Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:9][C:8]([C:6]1[C:5]([F:11])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1nc(Cl)ccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1nc(Cl)ccc1F

Procedure:
To a solution of 6-chloro-3-fluoropyridin-2-carboxylic acid (250 mg) in methanol (3 ml), 0.3 ml of concentrated sulfuric acid was added, and the reaction solution was heated to reflux for 2.5 hours. The reaction solution was cooled, and then the solvent was distilled off under reduced pressure. To the residue obtained was added 1N aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]2[CH:16]=[C:17]([F:27])[C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[O:40][CH3:41]>>[Cl:29][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[C:17]([F:27])[C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cc(F)c2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COc1cc(B(O)O)ccc1F
Product: COc1cc(-c2ccc(C(C)C(O)(c3cc(F)c4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 45, step 3) was reacted with 4-fluoro-3-methoxyphenylboronic acid to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=540.3 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[CH:12][CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: CC(C)(CO)Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a solution of 2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropan-1-ol (5.8 g, 15.6 mmol) in THF (23 mL) was added a solution of HCOOK (9.16 g, 10.9 mmol) in water (7.8 mL), followed by a catalytic amount of Pd/C (5%, 53%˜55% water content). The mixture was heated to 45° C. and stirred for 12 hours, and then filtered through a celite pad. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to afford a yellow foam solid. The title compound was purified by a silica gel chromatography (EtOAc/DCM=1/1) to give a light yellow solid (4.0 g, 75%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:58]([NH2:76])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][Cl:23])[C:6]1[CH:5]=[CH:4][C:3]2[N:2]([CH3:1])[C:10]([CH2:11][CH2:12][CH2:13][C:14]([NH:76][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[O:16])=[N:9][C:8]=2[CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 2 °C
Yield: 33.1 %

