Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33].CN(C)C=O>O>[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Reactant: COC(=O)COc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
First, 2.08 g of potassium carbonate was added to a solution of 3.0 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 2.95 g of N-(2,5-difluoro-4-nitrophenyl)acetamide, and 40 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. to 70° C. for 2 hours, cooled to room temperature, and then poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated to give crude crystals. The crude crystals were washed with diisopropyl ether to give 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]acetamide.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=[CH2:3].[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C>ClCCCl.O>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:27][CH2:28][N:29]([S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[CH2:30][CH2:31]2)[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(S(=O)(=O)C3CC3)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B) (60 mg, 0.117 mmol) in DCE (1.2 mL) was added cyclopropanesulfonyl chloride (23.76 μL, 0.233 mmol) followed by diisopropylethylamine (40.6 μL, 0.233 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with saturated NaCl solution (10 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the title compound as a solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51](Br)(Br)([Br:53])[Br:52]>O>[Br:52][C:51]([Br:53])=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCC(CC=C(Br)Br)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0° C., triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added. The reaction was stirred at 0° C. for 10 min, water was added and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, NH4OH) to give 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%). 1H NMR (400 MHz, CDCl3): δ □□8.9 (s, 2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS (M+H)+: m/z=556
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cncnc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
n-Butyl lithium (2.5 M, 1.8 mL, 4.5 mmol) was added dropwise to a solution of 5-bromo-pyrimidine (0.668 g, 4.2 mmol) in THF (10 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added dropwise at −78° C. and the reaction mixture warmed to room temperature over 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10% methanol/ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 306 [M+H]+. R.T.=2.89 min (Analytical Method 3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](C)[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>O>[NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([NH:12][CH2:10][CH3:11])[N:7]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CCN
Solvent: O
Product: CCNc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 3-necked 3-L flask, that was equipped with an overhead stirrer, was added in order 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 100 g, 0.696 mol, 1 equiv.), ethylamine (70% ethylamine in water, Lancaster, 625 mL), 625 mL H2O, and 125 mL TEA (0.889 mol, 1.28 equiv.). The mixture was stirred and heated at reflux for 20 h, during which time the reaction turned homogeneous. The reaction was allowed to cool to room temperature. The volatile ethylamine was removed on a rotary evaporator. A precipitate formed. The aqueous mixture containing the precipitate was allowed to stand at room temperature for 2 h and then filtered. After drying under vacuum, 106 g (100% yield) of 2-amino-6-ethylaminopyrimidine was obtained as a colorless solid. This material was used as such in the following reaction.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5].[OH-].[Na+].C1COCC1.Cl>CO>[CH3:33][C:2]([CH3:1])([CH3:34])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]
Reactant: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)CC(=O)O)cc1)CO2
Yield: 76.4 %

Procedure:
Ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoate (150 mg, 0.32 mmol) obtained in Example 182, 1 N aqueous sodium hydroxide solution (2 mL) and THF (3 mL)-methanol (3 mL) were stirred at room temperature for 16 hours. To the reaction solution was added 1 N hydrochloric acid to make the solution acidic, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 107 mg (yield: 74%) of the title compound. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.N1C=CC=CC=1>CO>[N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][S:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccnc1
Yield: 17.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, pyridine-3-sulfonyl chloride hydrochloride (0.30 g, 1.39 mmol), 8-aminoquinoline (0.20 g, 1.39 mmol) in pyridine (0.56 ml, 6.94 mmol) gave the title compound (70 mg, 18%) after trituration from MeOH.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](Cl)Cl.O1[CH2:21][CH2:20]OCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)([CH3:21])[CH3:13]
Reactant: ClCCl
Reactant: C1COCCO1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)c1ccc(C(C)C)cc1C
Temperature: 100 °C
Yield: 96 %

Procedure:
A dried round bottom flask with stir bar was purged with nitrogen and charged with diisopropyl zinc (25 mL of a 1 M solution in THF, 25 mmol, 2.0 equiv). Methyl 4-bromo-2-methylbenzoate (compound 152.1, 2.86 g, 12.5 mmol, 1.0 equiv) in 1,4-dioxane (25 mL) was added followed by addition of Pd(dppf)2Cl2.DCM (1.02 g, 1.25 mmol, 0.1 equiv) (exothermic upon catalyst addition). The system was purged with additional nitrogen then argon and heated to 100° C. for 4 hours then stirred at room temperature for 12 hours. The mixture was carefully quenched with 1M HCl (ag., 12 mL) (some bubbling) and then diluted with water (100 mL) and ethyl acetate (150 mL) and mixed. The mixture was filtered through celite and washed with water and ethyl acetate (2×25 mL each). The layers were separated and the aqueous was extracted with addition ethyl acetate (50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexanes to 6% ethyl acetate) to obtain the title compound as a colorless oil (2.31 g, 96%). 1H NMR (400 MHz, CDCl3): δ 7.86 (d with fine str, J=8.8 Hz, 1H), 7.12-7.07 (m, 2H), 3.87 (s, 3H), 2.90 (septet, J=6.8 Hz, 1H), 2.59 (s, 3H), 1.25 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH:32]([OH:33])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCC(O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC(O)c3ccccc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-amino-1-phenylethanol (27 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-[(2-hydroxy-2-phenylethyl)aminomethyl]indol-2-yl]isoindolinone.
