Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:7]=1.C(O)(=O)C>[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)ccc2C(F)(F)F)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2C(F)(F)F)CC1
Yield: 48.8 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.614 g, 1.70 mmol), platinum oxide (0.200 g, 0.881 mmol), acetic acid (1 mL), and ethyl acetate (15 mL) was hydrogenated using a balloon of H2 for 16 h and filtered. After concentration, the residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate as colorless thick oil (0.302 g, 48%): 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J=1.3 Hz, 1H), 4.26 (br, 2H), 3.04 (m, 1H), 2.80 (m, 2H), 1.80-1.55 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 308 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](=[O:31])[CH:29]=[CH2:30]>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:30][CH2:29][C:28](=[O:31])[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: C=CC(=O)Cc1ccccc1OC
Solvent: CCO
Product: COc1ccccc1CC(=O)CCN1CCN(CC(=O)Nc2c(C)cccc2C)CC1

Procedure:
A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (100 mg, 0.4 mmol) and 1-(2-methoxyphenyl)but-3-en-2-one (100 mg, 0.56 mmol), a compound of formula (12), in ethanol (2 mL) was heated at reflux for 16 hours. Ethanol was removed under reduced pressure and the residue was purified by preparative TLC, using 10% methanol in dichloromethane as mobile phase, to afford N-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-yl}acetamide, a compound of formula (13).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([S:26]([N:8]2[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1nc(-c2ccncc2)nc1-c1ccncc1

Procedure:
To 1.06 g. (0.005 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 100 ml. of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.21 g., 0.005 mole). The reaction mixture is heated at reflux for 1/2 hour, cooled and a solution of benzenesulfonyl chloride (0.88 g., 0.005 mole) is added. The reaction mixture is heated at reflux for 1/2 hour, cooled, filtered and concentrated to a solid. After recrystallization from acetonitrile 0.4 g. of 1-benzenesulfonyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at 210°-212°C. is obtained.
Reaction SMILES: [Li+].[Br-:2].C1(C)C=CC(S(O[CH2:13][CH:14]([F:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)=O)=CC=1>C(#N)C>[F:21][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][Br:2]
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CCCCCCC(F)CBr
Reaction time: 5 h
Yield: 91 %

Procedure:
1.51 g (17.4 raM) of LiBr was charged in a 30 ml-round bottomed flask with two ports with grinding fitting, and the interior atmosphere was sufficiently replaced with nitrogen. Dry acetonitrile in an amount of 40 ml was added thereto, and a solution of 3.50 g (11.60 mM) of 2-fluorooctyl p-toluenesulfonate in 4 ml of dry acetonitrile was further added. Thereafter, the system was subjected to about 5 hours of heat refluxing. At this time, as the temperature was raised, the solution became uniform to immediately precipitate a TSO Li salt. After the reaction, the acetonitrile was distilled off, and 10 ml of water and 10 ml of ether were added for extraction. Further, the mixture was subjected to two times of extraction each with 10 ml of ether, and the ether layer was dried with anhydrous sodium sulfate. After the distilling-off of the solvent, 2-fluorooctyl bromide was obtained through distillation in an amount of 2.24 g (yield: 91%, 87°-88° C./28 mm Hg). [α]D26.4 =-24° (C1, CH2Cl2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)cc1Cl

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-chloro-4-hydroxybenzonitrile.
Reaction SMILES: [N+:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1)[OH:6])([O-])=O>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:8]=1)[OH:6]
Reactant: O=[N+]([O-])C[C@@H](O)c1cccc(OCCCOCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: NC[C@@H](O)c1cccc(OCCCOCc2ccccc2)c1

Procedure:
The (1S)-2-nitro-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol in ethanol solution (8 g in 160 mL) was hydrogenated using a Pd (4%)/Pt(1%)/C catalyst (1.6 g). Upon consumption of the starting material and the hydroxylamine intermediate, the reaction product in ethanol was filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145) (57 mg, 0.26 mmol) was coupled to aniline (64) (50 mg, 0.26 mmol) using Method C to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[CH:23])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:26]([O:25][CH3:24])=[O:35])=[CH:29][CH:30]=2)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C(=O)OC(C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl ester (Intermediate 52, 0.051 g, 0.16 mmol), 4-iodo phenyl acetic acid methyl ester (0.053 g, 0.19 mmol), triethyl amine (3 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.03 g, 0.043 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.014 g, 19%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1>O.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccncc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CC1CCNCC1
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
4-Pyridylacetic acid (7 grams) (40.4 mmoles) was hydrogensted in water (100 ml) using 10% Pd-C at 40 psi at 25° C. for 24 hours. The catalyst was filtered off and washed with water. The aqueous solution was shaken with BioRad AG1X8 resin (OH-- form) (23 ml bed) and after 5 minutes the resin was filtered off and washed with water. The aqueous solution was evaporated to give the title compound (Yield: 5.2 grams, 90%, MH+ 144).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17](I)[CH3:18]>>[CH2:17]([O:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16])[CH3:18]
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: CCI
Product: CCOC(=O)/C=C/c1ccc(OCC)c(OC)c1
Yield: 84.5 %

