:
2-benzotriazolyl-1-(2,4-dichlorophenyl)ethan-1-one was dissolved in dimethylformamide dimethyl acetal (5 mL) and the solution refluxed for 8 h. Evaporation of the solvent gave 2-benzotriazolyl-1-(2,4-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one as an air sensitive red solid which was used in the next step without further purification.
Reaction SMILES: [N:1]([C@H:4]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][CH:6]([O:7][CH3:8])[C@@H:5]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[N:1]([C@H:4]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][O:14][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][CH:6]([O:7][CH3:8])[C@@H:5]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1O[C@H](CO)[C@@H](O)[C@H](N=[N+]=[N-])[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC1O[C@H](COC(=O)c2ccccc2)[C@@H](O)[C@H](N=[N+]=[N-])[C@H]1OCc1ccccc1
Yield: 78 %

Procedure:
Methyl 3-azido-2-O-benzyl-3-deoxy-D-glucopyranoside (93 mg) was dissolved in 0.84 mL of pyridine. Benzoyl chloride (45 μL) was added to the solution at −20° C. with stirring, and the mixture was stirred at −20° C. for one hr. Water (14 μL) was added thereto, and the mixture was stirred at −20° C. for 30 min. The contents were concentrated to dryness. Chloroform (10 mL) was added thereto, and the mixture was washed three times with 5 mL of a saturated aqueous sodium bicarbonate solution, three times with 5 mL of a 5% aqueous potassium bisulfate solution and three times with 5 mL of water, was dried over a Glauber's salt and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (25 g, hexane:ethyl acetate=3:1) to give the title compound (97 mg, yield 78%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[NH:27][C:28]([CH3:41])=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=5)[N:30]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)=O.ClC(Cl)C.C(O)(=O)C>[CH3:6][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[NH:27][C:28]([CH3:41])=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=5)[N:30]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH2:12][CH2:13]1
Reactant: Cc1[nH]c(-c2ccc3c(ccn3CCCN3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1-c1cccc(C(F)(F)F)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O=CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1[nH]c(-c2ccc3c(ccn3CCCN3CCN(C)CC3)c2)nc1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 4-(3-{5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-indol-1-yl}-propyl)-piperazine-1-carboxylic acid tert-butyl ester (91 mg, 0.16 mmol) in formic acid (2 mL) was added 4 M HCl (0.5 mL). The mixture was stirred for 30 min. The mixture was concentrated and the residue was partitioned between CHCl3 (2×) and 1 M NaOH (5 mL). The combined organic layers were dried and concentrated to give a crude product (52 mg). To a solution of this crude material in dichloroethane (3 mL) was added acetic acid (1 drop) and formaldehyde (37% in water; 0.04 mL, 0.60 mmol) followed by Na(OAc)3BH (127 mg, 0.60 mmol). The resulting mixture was stirred for 2 h before neutralizing with satd. aq. NaHCO3 and extracting with 10% isopropanol in CHCl3 (2×10 mL). The combined organic extracts were dried and concentrated, and purified by FCC to afford 32 mg (42%) of the title compound.
Reaction SMILES: F[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1)=[O:5].Cl.Cl.[N:23]1[C:28]2[NH:29][CH:30]=[CH:31][C:27]=2[C:26]([CH2:32][NH2:33])=[N:25][CH:24]=1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CC(O)(C)C.CCOC(C)=O>[CH3:15][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4]([C:3]3[C:2]([NH:33][CH2:32][C:26]4[C:27]5[CH:31]=[CH:30][NH:29][C:28]=5[N:23]=[CH:24][N:25]=4)=[N:20][CH:19]=[CH:18][CH:17]=3)=[O:5])=[CH:16][C:11]=2[N:12]=1
Reactant: Cc1nc2cc(NC(=O)c3cccnc3F)ccc2s1
Reactant: NCc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(NC(=O)c3cccnc3NCc3ncnc4[nH]ccc34)ccc2s1
Temperature: 100 °C

Procedure:
2-Fluoro-N-(2-methyl-benzothiazol-5-yl)-nicotinamide (109 mg, 0.38 mmol) was dissolved in t-BuOH (1 mL), then added C-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methylamine dihydrochloride (126 mg, 0.57 mmol) and DIEA (132 μL, 0.76 mmol). The reaction was heated at 100° C. for 21 h. The t-BuOH was replaced with NMP (0.5 mL), then additional C-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methylamine dihydrochloride (42 mg, 0.19 mmol) and DIEA (0.15 mL, 0.874 mmol) were added and the mixture was heated at 120° C. for another 21 h. The mixture was diluted with EtOAc. A precipitate formed and was collected by decanting off the EtOAc. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2) to give N-(2-methyl-1,3-benzothiazol-5-yl)-2-((7H-pyrrolo[2,3-d]pyrimidin-4-ylmethyl)amino)-3-pyridinecarboxamide as a light yellow solid. MS m/e 416.1 (M+H)+ Calc'd for C21H17N7OS—415.4.