Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:3]=1.[OH-].[Na+:35]>C(O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])[CH:3]=1.[Na+:35]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)OCC)no2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)[O-])no2)cc1Cl
Temperature: 50 °C

Procedure:
To ethyl 3-(3-chloro-5-{5-[3-chloro-4-(propyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanoate (D101) (120 mg, 2.5 mmol) in ethanol (10 ml) was added 2N NaOH (2 ml) and the mixture heated at 50° C. for 30 minutes. Evaporated off the ethanol and filtered off the white solid which had precipitated out of the remaining solution. Mass of title compound obtained on drying was 85 mg. δH (400 MHz, d6-DMSO) 1.03 (3H, t), 1.77-1.86 (2H, m), 2.34 (2H, t), 4.17 (2H, t), 4.35 (2H, t), 7.40 (1H, d), 7.71-7.74 (2H, m), 7.91 (1H, d), 8.15 (1H, dd), 8.20-8.21 (2H, m). MS (ES) C22H1935Cl2N3O4 requires 459; found 460 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Product: O=C(C1CC1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 3.7 g (0.011 mol) of (-)-3-phenoxy-N-methylmorphinan in 50 ml of toluene, 5.8 g of cyclopropane carboxylic acid chloride in 25 ml of toluene was added dropwise at 5°. The mixture was allowed to warm to room temperature and was then refluxed for 15 hours. The solvent was removed in vacuo and the residue partitioned between ether and dilute hydrochloric acid. The ether solution was washed with water and dried. Removal of the solvent in vacuo afforded 4.2 g (99%) of (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan. For analysis, a sample of this compound was distilled, bp 230°-240°/0.05 mmHg, [α]25D-173.45° (c 0.99, MeOH).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20]>C(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc(F)c(F)c1
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (23.88 g, 0.2384 mol) in methylene chloride (150 mL) and pyridine (38.0 mL, 0.470 mol) was added dropwise a solution of 3,4-difluorobenzenesulphonyl chloride (25.0 g, 0.118 mol) in 10 mL of methylene chloride. After stirring for 48 hours the reaction was diluted with more dichloromethane and extracted with 1N HCl. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give 3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide as a white solid. LCMS Rt=1.24 minutes MS m/z 277 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Cl:26][C:27]1[N:32]=[N:31][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:39]([CH:36]3[CH2:37][CH2:38][N:33]([C:30]4[N:31]=[N:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[CH2:34][CH2:35]3)=[O:40])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(c2ccc(Cl)nn2)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ccc(Cl)nn3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-[1-(6-Chloro-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(6-chloro-3-pyridazinyl)-4-piperidinecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 608.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c2nc[nH]c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 7-Methyl-1H-benzimidazole-4-carboxylic Acid (22) (4.944 g, 28.10 mmol) and concentrated H2SO4 (30 mL) is heated to about 60° C. to obtain a solution which is then cooled to about 0° C. To this solution is added KNO3 (3.12 g, 30.9 mmol) portionwise, so as to maintain the internal reaction temperature <10° C. Following complete addition, the cooling source is removed and the reaction mixture is allowed to warm to ambient temperature, whereupon the mixture is stirred for about 1 hour. The reaction mixture is then added to ice water (100 mL) and held at about 0° C. for about 4 hours. The resulting solids are filtered, washed with water, and dried to provide 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) as an off white solid (6.12 g, 98% Yield).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:33]>CO>[NH2:33][CH2:28][C@H:26]([OH:27])[CH2:25][O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:15]2[O:14][N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:31][CH3:32])[N:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=3)[N:16]=2)=[CH:18][C:19]=1[CH2:29][CH3:30]
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H]1CO1
Reactant: N
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CN

Procedure:
A solution of 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg, 220 μmol) in 7 N NH3 in methanol (5 mL) is stirred at 65° C. for 24 h. The mixture is evaporated and dried to give crude (2S)-1-amino-3-{4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (101 mg) as a pale yellow oil; LC-MS**: tR=0.72 min, [M+H]+=453.27.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[NH:13][C:12](=[O:21])[N:11]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]2=[O:27])=[O:6].[BH4-].[Na+].Cl>CO.O>[OH:6][CH:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20])[NH:13][C:12](=[O:21])[N:11]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]2=[O:27])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 94.5 %

