Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[SiH:11]([CH3:13])[CH3:12])C=C.[C:14]([Li])([CH3:17])(C)[CH3:15].CN(C=[O:23])C.[NH4+].[Cl-]>C1COCC1>[CH2:15]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]=[O:23])=[C:5]([SiH:11]([CH3:12])[CH3:13])[CH:6]=1)[CH:14]=[CH2:17]
Reactant: [Li]C(C)(C)C
Reactant: C=CCc1ccc(Br)cc1[SiH](C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1ccc(C=O)c([SiH](C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 1-allyldimethylsilyl-4-bromobenzene (1 Scheme 1, 1.3 g, 5 mmol) in dry THF (70 mL) at −78° C. was added t-butyllithium (3.0 mL, 1.7 M solution in pentane, 5.1 mmol) over a period of 10 min. After 30 min stirring at −78° C., anhydrous DMF (750 μL, 10 mmol) was added dropwise. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (2 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (20 mL) and brine (5 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:15 ethyl acetate/hexanes) to afford a colorless oil (860 mg, 82%); 1H NMR (300 MHz, CDCl3) δ 0.32 (s, 6 H), 1.78 (d, J=8.10 Hz, 2 H), 4.84 (s, 1 H), 4.89 (m, 1 H), 5.76 (m, 1 H), 7.67 (d, J=8.10 Hz, 2 H), 7.85 (d, J=8.10 Hz, 2 H), 10.05 (s, 1 H); 13C NMR (75 MHz, CDCl3) −3.4 (2C), 23.5, 114.2, 128.8 (2C) 133.7, 134.4, (2C), 136.9, 147.6, 192.8; HRMS calcd for C12H16OSi 204.0971, found 204.0972
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.C(OC(C)C)(C)C.[C:30]1([CH2:36][O:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:36]([O:37][C:38](=[O:39])[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:4]([CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:5]=2)[CH:9]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COC(OC)c1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.14 mol), prepared as in Example 65, and diisopropyl ether (0.16 mol) in DCM (1000 mL) was cooled to 10° C., and carbonochloridic acid phenylmethyl ester (also known as benzyl chloroformate) (0.16 mol) was added dropwise, then the reaction mixture was stirred overnight at room temperature and washed with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][N:8]=1.[H-].[Na+].O>CN(C)C=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:9][N:8]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CSCCN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCNCc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
2-methylthioethylamine (3.0 g, 33 mmol) was dissolved in 25 mL of anhydrous dimethylformamide, following which 5.3 g (33 mmol) of 2-chloro-5-chloromethylpyridine, 1.6 g of 60% sodium hydride (net weight, 950 mg; 40 mmol) were added in this order, and stirring at 70° C. was carried out for 90 minutes. The reaction mixture was cooled to 0° C. and the reaction was brought to completion by adding about 30 mL of water a little at a time, after which the reaction mixture was extracted twice with about 50 mL of dichloromethane. The dichloromethane phase was dried over anhydrous magnesium sulfate, concentrated, and subsequently purified by silica gel column chromatography (hexane/ethyl acetate=1:1→ethyl acetate→dichloromethane/methanol=1:19→dichloromethane/methanol=1:10), giving 4.6 g of the target compound (yield, 64%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](OC4C=CC=CC=4)=[O:27])[CH2:22][C@@H:21]3[C:35]([NH:37][O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)=[O:36])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>CN(C=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([NH:1][CH2:2][CH2:3][OH:4])=[O:27])[CH2:22][C@@H:21]3[C:35]([NH:37][O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)=[O:36])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Oc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)NCCO)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
2-Aminoethanol (129 mg) was added to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-phenoxycarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (250 mg) in DMF (2 ml). The reaction mixture was stirred at 80° C. overnight. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with MeOH in CHCl3=2%, then 4%, to give 138 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[N-(2-hydroxyethyl)-aminocarbonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][N:20]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH3:33])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CNc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccc(S(C)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
4-{4-[(4-Methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (Example 138) (0.10 mmol) was dissolved in DMF (2 mL) and NaH (2 eq.) was added in a single portion at room temperature. The reaction was stirred for 30 minutes and methyliodide (10 eq.) was added. After stirring for 3 hours, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (Hexanes/EtOAc 1:1) provided the expected product. 1H NMR (CDCl3): δ 7.73 (2H, m), 6.78 (2H, m), 6.76 (1H, s), 4.70 (2H, s), 4.20 (2H, br), 3.19 (3H, s), 3.12 (1H, m), 3.01 (3H, s), 2.87 (2H, m), 2.07 (2H, m), 1.80 (2H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccco1