Procedure:
A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, 60 mL pressure equalizing dropping funnel and nitrogen in/outlet was charged with 10.0 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of N,N-dimethylformamide (DMF). To this stirred yellow solution was added 4.41 mL (3.27 g, 25.3 mmol) of N,N-diisopropylethylamine (DIPEA). An exotherm to 27.1° C. was noted and the solution became a darker yellow. The reaction was cooled to 2.0° C. where a suspension of 6.2 mL (4.59 g, 35.5 mmol) of DIPEA, 7.65 g (25.6 mmol) of octadecyl amine in 0 mL of DMF was added via pipette. Once addition was complete the reaction became very thick and difficult to stir. It was warmed to room temperature and the magnetic stir bar was replaced with an overhead stirrer. The batch was stirred at RT overnight after which time an in process analysis indicated the reaction was complete. The batch was quenched onto 300 mL of DI water and extracted with dichloromethane (2×150 mL). The organic phases were combined, washed with 10% sodium hydrogen phosphate (1×300 mL), 8% aqueous sodium bicarbonate (1×300 mL) and brine (1×300 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (2 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (1 L) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 5.11 g (8.38 mmol, 33%) of the desired product as a white solid with an HPLC purity of 90.9 A %. The major impurity was shown to be the C-16 amide which results from an impurity in the starting amine 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, b, 1H), 7.33 (d, J=8.84 Hz, 1H), 6.91 (d, J=2.22 Hz, 1H), 6.80 (dd, J=2.36, 8.84 Hz), 3.71 (s, 8H), 3.70 (s, 3H), 3.01 (q, J=6.8, 12.68, 2H), 2.79 (t, J=7.44 Hz, 2H), 2.18 (t, J=7.36 Hz, 2H), 1.97 (m, 2H), 1.36 (m, 2H), 1.28 (s, b, 30H), 0.85 (t, J=6.32 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[NH:12][C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[N:12]([CH2:33][CH:32]=[CH2:31])[C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: C=CCBr
Reactant: COC(=O)[C@H](Cc1c(Br)[nH]c2cc(Br)c(OC)c(Br)c12)NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(Br)c(C[C@H](NC(C)=O)C(=O)OC)c2c(Br)c(OC)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 39.8 mg (0.08 mmol) of (S)-(+)-N-acetyl-2,4,6-tribromo-5-methoxytryptophan methyl ester (4) dissolved in 2.5 mL of N,N-dimethylformamide was charged with 36.5 mg (0.26 mmol) of potassium carbonate and subsequently with 0.13 mL (d=1.398, 1.51 mmol) of allyl bromide. The mixture was stirred at room temperature for 30 minutes. The reaction solution was charged with water and subjected to extraction with ethyl acetate. The organic phase was washed with a saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain yellow oil. Purification by column chromatography using silica gel as a carrier and chloroform as an elution solvent was performed to obtain the substance of interest (6) at a yield of 42.4 mg (99%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[C:17]([Cl:30])[CH:16]=2)[NH:7][N:6]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: CN1CCNCC1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Product: CN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Yield: 16 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12) and N-methylpiperazine to give the title compound in 16% yield; NMR Spectrum: 2.10 (s, 3H), 2.28 (br s, 4H), 2.50 (hidden by DMSO, 4H), 2.77 (t, 2H), 4.41 (t, 2H), 5.25 (s, 2H), 7.19 (t, 1H), 7.23 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.48 (m, 1H), 7.57 (d, 1H), 7.89-7.91 (m, 1H), 8.29 (s, 1H), 8.53 (br s, 1H); Mass Spectrum: 512 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>>[N:19]1([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1
Reactant: C1CSCCN1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Product: C(#Cc1cccc(CN2CCSCC2)c1)CCN1CCOCC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and thiomorpholine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13]([NH:14][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1NC1CCCC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
trans-(4-Amino-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (intermediate G, 1.0 g, 4.63 mmol) was dissolved in 90 mL methanol. Acetic acid (1.4 g, 23 mmol) and cyclopentanone (1.18 g, 14 mmol) were added and the reaction mixture was stirred at 45° C. overnight. Sodium cyanoborohydride (612 mg, 9.7 mmol) was added and stirring was continued at 45° C. for 2 h. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→90:10:1) yielded the title compound as a yellow solid (815 mg, 62%), MS: m/e=229.4 [(M-butene)+].
Reaction SMILES: [P:1]([Cl:16])(Cl)([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH:12]([CH3:14])[CH3:13])=[O:2].Cl.[CH2:18]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH3:19].CCN(CC)CC>C(Cl)Cl>[Cl:16][P:1]([NH:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:25])[CH3:24])([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH:12]([CH3:13])[CH3:14])=[O:2]
Reactant: Cc1cc(OP(=O)(Cl)Cl)c(C(C)C)cc1Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cc(C)c(Cl)cc1C(C)C

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.098 M) of 4-chloro-2-isopropyl-5-methylphenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1.35* mixture of diastereoisomers. 31P NMR (300 MHz, CD3OD): δ 8.5 and 8.8*.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:8]=1[C:9]#[N:10].C1CCCCC=1>CCO.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: COCCCNc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COCCCNc1cccc(N)c1C#N
Temperature: 100 °C
Yield: 84.5 %

Procedure:
To a solution of 2-(3-methoxypropylamino)-6-nitrobenzonitrile (Example 258c) (0.58 g, 2.48 mmol) in EtOH (20 mL) was added cyclohexene (1.26 mL, 12.4 mmol). Then 10% Pd/C (1.32 g) was added, and the reaction mixture was refluxed at 100° C. for 20 minutes, cooled to room temperature, filtered through Celite which was washed with EtOH (3×20 mL), and evaporated to give 2-amino-6-(3-methoxypropylamino)benzonitrile (0.43 g, 84%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 1.71-1.77 (m, 2H), 3.10 (q, J=6.8 Hz, J=6.8 Hz, 2H), 3.22 (s, 3H), 3.37 (t, J=3.2 Hz, 2H), 5.55 (t, J=5.2 Hz, NH), 5.63 (s, NH2), 5.79 (d, J=7.6 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H). MS 206 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23]O)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:32][N:2]([CH3:1])[C:3]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CN4CCCC4)no3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (111 mg, 0.25 mmol) by treatment with SOCl2 (3 eq.) and pyrrolidine (10 eq.) as described in Example 45. Obtained as a yellow solid (28 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.C1COCC1.O[Li].O.Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.3 %