Procedure:
A solution of N-[6-(3-methoxy-propionyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (118 mg, 0.288 mmol) in MeOH (3 mL) at r.t. was treated with NaBH4 (77 mg, 2.03 mmol), added portionwise over a period of 3 h. After disappearance of the starting material, the reaction mixture was acidified with 2M aq HCl and diluted with water. The aqueous phase was extracted with EtOAc (2×), the organic phases were combined, washed with brine and dried (Na2SO4) and evaporated. The white powder obtained was purified by MPLC(RP-C18 column (particle size 5-21 μM) with CH3CN/water 1:2. The fractions containing the product were combined, the acetonitrile is distilled off and the residual water phase was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4) and the solvent was removed in vacuo to provide the title compound (112 mg, 94%) as a white powder, mp 180-184° C. 1H-NMR (DMSO-d6, 400 MHz): 11.80 (br s, 1H), 10.35 (br s, 1H), 8.33 (s, 1H), 7.45 (s, 1H), 5.65 (d, J=6 Hz, 1H), 4.98-4.92 (m, 1H), 3.60-3.52 (m, 1H), 3.42-3.35 (m, 1H), 3.20 (s, 3H), 3.15 (s, 3H), 1.86-1.67 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:13]=3)[NH:8][C:7]=2[N:6]=[CH:5][CH:4]=1)#[CH:2].[N:29]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[N+:30]=[N-:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I>[CH3:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:29]2[CH:2]=[C:1]([C:3]3[C:15]4[C:14]5[C:9](=[CH:10][CH:11]=[C:12]([C:16]6[CH:17]=[CH:18][C:19]([N:22]7[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]7)=[CH:20][CH:21]=6)[CH:13]=5)[NH:8][C:7]=4[N:6]=[CH:5][CH:4]=3)[N:31]=[N:30]2)=[CH:38][CH:37]=1
Reactant: C#Cc1ccnc2[nH]c3ccc(-c4ccc(N5CCN(C)CC5)cc4)cc3c12
Reactant: Cc1ccc(CN=[N+]=[N-])cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cn2cc(-c3ccnc4[nH]c5ccc(-c6ccc(N7CCN(C)CC7)cc6)cc5c34)nn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
To a solution of 4-ethynyl-6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole (example 44, 26.1 mg, 0.071 mmol) in 1.4 mL of anhydrous DMF (C=0.05M), was added CuI (2 mg, 0.15 eq) and 185 μL of a 0.5M solution of 1-(azidomethyl)-4-methylbenzene (1.3 eq). Then, diisopropylethylamine (82 μL, 7 eq) was introduced. The reaction mixture was stirred at room temperature for 15 h. The mixture was then hydrolysed with water (30 mL) The aqueous layer was extracted with AcOEt (4×15 mL). The combined organic layers were washed twice with brine, dried over MgSO4, filtered and concentrated under reduced pressure. A light brown solid was obtained in 66% yield (24.2 mg) after trituration of the crude product in MeOH and filtration. 1H NMR (500 MHz, DMSO) δ 11.99 (s, 1H), 9.01-8.92 (m, 2H), 8.47 (s, 1H), 7.70 (dd, J=8.4, 1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.41 (d, J=3.6 Hz, 1H), 7.34 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 5.73 (s, 2H), 3.19 (s, 4H), 2.29 (s, 3H), 2.25 (s, 3H); 13C NMR (126 MHz, DMSO) δ 153.1 (s), 149.5 (s), 145.5 (CH), 144.9 (s), 137.9 (s), 137.3 (s), 132.8 (s), 132.6 (s), 131.6 (s), 131.5 (s), 129.1 (CH), 127.7 (CH), 126.7 (CH), 125.0 (CH), 124.4 (CH), 121.5 (CH), 120.5 (s), 115.5 (CH), 110.9 (CH), 54.4 (2CH2), 52.8 (CH2), 47.9 (2CH2), 45.4 (NCH3), 20.4 (CH3); HRMS calcd for C32H32N7 [M+H]+ 514.2714 found 514.2699.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[F:1][C:2]1[C:3](=[O:9])[N:4]([C:5](=[O:8])[NH2:6])[C:21](=[O:22])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)n1c(=O)c(F)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
10.4 g. (0.08 mole) of 5-fluorouracil was dissolved in 100 ml. of dimethyl sulfoxide, then 14.3 g. (0.12 mole) of phenyl isocyanate was added thereto and stirred at room temperature for 1 hour. The milky reaction mixture was filtered off and a fine precipitate was obtained. The precipitate was suspended in hot ethanol and again filtered. There was obtained 16.2 g. (81.4% yield) of 5-fluoro-1-phenyl carbamoyluracil melting at 280° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([Br:3])[CH:5]=2)[CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Sodium hydride (1.16 g, 29.12 mmol) was added to 6-bromo-2-naphthol (5.00 g, 22.41 mmol) in anhydrous N,N-dimethylformamide (162 mL) at 0° C. After 15 minutes, benzyl bromide (2.40 mL, 3.45 g, 20.18 mmol) was added and the reaction warmed to room temperature over 18 hours. The reaction was diluted with EtOAc (500 mL), saturated aqueous NaHCO3 (200 mL) was added, and the solution was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (3×1 L), saturated aqueous NaCl solution (1 L), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1 Hexanes:CH2Cl2) to give 36 as a colorless amorphous solid (5.71 g, 90%): 1H NMR (CDCl3, 500 MHz) δ 7.94 (d, J=1.9 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.40 (m, 2H), 7.37 (m, 1H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 5.18 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 157.2, 136.8, 133.2, 130.3, 129.9, 129.9, 128.9 (2C), 128.8, 128.7, 128.4, 127.8 (2C), 120.3, 117.4, 107.3, 70.3; IR (film) νmax 1585, 1452, 1256, 1219, 1204, 1165, 1065, 997, 924, 852, 820, 800, 733, 698, 476 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([OH:35])=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([C:33]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:35])[CH:36]=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCOCC4)c3)cn2)cc1
Yield: 87.7 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38.2 mg, 0.0579 mmol) obtained in Step A instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and morpholine (10.1 μl, 0.116 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-morpholin-4-yl-methanone as a yellow liquid (37 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-53) as a yellow powder (22.3 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C1C=CC=CN=1)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][O:16][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of cis(+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate (1.0 eq.), imidazole (1.1 eq.), tert-butyldimethylsilylchloride (1.1 eq.) and dimethylaminopyridine (0.1 eq.) in dichloromethane at a concentration of 0.1 M was stirred for 18 hours at which time the volatiles were removed in vacuo. Direct purification of the crude material by column chromatography (20% ethyl acetate/hexanes) yielded cis(+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-((tert-butyldimethylsilyloxy)methyl)piperidine-1-carboxylate. LCMS (m/z): 379.0 (MH-Boc+); LC Rt=5.95 min.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].CN(C1C=CC=CN=1)C.[C:34](O)([CH3:37])([CH3:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)C>[C:1]([O:24][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
The acid (32) (6.4 g, 0.019 mol) was dissolved in dry, ethanol free, chloroform (120 ml) at room temperature under nitrogen and sequentially treated with dimethylaminopyridine (2.55 g, 0.0209 mol), tert butanol (14.09 g, 0.19 mol), dimethylaminopyridine-trifluoroacetic acid complex (4.94 g, 0.0209 mol) and dicyclohexylcarbodiimide (4.31 g, 0.0209 mol). The resulting solution was stirred at room temperature overnight then filtered, the organic layer washed with 5% acetic acid in water, then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel (50 g). Elution with 10% ether in petrol gave the title compound (33) as white crystals (6.45 g, 86%) mp 44°-45° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)s4)nc23)CC1
Yield: 73.9 %