Reaction SMILES: Br[C:2]1[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:15])=[N:12][O:13][CH:14]=1)=[O:8].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:2]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[C:11]([CH3:15])=[N:12][O:13][CH:14]=1)=[O:8]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(C)c2)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-(3-methyl-4-isoxazolyl)-4-(4-morpholinylmethyl)benzamide (may be prepared as described in Example 21; 89 mg, 0.18 mmol) in 1,2-dimethoxyethane (3 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.4 mg, 0.19 mmol), sodium carbonate (0.35 ml, 0.35 mmol) and Pd(Ph3P)4 (12.23 mg, 10.59 μmol). The mixture was heated at 120° C. in a microwave for 35 minutes, the solvent removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 12 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=O)[CH:12]=2.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:10]3)=[CH:15][CH:14]=2)=[O:20])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Cc1ccc(N)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc3cc(-c4c(Cl)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (150 mg, 490 μmol), 3,4-dimethylaniline (60 mg, 500 μmol), HATU (280 mg, 740 μmol), and triethylamine (137 μL, 99 mg, 980 μmol) in DMF (10 mL) was stirred 18 h at ambient temperature. The solution was decanted into ethyl acetate and extracted once with water and five times with brine, then dried, filtered, and the solvent removed under reduced pressure to leave an oil, which was purified by chromatography using a gradient of 10-50% heptane/ethyl acetate to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (3,4-dimethylphenyl)-amide. 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, broad, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.46 (m, 3H), 7.38 (dd, J=10.4, 2.1 Hz, 1H), 7.31 (m, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.72 (s, 1H), 2.29 (s, 3H), 2.25 (s, 2H). MS (m/z) 409.1 (M+1); retention time=1.68 min (Method 10). High Resolution, MS (M+H): theory, 409.0874; measured 409.0867.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.C([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[OH:9][CH:6]1[CH2:7][CH2:8][CH:3]([N:2]2[C:19](=[O:20])[C:18]3[C:17](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[O:25])[CH2:4][CH2:5]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC1CCC(O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 15.6 h
Yield: 76.1 %

Procedure:
A solution of 4-aminocyclohexanol hydrochloride (2.52 g, 16.6 mmol) in water (20.0 mL) was treated with N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na2CO3 (3.77 g, 35.6 mmol). The reaction was stirred at room temperature for 15.6 hours. The reaction was cooled to 0° C. and quenched with 10% HCl, filtered, and washed with water to give a white solid. The solid was dissolved in ethyl acetate washed with water, brine, dried over MgSO4 and concentrated in vacuo to give 3.10 g (76%) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione as a colorless solid: mp 176.9-177.0° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.82 4.09, 3.74, 3.62, 2.28, 2.04, 1.76, 1.39; 13C NMR (100 MHz, acetone-d6) δ 168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389, 3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088, 1075, 1061, 720 cm−1; HRMS (FAB) calcd for C14H16NO3: 246.1130, found 246.1128; Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39; H, 6.21; N, 5.70.