Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C(C)=CSC=2)C=1)C(O)=O)=O)C.C([O:49][C:50](=[O:96])[C:51]1[CH:56]=[C:55]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([O:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77][CH3:78])=[O:75])[C:65]=2[CH2:79][CH2:80][C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH:54]=[C:53]([C:86]2[CH:95]=[CH:94][C:89]3[O:90][CH2:91][CH2:92][O:93][C:88]=3[CH:87]=2)[CH:52]=1)(C)(C)C>>[O:90]1[C:89]2[CH:94]=[CH:95][C:86]([C:53]3[CH:52]=[C:51]([CH:56]=[C:55]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][C:64]4[CH:69]=[CH:68][CH:67]=[C:66]([O:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77][CH3:78])=[O:75])[C:65]=4[CH2:79][CH2:80][C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH:54]=3)[C:50]([OH:96])=[O:49])=[CH:87][C:88]=2[O:93][CH2:92][CH2:91]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC

Procedure:
The title compound was prepared by the same method as 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:31])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=4)[CH:17]=[CH:16][C:15]=3[F:32])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[Cl:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.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].O>[Cl:33][C:34]1[N:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:19]=[C:18]([C:20](=[O:31])[NH:21][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)[CH:17]=[CH:16][C:15]=4[F:32])=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:36][CH:35]=1
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(Cl)nc4)ccn23)c1

Procedure:
A mixture comprising 7-bromo-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 3A) 100 mg, 0.199 mmol), 6-chloropyridin-3-ylboronic acid (31.3 mg, 0.199 mmol) and cesium carbonate (259 mg, 0.795 mmol) in DME (631 μL)/water (31.5 μL) was purged with nitrogen and treated with PdCl2(dppf).CH2Cl2 adduct (8.11 mg, 9.93 μmol) The resulting mixture was heated using microwave radiation at 100° C. for 15 mins. The water was removed by pipette and the reaction mixture was diluted with MeOH. Purification of the mixture by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM afforded the title compound;
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15]Cl)([CH3:12])[CH3:11])[CH3:7])=[O:4].[CH2:19]([CH2:21][NH2:22])[OH:20]>C(Cl)Cl>[OH:20][CH2:19][CH2:21][NH:22][CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15][NH:22][CH2:21][CH2:19][OH:20])([CH3:12])[CH3:11])[CH3:7])=[O:4]
Reactant: NCCO
Reactant: CC(C)(CCC(C)(C)OC(=O)CCl)OC(=O)CCl
Solvent: ClCCl
Product: CC(C)(CCC(C)(C)OC(=O)CNCCO)OC(=O)CNCCO
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of compound (61) (0.898 g, 3 mmol) in 5 mL of methylene chloride at 0° C., ethanolamine (40) (2.504 g, 41 mmol) was added drop wise over the course of one hour. The solution was then allowed to warm to 20° C. and stirred for 18 hours. On completion, the reaction was diluted with CH2Cl2 (15 mL) and washed with brine (1×20 mL) and dried. The solvent was evaporated to get clear yellow oil. (0.380 g) 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 12H), 1.79 (s, 4H), 2.68-2.71 (t, J=5.1, 4H), 3.08 (b, 4H), 3.26 (s, 4H), 3.58-3.60 (t, J=5.1, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH2:29][CH2:30][CH3:31].CN1CCCC1=O>[Cl-].[Na+].O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(O)ccc12
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCOc1ccc2c(CCNC(=O)OC(C)(C)C)c[nH]c2c1

