Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[O:44][CH3:45])[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[O:44][CH3:45])[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(NC2CCCc3cccc(OC)c32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3cccc(OC)c32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.23, 6.78, 5.32, 4.31, 3.71, 2.89-2.77, 2.50-2.35, 1.81-1.65, 1.32, 1.18; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1172.
Reaction SMILES: C(S[C:5]1[NH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:8][N:9]=1)C#C>C(O)C.[Ni]>[N:9]1[N:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][CH:5]=1
Reactant: C#CCSc1nnc(-c2ccncc2)[nH]1
Agent: [Ni]
Solvent: CCO
Product: c1cc(-c2nnc[nH]2)ccn1
Yield: 37 %

Procedure:
A mixture of 4-(5-(prop-2-ynylthio)-4H-1,2,4-triazol-3-yl)pyridine (1.6 g, 7.4 mmol) and Raney Ni in ethanol (30 mL) was stirred at reflux for 8 h. The reaction mixture was then filtered through a Celite pad and the solution was concentrated to obtain the crude compound. The crude product was purified by column chromatography to give 4-(4H-1,2,4-triazol-3-yl)pyridine (0.4 g).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>>[OH:30][CH:27]1[CH2:28][CH2:29][N:25]([C:3]([C:4]2[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[CH:8][CH:9]=2)=[O:24])[CH2:26]1
Reactant: OC1CCNC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)C2)cn1
Yield: 87 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using 3-pyrrolidinol instead of 3-amino-1-propanol, to the title compound (122 mg, 87%) which was obtained as a colourless oil. MS: m/e=380.3 [M+H]+.
Reaction SMILES: C(O)C.[CH:4]1([CH2:10][C@@H:11]2[NH:15][C:14](=[O:16])[C:13](C(OCC)=O)=[C:12]2[OH:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(=O)=O>O>[CH:4]1([CH2:10][C@@H:11]2[NH:15][C:14](=[O:16])[CH2:13][C:12]2=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C1=C(O)[C@H](CC2CCCCC2)NC1=O
Agent: O=C=O
Solvent: O
Solvent: CCO
Product: O=C1CC(=O)[C@H](CC2CCCCC2)N1
Yield: 97.4 %