Procedure:
Beginning with 0.30 gm (1.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.29 gm (1.56 mMol) 5-chloro-2-thiophenecarbonyl chloride, 0.36 gm (75%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C=O)C.O>[F:19][C:10]1[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 60 °C

Procedure:
4-Hydroxypiperidine (658 mg, 6 5 mmol) and 1,2-difluoro-4-(methanesufonyl)benzene (1.98 g, 5.1 mmol) were combined in DMF (5 mL). Sodium carbonate (705 mg, 6.7 mmol) was added and the mixture was heated at 60 ° C. for 18 h. The mixture was cooled to room temperature and then poured into a mixture of water (10 mL) and a saturated sodium chloride solution (10 mL). The mixture was extracted three times with ethyl acetate (15 mL) and the extracts were combined, washed with brine, dried (MgSO4), and concentrated under vacuum to afford 1.46 g of crude 1a, which was used in the subsequent step without purification: LC-MS 274.1 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=2)=[CH:57][CH:56]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=2)=[CH:59][CH:60]=1
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.021 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.019 g of product in 55% yield: LCMS (ESI) m/z 456 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].CO.[Br:12]Br>O>[Br:12][CH2:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)C1CCCCC1
Solvent: O
Solvent: CO
Product: O=C(CBr)C1CCCCC1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Cyclohexyl methyl ketone (0.30 mL, 2.4 mmol) [Alfa Aesar cat#L05501] was dissolved in methanol (3.0 mL, 74 mmol) cooled in an ice bath and bromine (0.38 g, 2.4 mmol) was added drop wise. The mixture was stirred for 2 h and then water (3.0 mL) was added and the reaction mixture was allowed to stir for 4 h. The reaction mixture was extracted with EtOAc:hexane (3:1). The combined organic layer was washed with water saturated potassium carbonate, brine, dried over magnesium sulfate and concentrated to give as 2-bromo-1-cyclohexylethanone as a clear oil (0.49 g, 100%). 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 2H), 2.86-2.55 (m, 1H), 2.24-1.08 (m, 10H).