Procedure:
Following a procedure similar to that described in Preparation 116, but using 5.83 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 5.61 g of ethyl iodide, 5.55 g of the title compound were obtained as a solid material.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[CH2:49][CH2:50]2)[OH:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: COc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 49.2 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of α,α-bis (p-fluorophenyl)-4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(4-methoxyphenoxy) propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 2.3 g (49% yield) of title compound as a white solid, mp 107°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[N:12]=[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[C:14]([C:19]([NH2:21])=[O:20])=[N:15][C:16]=1[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[NH2:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:11]1[N:12]=[C:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[C:14]([C:19]([NH2:21])=[O:20])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Reactant: Nc1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 3-amino-2-fluorophenol (50 mg), 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (162 mg), potassium carbonate (65 mg), and N-methylpyrrolidone (1 mL) was stirred at 100° C. for 2 hours. To the reaction mixture was added water-saturated brine (1:1), followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-amino-2-fluorophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (126 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:11]2[N:12]=[N:13][CH:14]=[CH:15][C:10]=2[CH:9]=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[N:30]=[N:31][C:32]([CH2:35]Cl)=[CH:33][CH:34]=1>>[F:38][C:18]([F:17])([F:37])[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=1[C:29]1[N:30]=[N:31][C:32]([CH2:35][N:13]2[CH:14]=[CH:15][C:10]3=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:16][C:11]3=[N:12]2)=[CH:33][CH:34]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)nn2)c(C(F)(F)F)c1
Reactant: Fc1ccccc1-c1cc2ccnnc2[nH]1
Product: Fc1ccccc1-c1cc2ccn(Cc3ccc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)nn3)nc-2n1
Yield: 17.8 %

Procedure:
Prepared analogously to the method described for 2-[5[(4-methoxy-2-trifluoro-methylphenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-2H-pyrrolo[2,3-c]pyridazine beginning with 6-(2-fluorophenyl)-7H-pyrrolo[2,3-c]pyridazine (50 mg, 0.234 mmol) and 3-(2,4-Bis-trifluoromethylphenyl)-6-chloromethylpyridazine (95 mg, 0.27 mmol) to produce the titled compound (21.6 mg, 18%). 1H-NMR: (d6-DMSO, 400 MHz) δ 8.78 (d, 1H), 8.38 (dt, 1H), 8.21 (d, 2H), 8.02 (d, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.86 (d, 1H), 7.47 (m, 1H), 7.31 (m, 2H), 7.12 (d, 1H), 6.22 (s, 2H). LCMS calculated for C25H14F7N5: 517.11, found 518.15 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[C:27]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH3:30])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]S(C(F)(F)F)(=O)=O)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Br[CH2:50][CH2:51][CH2:52][F:53]>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:50][CH2:51][CH2:52][F:53])[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[C:27]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH3:30])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1
Reactant: FCCCBr
Reactant: C[C@@H]1CN([C@@H](c2cccc(OS(=O)(=O)C(F)(F)F)c2)c2cccc(C(=O)N(C)c3cccc(F)c3)c2)[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)c3cccc(F)c3)c2)[C@@H](C)CN1CCCF
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.2 %