Procedure:
A solution of 1 L of 50% ethanol in water is brought to the boiling point in a large beaker and 68.2 g (0.255 mol) of (S)-5-(cyclohexylmethyl)-2,5-dihydro-4-hydroxy-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester is added over about 5 minutes (pot temperature is 82°-84° C.). The solid goes into solution as carbon dioxide evolves. The ethanol is allowed to boil-off over a period of one-half hour (pot temperature is 87° C.). The volume is about 750 ml, a slight turbidity develops and crystals separate on cooling to afford 48.5 g of (S)-5-(cyclohexylmethyl)-2,4-pyrrolidinedione after recrystallization from ethyl acetate; mp 165°-167° C.; [α]D23 =-75° (c=1.1% chloroform).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[C:39]([O:40][Si](C(C)C)(C(C)C)C(C)C)=[CH:38][CH:37]=[C:36]([Cl:51])[C:21]=1[C:22]([NH:24][C:25]1[C:30]2[O:31][C:32]([CH3:35])=[C:33]([CH3:34])[C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:23]>O1CCCC1>[Cl:19][C:20]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]([Cl:51])[C:21]=1[C:22]([NH:24][C:25]1[C:30]2[O:31][C:32]([CH3:35])=[C:33]([CH3:34])[C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)ccc(O[Si](C(C)C)(C(C)C)C(C)C)c3Cl)cccc2c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1oc2c(NC(=O)c3c(Cl)ccc(O)c3Cl)cccc2c1C
Temperature: 4 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M solution, 0.58 ml) was added to a solution of 7-(2,6-dichloro-3-triisopropylsilyloxybenzoylamino)-2,3-dimethylbenzo[b]furan (221 mg) in tetrahydrofuran (2 ml) at 4° C. The solution was stirred at 4° C. for 1 hour and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diisopropyl ether to give 7-(2,6-dichloro-3-hydroxybenzoylamino)-2,3-dimethylbenzo[b]furan (152 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>>[NH:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2N)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of tert-butyl 4-[2-amino-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylate (176 mg, 0.39 mmol), methylsulfonyl chloride (0.040 mL, 0.47 mmol) and pyridine (0.285 mL, 3.51 mmol) in CH2CL2 (5 mL) was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 aq (3×30 mL). The organic phase was separated, dried (MgSO4) and filtered. The volatiles were evaporated followed by purification of the oily residue by chromatography (SiO2, hexane/EtOAc 4:1) to give 110 mg of tert-butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (yield 58%). 1H NMR (CDCl3) δ 7.90-7.85 (m, 1H), 7.50-7.43 (m, 1H), 7.30-7.24 (m, 2H), 7.20-7.08 (m, 4H), 6.84-6.79 (m, 1H), 3.65-3.51 (m, 4H), 3.12-3.06 (m, 1H), 3.04-2.96 (m, 6H), 2.04-1.91 (m, 2H), 1.49 (s, 3H); MS (posEI-DIP) m/z=524 (M+H+). tert-Butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (0.077 g, 0.147 mmol) was dissolved in MeOH, and ether saturated with HCl gas was added. The mixture was stirred at room temperature for 4 h and then concentrated. The crude solid was dissolved in a small amount of MeOH, and ether was added. The precipitate was collected and dried to give 30 mg of the pure product as the HCl salt (yield 48%): 1H NMR (DMSO-d6) δ 7.72-7.70 (m, 1H), 7.46-7.42 (m, 1H), 7.25-7.20 (m, 3H), 7.14-7.09 (m, 2H), 7.03-6.99 (m, 1H), 3.45-3.15 (m, partly obscured by solvent signal, HDO, 6H), 2.96 (s, 3H), 2.02-1.95 (m, 2H); MS (posES-FIA) m/z=425 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1>>[C:24]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:25]=[CH:26][C:27]([C:30]([O:1][C:2]2[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14]/[N:15]=[C:16](/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)\[CH3:17])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:31])=[CH:28][CH:29]=1
Reactant: CC(=NOCCOc1ccc(C(=O)O)c(O)c1)c1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: C/C(=N\OCCOc1ccc(C(=O)O)c(OC(=O)c2ccc(-c3ccccc3)cc2)c1)c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.076 g, 40%) from 2-hydroxy-4-[2-({[1-phenylethylidene]amino}oxy)ethoxy]benzoic acid and biphenyl-4-carbonyl chloride using a procedure similar to example 8. mp=157.5-159.1° C.; mass spectrum (+EI, M+) m/z 495. 1H NMR (400 MHz, DMSO-d6); δ 12.67 (s, 1H), 8.14 (d, 2H), 7.93 (d, 1H), 7.88 (d, 1H), 7.78 (d, 2H), 7.65 (dd, 2H), 7.52 (dd, 2H), 7.45 (dd, 1H), 7.38 (s, 1H), 7.36 (d, 2H), 7.04 (dd, 1H), 7.02 (s, 1H), 4.47(t, 2H), 4.40 (t, 2H), 2.17 (s, 3H). Elemental analysis: Calcd. for C30H25NO6: C, 70.72H, 5.09; N, 2.83, Found: C, 70.92; H, 4.92; N, 2.76.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1C(=O)C2=CC=CC=C2C1=O.CNN>ClCCl>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][O:8][NH2:9]
Reactant: COCOCCCON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: ClCCl
Product: COCOCCCON
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A solution of N[3-(methoxymethoxy)propoxy]phthalimide (4.5 g, 17 mmol) in dry dichloromethane (50 ml) was cooled to 0°-5° and treated with N-methylhydrazine (1.2 g, 26 mmol). The reaction mixture was stirred for 2 hr then filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with hexane:ethyl acetate (60:40) to give the title compound as a colourless oil (1.1 g, 50%). νmax (Film) 3310, 3240, 3160, 2960, 2910, 1590, 1465, and 1380 cm-1 ; δH (CDCl3) 2.07 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.38 (3H, s, CH3O), 3.50 (2H, t, J=6.3 Hz, CH2OCH2OCH3), 3.70 (2H, t, J 6.3 Hz, CH2ONH2), 4.66 (2H, s, OCH 2 O), 5.2-5.5 (2H, br.s, D2O exchangeable, NH2).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Cl.Cl[CH2:35][C:36]#[C:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][C:36]#[C:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: ClCC#Cc1cccnc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#Cc2cccnc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine (0.67 g), 1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (0.3 g) and potassium carbonate (0.52 g) in N,N-dimethylformamide (5 ml) was stirred for 5 hours at 50° C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine (0.25 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O.CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C@@H:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C@@H:5]3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)[C@H]1CN3CCC(CC3)[C@H]1N2
Temperature: 25 °C