Procedure:
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (8 g, 0.02 mol) in MeOH: THF (300 mL; 1:1) was added LiOH.H2O (5.21 g, 0.124 mol) and the mixture was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude compound. The crude material was acidified with HCl (IN), filtered and dried in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (7.0 g, 95%) as a solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:14])[CH:10]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:38])([CH3:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][C:25]=2[O:39]CC2C=CC=CC=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:38][C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH:10]2[C:11]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]2)=[C:25]([OH:39])[CH:26]=1)([CH3:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2(O)CCCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CNCCC2(O)CCCc2ccccc2)c(O)c1

Procedure:
A mixture of 6.17 g. (10.0 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol, 2.0 g. of 10% palladium-on-carbon and 50 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated. The residue is purified via crystallization from ether-pentane to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:40])[CH2:23][CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].Cl>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:27]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:40])[CH2:28][CH2:29]4)(=[O:37])=[O:38])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CCC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC(=O)N1CCc2cc(S(=O)(=O)N3CCN(c4ccc(F)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
1-(4-Fluorophenyl)piperazine (185 mg, 1.0 mmol) and pyridine (1 mL) were dissolved in dichloromethane (60 mL) under argon. The solution was chilled in ice-water bath and XW2-004 1-(4-methoxy-4-oxobutanoyl)indoline-5-sulfonyl chloride (333 mg, 1.0 mmol) was added. The reaction solution was then warmed to room temperature and stirred for 3 hours. After the reaction, water [(50 mL with 37% HCl (1 L)] was added to the solution. The organic layer was separated and washed with water, brine and dried over magnesium sulfate. Removal of dichloromethane afforded light green solid product which was then triturated with methanol (10 mL). The white solid product was filtered off to give methyl 4-(5-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl)indolin-1-yl)-4-oxobutanoate, the methyl ester of XW2-011B, (320 mg, yield 67%); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.3 Hz, 1H), 7.62 (dd, 1H, J=8.3, 2.0 Hz), 7.58 (d, 1H, J=2.0 Hz), 6.95 (t, J=9.0 Hz, 2H), 6.84 (m, 2H), 4.21 (t, J=8.6 Hz, 2H), 3.72 (s, 3H), 3.30 (t, J=8.6 Hz, 2H), 3.15 (s, 8H), 2.77 (s, 4H). The white solid obtained from the above reaction (289 mg, 0.63 mmol) was mixed with methanol (10 mL) and lithium hydroxide (1 mL of a 1.0 M aq. solution) in a 20 mL microwave reaction tube. The tube was capped and irradiated in the microwave reactor (Biotage Initiator I) at 90° C. for 10 minutes. The reaction solution was concentrated under vacuum and the residue was diluted with 20 mL of water treated with NaOH solution (1.0 M) till pH>10. The aqueous solution was extracted with ethyl acetate (2×10 mL). Then the aqueous layer was acidified to pH˜4, extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The resulted solid was washed with dichloromethane to afford XW2-011B (180 mg, 69%) as a light orange solid product. Mp=213-215° C.; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.3 Hz, 1H), 7.58-7.65 (m, 2H), 6.95 (t, J=9.0 Hz, 2H), 6.82 (dd, J=4.5, 4.5 Hz, 2H), 4.20 (t, J=8.6 Hz, 2H), 3.31 (t, J=8.6 Hz, 2H), 3.15 (s, 8H), 2.80 (s, 4H); HPLC 98% (Rt=3.30, 90% methanol in acetonitrile); HRMS (ESI-ve) m/z calculated for C22H23FN3O5S (M−H)−460.13479. found 460.13475.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC[O-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[N:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(-c2n[nH]c3ccccc23)cc1
Agent: CC[O-]
Agent: [Na+]
Product: Cc1ccc(-c2c3ccccc3nn2Cc2ccccc2)cc1
Yield: 5 %