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(-c4ccco4)cccc23)n1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]pyrimidin-2-amine (35 mg, 0.089 mmol), 2-furylboronic acid (30 mg, 0.27 mmol), sodium carbonate (155 μL, 2.0 M aqueous, 0.31 mmol), and dichlorobis(triphenylphosphine)palladium(II) (3 mg, 0.004 mmol) was heated at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (4:1 hexanes:ethyl acetate) provided N-butyl-4-[2-(4-fluorophenyl)-7-(2-furyl)pyrazolo[1,5-α]pyridin-3-yl]pyrimidin-2-amine (15 mg, 39%) as a yellow solid. Rf 0.19 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.35 (d, 1H), 8.11–8.07 (m, 2H), 7.73 (m, 2H), 7.63 (s, 1H), 7.57 (d, 1H), 7.43 (t, 1H), 7.16 (t, 2H), 6.66 (m, 1H), 6.41 (d, 1H), 5.17 (m, 1H), 3.50 (q, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 0.99 (t, 3H); MS m/z 428 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CC#N.[Cl-].[Na+].O>[CH3:9][C:7]1[CH:6]=[C:5]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)(=[O:37])=[O:36])=[O:12])[CH:4]=[C:3]([CH3:2])[CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)Nc2cc(C)cc(C)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
(S)—N-(3,5-dimethylphenyl)pyrrolidine-2-carboxamide hydrochloride (18, 3.299 g; 10.7 mmol) is dissolved in MeCN (40 ml) at rt and DIPEA (4.4 g; 34 mmol) is slowly added over 10 minutes followed by the careful addition of commercially available 4-methoxybenzenesulfonyl chloride (19, 2.8 g; 13.6 mmol). The reaction mixture is stirred for 12 h at rt followed by the addition of brine (50 ml) and the extraction of the product with DCM (3×35 ml). The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure to give 3.95 g (95%) of (S)—N-(3,5-dimethylphenyl)-1-((4-methoxyphenyl)sulfonyl)-pyrrolidine-2-carboxamide (Example 26) as amorphous solid. LC-MS: tR=0.83 min; [M+H]+=389.3.
Reaction SMILES: CN1C(=O)CCC1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22](S(C)=O)[C:21]([C:27]([NH2:29])=[O:28])=[CH:20][N:19]=2)=[CH:11][CH:10]=1.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([NH:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([C:27]([NH2:29])=[O:28])=[CH:20][N:19]=2)=[CH:11][CH:10]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)c1nc(NCCc2ccc(O)cc2)ncc1C(N)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(NCCc2ccc(O)cc2)nc1NC1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A 8 ml portion of NMP solution containing 800 mg of 2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-(methylsulfinyl)pyrimidine-5-carboxamide was mixed with 373 mg of cyclohexylamine and 0.87 ml of diisopropylethylamine, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol), and the resulting crude crystals were recrystallized (methanol-ethyl acetate) to obtain 547 mg of 2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-cyclohexylaminopyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[CH2:16]([O:15][C:13]([C:12]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]2[CH:11]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N#Cc1ccnc(N)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ccc(C#N)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-amino-4-cyanopyridine (4.00 g, 33.6 mmol) in THF (100 mL) add ethyl bromopyruvate (6.55 g, 33.6 mmol). Stir the mixture at rt overnight. A light yellow suspension forms. After filtration and washing with THF, dissolve the light yellow solid in EtOH (50 mL) and heat to reflux for 4 h. Concentrate in vacuo to afford the desired product 7-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a solid (6.21 g, 28.9 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.CCOC(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:21](=[O:22])[NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)N=C=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(C(=O)NC(C)(C)C)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Step I (I): To a solution of methyl 2-(5-bromo-1H-indol-3-yl)acetate ( 268 mg, 1.0 mmol) and tert-butyl isocyanate (149 mg, 1.5 mmol) in dichloromethane was added boron trifluoride diethyl etherate dropwise at −5° C. under nitrogen. The mixture was stirred from −5° C. to rt and at rt overnight. 100 mL of EtOAc was added, and the resulting solution was washed with 0.1 N HCl and water. The organic layer was dried over Na2SO4, and the solvents was removed to give 340 mg of the crude methyl 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetate (yield 92.6%). MS (ESI) (M+H)+=369.05. 1H NMR (500 MHz, CDCl3) δ ppm 1.51 (s, 9 H) 3.74 (s, 3 H) 3.86 (s, 2 H) 7.26 (d, J=8.55 Hz, 1 H) 7.35 (dd, J=8.55, 1.83 Hz, 1 H) 7.79 (d, J=1.53 Hz, 1 H) 8.01 (s, 1 H) 9.17 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[CH3:12][NH2:13].CCO>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:13][CH3:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)Cc1cncc(Br)c1
Solvent: CCO
Product: CNC(=O)Cc1cncc(Br)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 103 using (5-bromo-pyridin-3-yl)-acetic acid (ABCR, Karlsruhe, Germany, 1.815 mmol) and 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 7.26 mmol) to give the title compound as an off-white solid. (HPLC: tR 1.74 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:31]([CH3:32])[C:30](=[O:33])[C:14]2[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:16]3[C:21]([C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1.CO>[C:1]([O:5][CH:6]([C:11]1[N:31]([CH3:32])[C:30](=[O:33])[C:14]2[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:16]3[C:21]([C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Temperature: 70 °C