Procedure:
A solution of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (1.2 g, 5.3 mmol; Example 2B) in trifluoroacetic acid (20 mL) was cooled to −30° C. A solution of sodium cyanoborohydride (1.75 g, 26.5 mmol; Aldrich) in methanol (6.5 mL) was added dropwise over a period of 30 minutes. The reaction mixture was allowed to slowly warm to ambient temperature over a period of 30 minutes, then diluted with methanol (60 mL) and concentrated under vacuum. The residue was purified by preparative HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.54-1.75 (m, 1H), 1.89-2.04 (m, 2H), 2.20 (s, 3H), 2.41-2.58 (m, 1H), 2.89-2.99 (m, 2H), 2.99-3.13 (m, 2H), 3.21-3.41 (m, 3H), 3.54-3.63 (m, 1H), 4.12 (dd, J=8.7, 5.0 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.83 (s, 1H); MS (+DCI) m/z 229 (M+H)+.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)=[C:9]([CH:21]2[O:25]CCO2)[CH:8]=1.CON(C)[C:29](=[O:31])[CH3:30]>C1COCC1>[C:29]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18]2)=[C:9]([CH:8]=1)[CH:21]=[O:25])(=[O:31])[CH3:30]
Reactant: CON(C)C(C)=O
Reactant: CC1CN(c2ccc(Br)cc2C2OCCO2)CC(C)O1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CC(C)OC(C)C2)c(C=O)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
t-Butyl lithium in hexanes (3.8 ml of a 1.7 M solution, 14.5 mmol) is added to THF at −78° C. in a flame dried round-bottomed flask. 4-[4-Bromo-2-(1,3-dioxolan-2-yl)phenyl]-2,6-dimethylmorpholine (from Step 2) (1.0 g, 2.9 mmol) is dissolved in THF (5 mL) and is slowly added to the t-BuLi solution over 7 minutes keeping the temperature below −70° C. The mixture is stirred for 30 minutes and N-methoxy-N-methyl-acetamide (0.34 mL, 3.2 mmol) is slowly added dropwise. The reaction is stirred at −78° C. for 30 minutes and then stored at 0° C. overnight. The reaction is quenched with 1 M HCl (22.5 mL) and then heated at 65° C. for 1 hour. The mixture is basified with 1 M aqueous Na2CO3 and extracted with EtOAc (2×). The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. The resulting residue is adsorbed onto silica gel and purified by silica gel chromatography using 15–20% EtOAc in heptane as the eluent to afford 0.35 g (45%) a clear oil. 1H NMR (400 MHz, CDCl3) δ 10.1, 8.35, 8.12, 7.08, 3.93, 3.25, 2.76, 2.60, 1.25.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH3:11])[C:5]1=[O:12].[Li+].[I-]>N1C(C)=CC(C)=CC=1C.CCOC(C)=O>[CH3:1][O:2][CH2:3][C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH3:11])[C:5]1=[O:12]
Reactant: COCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: COCC1(c2cccc(O)c2)CCCCN(C)C1=O

Procedure:
3-Methoxymethyl-3-(3-methoxy-phenyl)-1-methyl-azepan-2-one (as described in Example 6, Step A) (0.391 g, 1.48 mmol) and LiI (0.500 g, 3.73 mol) were heated in collidine (3.5 mL) at 200° C. for 10 h. The reaction mixture was cooled, diluted with EtOAc, washed with 1N HCl (2×), H2O, brine, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]([N:13]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([Br:23])=[C:19]([CH3:22])[CH:20]=2)[CH:15]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14]1)(=[O:12])[CH3:11]>CC(O)=O>[C:10]([N:13]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([Br:23])=[C:19]([CH3:22])[C:20]=2[N+:6]([O-:9])=[O:7])[CH:15]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14]1)(=[O:12])[CH3:11]
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2cc(C)c(Br)c(C)c21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CN(C(C)=O)c2c1c(C)c(Br)c(C)c2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mixture of AcOH (10 ml), conc. sulfuric acid (10 ml) and nitric acid (0.55 ml) was added by portions 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethylindoline (3.0 g) at 0° C., and the mixture was stirred at the same temperature for 5 hr. The reaction mixture was poured into ice water and extracted with CHCl3 (100 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 2.7 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethyl-7-nitroindoline.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][CH:48]([O:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH3:49].[BH3-]C#N.[Na+]>>[CH3:47][CH:48]([O:50][CH2:51][CH2:52][CH2:53][NH:54][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[CH3:49]
Reactant: CC(C)OCCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)OCCCNCc1ccc(B(O)O)s1
Yield: 36.5 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). After purification on an Agilent MDAP twice as shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, the impure title compound was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[OH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([N:20]2[CH2:21][CH2:22][C@@H:18]([OH:17])[CH2:19]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O[C@@H]1CCNC1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O[C@@H]1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 61.3 %