Procedure:
Combine N-t-butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine (250 mg, 0.9 mmol), cesium carbonate (295 mg, 0.9 mmol) and 1-iodobutane (200 mg, 1.1 mmol) and N-methylpyrrolidinone (10 mL) and stir at ambient temperature for 2 hours and pour into 75 mL brine. Extract the mixture twice with 25 mL EtOAc. Wash the combined extracts with brine 2×50 mL, dry over MgSO4, and concentrate under vacuum to give an oil. Chromatograph the oil on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a solid: ISMS 333 (M+1); Analysis for C19H28N2O3: calcd: C, 68.65; H, 8.49; N, 8.43. found: C, 68.83; H, 8.18; N, 8.33.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:54][OH:55])[C@@H:21]([OH:53])[C@@H:22]([OH:52])[C@H:23]([OH:51])[C:24]([NH:26][C@H:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:28][C:29]([O:31]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:54][OH:55])[C@@H:21]([OH:53])[C@@H:22]([OH:52])[C@H:23]([OH:51])[C:24]([NH:26][C@H:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Yield: 73.5 %

Procedure:
A solution of diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (1.5 g) in trifluoroacetic acid (100 ml) was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was passed through a column of silica gel, followed by elution with ethyl acetate:methanol (1:1). The effective fractions were combined and concentrated under reduced pressure. Recrystallization from ethyl acetate provided the title compound (0.86 g), which showed the same 1H-NMR with example 13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1Br.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C.C1COCC1>C(#N)C.O.[Cu]I.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[C:11]#[C:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(Br)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(Br)c(C#Cc2ccccc2)n1

Procedure:
A mixture of 5,6-dibromopyridin-2-amine (80 g, 318 mmol), ethynylbenzene (78 ml, 698 mmol), copper(I) iodide (1.51 g, 7.94 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (5.79 g, 7.94 mmol) and triethylamine (110 ml, 794 mmol) is stirred under argon atmosphere in ACN (500 ml) with THF (250 ml) for 21 h at 50° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 82 g (94%). HPLC-MS: M+H=273/275; tR=1.34 min (*Method—1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[Cl:17]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.CO>[Cl:17][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:12][C:13]([F:14])([F:15])[F:16])[C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(O)c(OC(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)c(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Reaction time: 19 h
Yield: 112.4 %

Procedure:
Methyl 4-hydroxy-3-trifluoromethoxybenzoate (2.05 g) was dissolved in chloroform (20 mL) and methanol (3 mL), and N-chlorosuccinimide (1.39 g) and trifluoromethanesulfonic acid (0.05 mL) were added to the solution, and then the mixture was stirred at 50° C. for 19 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.64 g) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[CH:21][C:22]([CH3:23])=[C:17]4[N:16]=[C:15]3[CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=2)=[C:4]([C:29]#[N:30])[CH:3]=1.[OH-].[K+].Cl.C(N(CC)CC)C>CO.[Pd]>[C:29]([C:4]1[CH:3]=[CH:2][N:6]([CH2:7][CH3:8])[C:5]=1[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=1)#[N:30]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2c(C#N)cc(Br)n2CC)cc1
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2c(C#N)ccn2CC)cc1

Procedure:
A mixture of 3-[4-(5-bromo-3-cyano-1-ethyl-2-pyrrolyl)benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine and 3-[4-(4-bromo-3-cyano-1-ethyl-2-pyrrolyl)benzyl]-7-methyl-2-propyl-3H-imiazo[4,5-b]pyridine was dissolved in methanol (15 ml) and hydrogenated with 10% palladium on charcoal (300 mg) and potassium hydroxide (180 mg) at atmospheric pressure at ambient temperature for two hours. Concentrated hydrochloric acid was added until the pH of the solution was adjusted to 1 and then triethylamine was added until the pH was alkaline. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate to give 3-[4-(3-cyano-1-ethyl-2-pyrrolyl)benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(Cl)=CC(Cl)=C(Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=C[C:31]=2[C:36]2[C:41](OC)=[CH:40][CH:39]=[CH:38][C:37]=2OC)CCCCC1.[F-].[K+].CB(O)O>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:38]([CH3:39])=[CH:37][C:36]([CH3:31])=[C:41]([CH3:40])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Yield: 306 %