Yield: 30.9 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetate (30 mg, 0.055 mmol) in Tetrahydrofuran (THF) (1 mL) and Methanol (1 mL) was treated with 2M LiOH (1 mL, 2.000 mmol) and then heated at 70° C. for 1 hour. The mixture was cooled to 0° C., treated with HCl (1M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(tert-butoxy)-2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetic acid (9.2 mg, 0.017 mmol, 32% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 13.35 (s, 1H), 7.73-7.66 (m, 1H), 7.50-7.32 (m, 7H), 7.19-7.09 (m, 2H), 6.98-6.89 (m, 1H), 6.49-6.51 (m, 1H), 6.14 (s, 2H), 5.17 (s, 1H), 3.66 (m, 3H), 2.49 (s, 3H), 0.97 (s, 9H); LCMS (m/z) ES+=527 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C:4]1([CH:18]([CH2:26][CH2:27][S:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:19]([O:21]C(C)(C)C)=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:34])[CH2:3][C:4]1([CH:18]([CH2:26][CH2:27][S:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:19]([OH:21])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17]
Reactant: CC(C)CC1(C(CCSc2cccs2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1(C(CCSc2cccs2)C(=O)O)CCN(CCc2ccccc2)C1=O
Yield: 95.6 %

Procedure:
A solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-α-[2-(2-thienylthio)ethyl]-3-pyrrolidineacetate (338 mg, 0.674 mmol), trifluoroacetic acid (3 mL), and CH2Cl2 (3 mL) is stirred at 0° C. for 15 minutes and at room temperature for 1.5 hour. Concentration and aqueous workup (CH2Cl2, MgSO4) gives 287 mg (96%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.2 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (63 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12]>S(=O)(=O)(O)O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][CH2:12][CH2:11][C:13](=[O:14])[CH3:15])=[CH:5][CH:4]=1
Reactant: C=CC(C)=O
Reactant: COc1ccc(CO)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(COCCC(C)=O)cc1
Reaction time: 1 h

Procedure:
Combine 4-methoxybenzyl alcohol (13.8 g, 0.10 mole) with methyl vinyl ketone (8.4 g, 0.12 mole), treat with 5 drops of concentrated sulfuric acid, and stir 1 hour. Dilute with ethyl ether, wash with 1.0 N sodium bicarbonate solution, dry the organic phase over anhydrous sodium sulfate and evaporate in vacuo to obtain the title compound, m.p. 48-9° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1>O1CCOCC1>[Br:16][C:14]1[N:15]=[C:11]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)[S:12][CH:13]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)N1CCNCC1
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2nc(Br)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL round bottom flask, 1-isopropylpiperazine (306 mg, 2.38 mmol) was dissolved in 4 mL dioxane. 2,4-Dibromothiazole (870 mg, 1.5 eq.) was added and the reaction was stirred at room temperature overnight. TLC and LC-MS showed desired product. DIEA (0.83 mL, 2 eq.) was added. The reaction was stirred at room temperature for 4 hours, then heated to 50° C. for 5 hours. Reaction was cooled and extracted using ethyl acetate/brine. The organic layer was concentrated and purified via combiflash to give desired compound. LCMS-ESI+: calc'd for C10H17BrN3S: 290.0 (M+H+); Found: 290.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([NH:12][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:3]([OH:20])[CH2:2][NH:1][CH2:21][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)c1cc(C=O)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (300 mg, 1.07 mmol) in THF was added methyl 3-formyl-5-methoxybenzoate (294 mg, ˜80% purity, 1.07 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (453.7 mg, 2.14 mmol) was then added portionwise in 30 min, finally 5 drops of acetic acid was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (MgSO4). Concentration in vacuo, followed purification with flash chromatography to give the desired product methyl 3-(((2R,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutylamino)methyl)-5-methoxybenzoate as a white solid (390 mg, % yield). 1H NMR (CDCl3): d: 8.583 (s, 1H), 7.447 (s, 1H), 7.298-7.166 (m, 5H), 7.092 (s, 1H), 3.899 (s, 3H), 3.832 (s, 4H), 3.779 (s, 2H), 3.572 (m, 1H), 2.2.946 (m, 1H), 2.777 (m, 1H), 2.711 (m, 2H), 1.330 (s, 9H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+:10].[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1.[C:25]([O:32][CH2:33][CH3:34])(=[O:31])[C:26]([O:28]CC)=O>CC1CCCCC1>[CH2:33]([O:32][C:25]([C:26](=[O:28])[CH:20]([CH3:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:18][CH:17]=1)[O-:22])=[O:31])[CH3:34].[Li+:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCCC1
Product: CCOC(=O)C(=O)C(C)C([O-])c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 118 ml of lithium bis(trimethylsilyl)amide (Lithium Hexamethyldisilazide; 0.9 M in methylcyclohexane) was added dropwise over 15 min, 20 g of 1-(4-Trifluoromethyl-phenyl)-propan-1-one in 51 ml methylcyclohexane at while maintaining the reaction mixture at 15-25° C. After stirring for 2 h, 15 ml of diethyl oxalate were added dropwise over 30 min and the reaction mixture was stirred for 16 h. Then, the precipitated product was collected by filtration and washed with n-heptane. The isolated crude product was used in the next reaction step after drying in vacuo. Yield: 19 g.