Procedure:
3-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-(trifluoromethylsulfonyloxy)-benzyl)-N-(3-fluorophenyl)-N-methylbenzamide (from Example 5, 0.70 g, 1.2 mmol) was combined with anhydrous sodium carbonate powder (0.65 g, 6.1 mmol), 10 mL anhydrous acetonitrile, sodium iodide (0.03 g, 0.2 mmol), and 1-bromo-3-fluoropropane (0.12 mL, 1.3 mmol). The reaction was stirred for three days at room temperature under nitrogen, and then concentrated under reduced pressure. The residue was suspended in 15 mL ethanol, 10 mL of 10% w/v aqueous NaOH solution was added, and the reaction was stirred 2 hours at room temperature. The ethanol was removed under vacuum and the residue was partitioned between water and dichloromethane. The solution was adjusted to pH 8.5 using 3 N HCl, separated and extracted again with dichloromethane (2×15 mL). The solution was dried (Na2SO4/MgSO4) and concentrated under reduced pressure. The residual oil was purified by chromatography on silica gel (EtOAc+2% NH4OH/CH2Cl2) to give 0.39 g (0.77 mmol) of the desired product as an off-white foam. 1H NMR (600 MHz, d6-DMSO): δ 9.28 (s, 1H), 7.17-7.24 (m, 5H), 7.04-7.07 (m, 2H), 6.97 (dt, J=2.2, 8.4 Hz, 1H), 6.88 (dd, J=1.2, 8.0 Hz, 1H), 6.61 (dd, J=1.8, 8.0 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.4 Hz, 1H), 4.74 (br s, 1H), 4.42 (dt, J=47.5, 6.0 Hz, 2H), 3.30 (s, 3H), 2.70 (dd, J=2.9, 11.0 Hz, 1H), 2.55-2.61 (m, 1H), 2.48-2.52 (m, 1H—partially obscured by DMSO peak), 2.38-2.42 (m, 1H), 2.26 (br d, J˜9.2 Hz, 1H), 2.19-2.24 (m, 1H), 2.00 (dd, J=7.3, 10.8 Hz, 1H), 1.70-1.75 (m, 1H), 1.64-1.70 (m, 2H), 0.95 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2, Hz, 3H). Calculated for C30H35F2N3O2: C, 70.98; H, 6.95; N, 8.28; F, 7.48%. Found: C, 70.78; H, 7.23; N, 8.19; F, 7.24%.
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.F[C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:34]2[C:33]2[CH:35]=[CH:36][C:30]([C:10]([CH3:15])([CH3:11])[CH3:9])=[CH:31][CH:32]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Product: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc(Br)cc2)cc1
Yield: 81 %

Procedure:
The product from Example 42B (5.2 g, 9.35 mmol) was subjected to the conditions described in Example 39D, substituting 4-tert-butylaniline (11.91 mL, 74.8 mmol) for 4-fluoroaniline to provide the title product (3.89 g, 81%) as a mixture of isomers.
Reaction SMILES: [CH3:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=[O:12].[Na+].O>OS(O)(=O)=O>[CH3:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:12]
Reactant: O=N[O-]
Reactant: COc1cccc(N)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cccc(O)c1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 2-methyl-3-(methyloxy)aniline (Intermediate 58, 1.31 g) in H2SO4 (6 M, 100 mL) was added portionwise NaNO2 (794 mg, 11 mmol) at 0° C. The mixture was stirred for another 2 hours at 40° C. and water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (3 times 100 mL) and the combined ethyl acetate phases were dried and evaporated. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1) to afford the title compound as a solid (569 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26]>O1CCOCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 37 g (0.1 mol) of p-nitrophenyl ester of benzyloxycarbonylproline in 360 ml of dioxane there is added a solution of 16 g (0.09 mol) of arginine in 160 ml of water under vigorous stirring. Two hours thereafter the solvent is evaporated and the precipitate is dissolved in 100 ml of dimethylformamide. The solution is stirred at room temperature for 72 hours and poured into 1 liter of ethylacetate. The resulting residue is filtered-off, washed on the filter with ethylacetate and reprecipitated from a mixture ethanol-ethylacetate. The yield of product (I) is 35 g (96%); the product has the following properties: M.p. 190° C., [α]D20 -46.6°; (c 1.0; H2O); Rf =0.53 (A, "Silufol") 0.66 (B, "Eastman"); EHis =0.56 (pH=2.4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:13]([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)=[CH:30][CH:29]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(N(Cc2ccc(CCl)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
A solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.78 g, 7.63 mmol), 4-chloromethylbenzyl alcohol (1.21 g, 7.70 mmol) and triphenylphosphine (3.93 g, 15.4 mmol) in toluene (150 mL) was stirred under ice-cooling. Diethyl azodicarboxylate (40% toluene solution, 6.98 μmL, 15.4 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 72 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane). Hexane-ethyl acetate was added to the obtained residue, and the resultant insoluble material was filtered off. The filtrate was concentrated to give the title compound (3.65 g, yield 95%) as a red oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:41]=1[Cl:42])[NH:38][N:37]=[C:36]2[C:43]([OH:45])=[O:44].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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.CCO>[Cl:42][C:41]1[CH:40]=[C:39]2[C:35]([C:36]([C:43]([OH:45])=[O:44])=[N:37][NH:38]2)=[CH:34][C:33]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: Brc1ccc2c(c1)CCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc4c(c3)CCC4)cc12
Temperature: 130 °C
Yield: 5.5 %

Procedure:
A suspension of 5-bromoindane (100.0 mg, 0.51 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (191 mg, 0.56 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42.0 mg, 0.025 mmol) and potassium acetate (150 mg, 1.50 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To this mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The reaction mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 80.0% H2O/20.0% MeCN linear to 70.0% H2O/30.0% MeCN in 8.5 min, 70.0% H2O/30.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 9.0 to 10.0 min. Flow: 25 mL/min) to afford the title compound (6.2 mg, 6% yield). MS (ES+) 313.1 (M+H)+. Retention time=3.11 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).