Procedure:
A mixed solution of 3,5-bis(trifluoromethyl)phenyl bromide (22.0 g), (R)-3-hydroxypyrrolidine hydrochloride (9.23 g), palladium(II) acetate (0.84 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.68 g) and cesium carbonate (73.4 g) in toluene (300 mL)-1,4-dioxane (100 mL) was stirred under an argon gas atmosphere at 80° C. for 16 hr. The solid was filtered off, and the filtrate was washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 10:1-3:1) to give the title compound (13.7 g, yield 61%) as a white solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]([S:7]([CH:9]=[CH2:10])=[O:8])=[CH2:6]>O>[OH:2][CH2:1][CH2:3][N:4]1[CH2:10][CH2:9][S:7](=[O:8])[CH2:5][CH2:6]1
Reactant: NCCO
Reactant: C=CS(=O)C=C
Solvent: O
Product: O=S1CCN(CCO)CC1
Yield: 104.2 %

Procedure:
Step 1. To a solution of ethanolamine (0.54 g, 8.82 mmol) in water (20 ml) was added divinylsulfoxide (1.0 g, 9.8 mmol). After the reaction mixture was refluxed for 0.5 h, the mixture was concentrated and dried at 50° C. to afford 4-(2-hydroxyethyl)thiomorpholine 1-oxide (1.50 g, 94%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 2.65 (t, J=5.4 Hz, 2H), 2.75-3.02 (m, 6H), 3.05-3.31 (m, 3H), 3.66 (t, J=5.4 Hz, 2H). Step 2. To a solution of OZ288 (0.50 g, 1.4 mmol), 4-(2-hydroxyethyl)thiomorpholine 1-oxide (0.34 g, 2.1 mmol), triphenylphosphine (0.55 g, 2.1 mmol), and triethylamine (0.29 ml, 2.1 mmol) in dry THF (50 ml) at 0° C. was added dropwise a solution of DIAD (0.43 g, 2.1 mmol) in THF (10 ml). After stirring at rt overnight, the solvent was removed under vacuum. The residue was dissolved in EtOAc (50 ml), washed with water (3×50 ml), dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 50% EtOH in EtOAc) to afford OZ464 free base (0.51 g, 73%) as a colorless solid. To a solution of OZ464 free base (0.51 g, 1.0 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.14 g, 1.4 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ464 (0.51 g, 85%) as a colorless solid. mp 139-141° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.45-1.98 (m, 22H), 2.37 (s, 3H), 2.53-2.64 (m, 1H), 3.08-3.26 (m, 4H), 3.41-3.92 (m, 6H), 4.36 (brs, 2H), 6.95 (J=8.8 Hz, 2H), 7.17 (J=8.3 Hz, 2H), 10.06 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 26.00, 26.41, 31.47, 34.26, 34.44, 35.97, 36.27, 39.90, 40.90, 42.09, 42.46, 55.80, 62.12, 108.29, 110.72, 114.89, 127.72, 139.13, 155.99. Anal. Calcd for C29H43NO8S2: C, 58.27; H, 7.25; N, 2.34. Found: C, 58.46; H, 7.14; N, 2.36.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:19][CH2:20][CH:21]1[O:23][CH2:22]1.[OH-].[NH4+]>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:20][CH:21]1[CH2:22][O:23][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:17]1
Reactant: COC(=O)c1ccccc1C(=O)c1ccccc1
Reactant: ClCC1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1
Reaction time: 0.33 h

Procedure:
To a solution of 33 g (0.138 mol) of 2-benzoyl benzoic acid methyl ester in 200 ml of dry carbon tetrachloride was added 10.1 ml (0.13 mol) of 1-chloro-3,4-epoxypropane. The reaction was cooled in an ice bath and a solution of 1.5 ml (0.013 mol) of stannic chloride in 10 ml of carbon tetrachloride was added with stirring over a 20 min period. The reaction was allowed to stand over the weekend, and then the same quantities of 1-chloro-2,3-epoxy-propane and stannic chloride were added. After 18 hours the reaction was cooled in an ice bath, and neutralized with concentrated ammonium hydroxide. The precipitate was filtered off and washed with dichloromethane and the combined filtrates were washed with 150 ml of water, dried with sodium sulfate and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of neutral alumina. Elution with 3 l of dichloromethane gave the end product as an oil which was about 95% pure by TLC. Crystallization and recrystallization of a small sample from ether/petrol gave white rods, mp 90°-91° C.