Procedure:
To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.27 g) described in Preparation Example 173, palladium (II) acetate (851 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (3.11 g), potassium fluoride (17.6 g) and methylboronic acid (9.08 g) was added tetrahydrofuran (190 mL), and the mixture was refluxed for 5.5 hr. After cooling, to the reaction mixture were added ethyl acetate and saturated brine and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (7.08 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH2:14][C:15]([CH3:17])([OH:18])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOc1ccccc1I
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of 2-iodophenol (6 g), 3-hydroxy-3-methylbutyl tosylate (7.4 g) and Cs2CO3 (13.3 g) in DMF (120 mL) was stirred at 0° C. for 2 h and at room temperature for 10 h. The mixture was diluted with EtOAc and washed with 1N HCl, saturated NaHCO3 aq., H2O, and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hexane/EtOAc=7/3) to obtain compound aa28-1 (8.02 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:27][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.5 g (4.7 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 9.4 mL of DMF was added sodium hydride (60% suspension in mineral oil, 244 mg, 6.1 mmol) at 0° C. The reaction was stirred at 0° C. for 20 min and then treated with cyclopropylmethyl bromide (759 μl, 5621 μmol).
Reaction SMILES: F[C:2]1[N:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=2[CH:17]=1)=[O:5].Cl.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[CH:24]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[O:16]=[C:13]1[NH:12][C:11]2[CH:17]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:18]=[CH:19][CH:20]=[N:21][C:2]=3[NH:33][CH2:32][C:31]3[CH:30]=[CH:29][N:28]=[C:27]4[NH:23][CH:24]=[CH:25][C:26]=34)[CH:8]=[CH:9][C:10]=2[S:15][CH2:14]1
Reactant: NCc1ccnc2[nH]ccc12
Reactant: O=C1CSc2ccc(NC(=O)c3cccnc3F)cc2N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: O=C1CSc2ccc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)cc2N1
Temperature: 170 °C