Procedure:
Compound 10 (6.24 g, 0.03 mol), EtONa (4.08 g, 0.06 mol) and benzyl chloride (10.18 g, 0.08 mol) were allowed to react as in the preparation of compound 15 to afford compound 26 (0.45 g, 5%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[C:14]2([CH3:24])[CH3:23])[CH:11]=[N:10][CH:9]=1)(C)(C)C.N1C=CC=CC=1.Cl.[CH2:34]([O:36][NH2:37])[CH3:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(O)C.[NH4+].[Cl-].C(OCC)(=O)C>[CH2:34]([O:36][N:37]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([N:12]2[C:8]([CH2:7][OH:6])=[CH:9][N:10]=[CH:11]2)[C:14]1([CH3:24])[CH3:23])[CH3:35]
Reactant: CCON
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2ccccc2C(=O)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCON=C1c2ccccc2C(n2cncc2CO)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-2,2-dimethyl-indan-1-one (1.07 g, 2.9 mmol), which can be prepared as described in Example 21, in ethanol (30 mL) is added pyridine (4.7 mL, 58 mmol) followed by the HCl salt of O-ethyl-hydroxylamine (850 mg, 8.7 mmol). The reaction is then heated at reflux for 1 hour, at which time it is cooled to room temperature and concentrated to near dryness. The resulting residue is diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is taken directly to the next step, wherein it is dissolved in THF (30 mL) and then treated with a 1N solution of tetrabutylammonium fluoride in THF (5.0 mL, 5.0 mmol). The reaction is permitted to stir for 1 hour, at which time it is diluted with saturated aqueous NH4Cl and ethyl acetate. The layers are separated and the aqueous layer is extracted an additional two times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:20) to furnish 3-(5-hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one O-ethyl-oxime as a mixture of geometric isomers; HRMS: (ESI) m/z 300.1710 [(M+H)+: Calcd for C17H21N3O2: 300.1712]; ˜1:1.25 isomeric mixture. Major: 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (s, 3 H), 1.32 (t, J=7.1 Hz, 3 H), 1.58 (s, 3 H), 4.20 (q, J=7.0 Hz, 2 H), 4.68-4.82 (m, 2 H), 5.59 (s, 1 H), 6.87-7.00 (m, 2 H), 7.17 (d, J=7.3 Hz, 1 H), 7.34-7.52 (m, 2 H), 7.71-7.79 (m, 1 H), Minor: 1H NMR (400 MHz, CDCl3) δ ppm 0.92 (s, 3 H), 1.38 (t, J=7.1 Hz, 3 H), 1.44 (s, 3 H), 4.27 (q, J=7.1 Hz, 2 H), 4.69-4.82 (m, 2 H), 5.60 (s, 1 H), 6.88-7.01 (m, 2 H), 7.28-7.30 (m, 1 H), 7.34-7.50 (m, 2 H), 8.37-8.45 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CN(C=O)C.CCOC(C)=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>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To compound of Step A (161.0 g, 561.8 mmol) in DMF (800 mL) is added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g, 1685.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.9 g, 11.2 mmol). The mixture is heated at 80° C. for about 32 hours. The mixture is cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueous sodium bisulfate. The aqueous portion is extracted three times with EtOAc and the combined organics are dried (Na2SO4) and concentrated to dryness. The residue is dissolved in a small amount of DCM and filtered through 7 inch of silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent is concentrated to dryness and recrystallized from EtOAc/hexanes to afford about 116.9 g (71%) of Step B compound.