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:40])[CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[NH2:32][CH2:31][CH2:30][C:29]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([S:41]([CH3:44])(=[O:42])=[O:43])[C:12]1[C:13]([CH:21]2[CH2:22][CH2:23]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]=2[C:17]([NH:18][CH3:19])=[O:20])=[O:40]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCNC(=O)CCNC(=O)OC(C)(C)C)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCNC(=O)CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A mixture of compound (ii) (20 mg, 0.029 mmol) and trifluoroacetic acid (50 uL) in DCM (0.5 mL) was stirred at 40° C. for 1 h. After cooling to RT, solid potassium carbonate (50 mg) was added and the mixture was stirred vigorously for 10 min. Water (0.5 mL) was then added and the organic phase was separated. The aqueous phase was extracted with DCM (1 mL) and the combined organics were dried (MgSO4) then concentrated in vacuo. The residue was purified by flash column chromatography eluting with MeOH/DCM (0-20%) to afford Compound (61) as a white solid (5.4 mg, 32%). ESI-MS m/z calculated for [M+H]+: 591.1/593.1; found: 591.1/593.1; 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.69-7.60 (m, 2H), 7.50-7.42 (m, 2H), 7.35 (s, 1H), 7.24 (t, J=4.3 Hz, 1H), 5.95 (brd, J=4.6 Hz, 1H), 3.92-3.68 (m, 2H), 3.46-3.22 (m, 2H), 3.06 (s, 3H), 3.02-2.90 (m, 5H), 2.38 (tt, J=8.4, 5.4 Hz, 1H), 2.31-2.16 (m, 2H), 1.92-1.68 (m, 2H), 1.12-0.96 (m, 3H), 0.67-0.54 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]C)=[O:23])[CH2:17]1.[Li+].[OH-]>CO.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17]1
Reactant: COC(=O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Methyl (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetate a13-1 (500 mg, 0.87 mmol, 1 eq) is dissolved in MeOH/H2O (4 ml/1 ml) and LiOH (47 mg, 1.7 mmol, 2 eq) is added. The reaction mixture is stirred at 30° C. for 1 hour, then quenched with HCl 1M (100 μl). The resulting mixture is diluted with n-butanol (15 ml), and stirred overnight at room temperature. After phase separation the organic layer is dried on Na2SO4, filtered and the filtrate is concentrated under reduced pressure to afford 229 mg of (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetic acid a14-1 as a colorless oil which is used in the next step without any further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.C[C@@H]1CC[C@H](N)CC1.Cl[C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].C(N(C(C)C)CC)(C)C.[Cl:39][C:40]1[CH:49]=[C:48]2[C:43]([C:44]([N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)=[CH:45][CH:46]=[N:47]2)=[CH:42][CH:41]=1>C(Cl)Cl.CO>[Cl:39][C:40]1[CH:49]=[C:48]2[C:43]([C:44]([N:50]3[CH2:55][CH2:54][N:53]([C:18]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]4)=[O:19])[CH2:52][CH2:51]3)=[CH:45][CH:46]=[N:47]2)=[CH:42][CH:41]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[C@H]1CC[C@@H](N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CC[C@H](NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)CC1

Procedure:
As described for example 78, trans-4-methyl-1-cyclohexanamine (170 mg, 1.5 mmol) prepared in a similar manner as for cis-4-methyl-1-cyclohexanamine, 4-nitrophenyl chloroformate (302 mg, 1.5 mmol), diisopropyl(ethyl)amine (258 mg, 2 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (248 mg, 1 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH. 1H NMR (DSMO-d6) δ 0.9 (d, 3H), 1.0–1.2 (m, 3H), 1.23–1.4 (m, 2H), 1.7 (m, 2H), 2.02 (m, 2H), 3.2 (m, 4H), 3.61 (m, 4H), 4.38 (m, 1H), 6.83 (d, 1H), 7.43 (d, 1H), 7.94 (d, 1H), 8.05 (s, 1H), 8.77 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[O:31])[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.[Cl-].[NH4+].C([N:53](C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C>[C:35]([CH2:34][CH2:33][NH:32][C:30]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:31])(=[O:37])[NH2:53]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)NCCC(=O)O)cn2)cc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)NCCC(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a DMF solution (1 ml) of 3-[(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-amino]-propionic acid (40 mg) obtained in Step A, ammonium chloride (6.5 mg), N-ethyldiisopropylamine (53 μl), HOBt (8.3 mg) and WSCI (17.6 mg) were added, followed by stirring at 80° C. for 3 hours. To this, water was added and the resulting solid was filtered, to obtain a crude product of the desired compound (33.5 mg, 84%).