Procedure:
To an oven-dry microwave tube was added 2-fluoro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-nicotinamide (150 mg, 0.5 mmol), C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine hydrochloride salt (220 mg, 1.0 mmol), DIEA (1 mL), and t-BuOH (2 mL). The resulting mixture was sealed off and underwent microwave heating at 170° C. for 20 min. Solvent was removed in vacuo. The crude solid was purified by chromatography on silica gel. Elution with DCM:MeOH mixture (97:3) gave final compound. MS (ES+): 430.6 (M+H). Calc'd. for C22H18N6O2S—430.49.
Reaction SMILES: ClCC1C=CC(C2C=CC(C(F)(F)F)=CC=2)=CC=1.FC(F)(F)C1C=CC(CC2C=CC(CO)=CC=2)=CC=1.S(Cl)(Cl)=O.C[O:43][C:44](=[O:75])[CH2:45][O:46][C:47]1[CH:55]=[CH:54][C:53]([S:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([C:71]([F:74])([F:73])[F:72])=[CH:67][CH:66]=3)=[CH:60][CH:59]=2)=[C:52]2[C:48]=1[CH2:49][CH2:50][CH2:51]2>>[F:73][C:71]([F:72])([F:74])[C:68]1[CH:69]=[CH:70][C:65]([CH2:64][C:61]2[CH:60]=[CH:59][C:58]([CH2:57][S:56][C:53]3[CH:54]=[CH:55][C:47]([O:46][CH2:45][C:44]([OH:75])=[O:43])=[C:48]4[C:52]=3[CH2:51][CH2:50][CH2:49]4)=[CH:63][CH:62]=2)=[CH:66][CH:67]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(Cc3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2
Agent: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Agent: OCc1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Solvent: O=S(Cl)Cl
Product: O=C(O)COc1ccc(SCc2ccc(Cc3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in a similar manner as described for 3B using 40B and thionyl chloride. 400 MHz 1H NMR (DMSO-d6) 7.59 (d, 2H, J=8.4 Hz), 7.40 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 4.67 (s, 2H), 3.99 (s, 2H). Step 4. Preparation of {7-[4-(4-Trifluoromethyl-benzyl)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (Compound 40D)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33])[CH2:6][CH2:5]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (1 g, 4.69 mmol), triethylamine (1.44 mL, 10.3 mmol) and dimethylaminopyridine (0.12 g, 0.94 mmol) in DCM (20 mL) at 0° C. was added TBSCl (1.56 g, 5.16 mmol). The reaction mixture was allowed to reach room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate (20 mL). The phases were separated and the aqueous layer was extracted twice with DCM (2×20 mL). The organics layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica eluting with Et2O and pentane to afford the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27](=[O:35])[C:28]([NH:31]C(=O)O)([CH3:30])[CH3:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C:28]([CH3:30])([CH3:29])[C:27]([N:25]1[CH2:24][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:26]1)=[O:35]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)NC(=O)O)C3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)N)C3)ccc1-2
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of (2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tent-butyl ester (203 mg, 0.36 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred for 1 hour then concentrated in vacuo. The residual solid was triturated with ether, filtered off and air-dried before being dissolved in DCM. The organic solution was washed (aqueous saturated sodium bicarbonate solution, followed by water and then brine), dried (MgSO4) and concentrated in vacuo. The residue was freeze-dried from MeOH/H2O to give 469 as a white solid (116 mg, 71%). LCMS: RT=8.13 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, s), 7.18 (1 H, dd, J=8.24, 1.86 Hz), 7.00 (1 H, d, J=1.82 Hz), 5.82-5.74 (1 H, m), 4.79 (1 H, s), 4.42 (1 H, s), 4.33 (2 H, t, J=5.13 Hz), 4.19 (1 H, s), 3.77-3.70 (2 H, m), 3.39 (2 H, t, J=5.02 Hz), 1.74 (2H, s), 1.50 (6 H, d, J=6.59 Hz), 1.17 (6 H, s)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>CO>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 91 %

Procedure:
By using (−)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 253-254° C. [α]D=−77.4° (c=0.500, methanol) 1H-NMR (CDCl3) δ: 1.03 (3H, s), 1.21 (6H, d, J=7.0 Hz), 1.51 (3H, s), 1.81 (3H, s), 2.18 (6H, s), 2.85 (1H, septet, J=7.0 Hz), 4.13 (1H, s), 6.8-7.4 (7H, m), 7.86-7.93 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: BrCCCc1cccnc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CO
Product: CC1(C)C(=O)N(CCCc2cccnc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 24.7 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 3-(3-bromo-propyl)-pyridine (3.04 g; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 4 days. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1), the pure alkylated acetamide (425 mg; 1.11 mmol) is de-acetylated under reflux conditions in 2-propanol (1.2 ml) and hydrochloric acid (6 N; 3.7 ml). 5-Amino-3,3-dimethyl-6-nitro-1-(3-pyridin-3-yl-propyl)-1,3-dihydro-indol-2-one (319 mg) is obtained by aqueous work-up and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:22])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN2CCC(=O)CC2)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To 4.25 g (21 mmol) of 1-(4-methylbenzyl)-4-piperidinone 124 in 200 mL of anhydrous methanol was added 32.2 g (420 mmol) of ammonium acetate and 25 g of 3A molecular sieves. After stirring 30 min, 5.25 g (84 mmol) of sodium cyanoborohydride was added portionwise. After stirring 16 hours, the mixture was gravity filtered and the methanol evaporated under vacuum. The residue was partitioned between ether and ice/HCl. The acidic aqueous layer was extracted twice with ether, made basic with 50% aqueous NaOH and ice, and extracted with CH2Cl2 to give 2.1 g (48%) of the title amine 125 as a thick oil. GC/MS showed a molecular ion of 204. The product was used as is without further purification.