Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][N:48]=1>ClCCl>[NH2:46][C:47]1[N:48]=[CH:49][C:50]([NH:53][C:10]([C:9]2[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=2[CH3:14])[C:3]([O:2][CH3:1])=[O:4])=[O:12])=[CH:51][CH:52]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)O)c1
Reactant: Nc1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(C(=O)Nc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a round-bottomed flask was charged 5-(methoxycarbonyl)-2-methylbenzoic acid (0.2 g, 1.0 mmol), dicloromethane (3 ml), n,n-diisopropylethylamine (0.7 ml, 4.0 mmol), HOBt (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.24 g, 1.2 mmol), and 2,5-diaminopyridine (0.11 g, 1.0 mmol) in that order. The reaction mixture was stirred at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 mL). The aqueous layer was back extracted with DCM (3×15 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in MeOH and absorbed on silica gel, purified by chromatography through a Redi-Sep 40 g column, eluting with a gradient of 0% to 10% MeOH in CH2Cl2, to provide methyl 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoate as a tan solid. MS (ESI, pos. ion) m/z: 286.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CN(C=O)C>[CH3:11][C:4]1[CH:3]=[CH:2][C:7]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 185.2 %

Procedure:
To a DMF solution (5.0 ml) of 4-bromo-2-methyl-1-nitro-benzene (500 mg), palladium acetate (10.4 mg), S-Phos (38.0 mg) and potassium phosphate (983 mg), phenylboronic acid-pinacol ester (496 mg) was added, and then the mixture was degassed under ultrasonic irradiation. After the mixture was stirred at 100° C. for 18 hours, water (20 ml) was added, followed by extraction with ethyl acetate (20 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane/ethyl acetate=100/1), to obtain the desired compound (457 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24](Br)[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:37][CH2:38]OC.O.B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Compound B (4.0 g), tetrakis(triphenylphosphine)palladium(0) (203 mg, 176 μmol) and 1,2-dimethoxyethane (100 Ml, 1 mol) were combined and stirred under nitrogen at room temperature for 20 minutes. Water (20.6 mL, 1.1 mol), 2,4,6-trivinylcyclotriboroxane pyridine complex (1.1 g, 44.4 mmol) and potassium carbonate (1.3 g, 9.3 mmol) were then added and the mixture was heated at 90° C. for 6-12 hours. The product was purified by flash chromatography in hexanes/EtOAc 0-75%) to yield compound C (3.2 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[Cl-].[NH4+:10].[OH-].[Na+]>CO.O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH2:10])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCc1ccncc1
Temperature: 0 °C
Yield: 29.5 %

Procedure:
4-Vinylpyridine (5.26 ml, 50 mmol) and ammonium chloride (5.35 g, 100 mmol, 2.0 eq) were dissolved in methanol (2.5 ml) and water (15 ml), and the mixture was stirred with reflux for 23 hours. This reaction mixture was poured into ice water, and a 15% aqueous sodium hydroxide solution was added to make the same strong alkaline. The mixture was extracted 3 times with chloroform (50 ml). The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was distilled under reduced pressure to give 2-(4-pyridyl)ethylamine (1) (1.80 g, 30%; 87° C./6 mmHg) as a colorless oil. The residue from the distillation was subjected to column chromatography (chloroform/methanol=30/1-9/1) to give bis[2-(4-pyridyl)ethyl]amine (2) (1.11 g, 20%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH3:31][N:32](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:31]#[N:32])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Nc2nc(Cl)nc3c2c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(Nc2nc(Cl)nc3c2c(C#N)cn3S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A solution of 2-chloro-5-iodo-N-(4-methoxyphenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (257 mg, 0.463 mmol), Pd2 dba3 (25 mg, 0.027 mmol) and dppf (51 mg, 0.092 mmol) in DMF (4 mL) was degassed with argon before being charged with Zn(CN)2 (65 mg, 0.555 mmol). The mixture was stirred at 70° C. for 3 h. DMF was removed in vacuo. The residue was dissolved in CH3CN. Water was added to induce precipitation. The precipitate was collected and dried on vacuum to give 2-chloro-4-(4-methoxyphenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (68 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:6]1[CH2:8][CH2:9][OH:10])=[O:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:6]1[CH2:8][CH2:9][O:10][S:20]([CH3:19])(=[O:22])=[O:21])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCO
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.5 %

Procedure:
1-tert-Butoxycarbonylamino-2-(2-hydroxyethyl)-cyclopropanecarboxylic acid methyl ester (0.500 g, 1.93 mmol, from Example 104) was diluted in 8 mL DCM and cooled to 0° C. under an Ar atmosphere. TEA (0.54 mL, 3.9 mmol) and methanesulfonyl chloride (0.30 mL, 3.9 mmol) were added sequentially. After 2.5 h, the solvent was removed in vacuo and the residue taken up in EtOAc and H2O (15 mL each). The aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, the residue was purified by column chromatography on SiO2 (0 to 50% Hex/EA) to produce 1-tert-butoxycarbonylamino-2-(2-methanesulfonyloxyethyl)cyclopropanecarboxylic acid methyl ester (0.55 g, 84%). LCMS found 360.1 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](OC)=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.[OH:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:33][CH2:32][CH2:31][OH:30])=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.18 (d, 1H, J=1.8 Hz), 7.80 (bs, 1H), 7.60 (m, 1H), 7.34–7.16 (m, 3H), 7.10 9t, 1H, 8.4 Hz), 6.85 (bdd, 1H), 6.62 (dd, 1H, J=1.5 and 8.1 Hz), 3.70 (t, 2H, J=4.8 Hz), 3.52 (t, 2H, J=4.0 Hz); LCMS: ret. time: 14.49 min.; purity: 97%; MS (m/e): 424 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 70A. mp 170-172° C.; IR (KBr) cm−1: 3054, 25.77, 1731, 1710, 1471, 1234; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.39 (s, 4H), 6.99-7.25 (m, 3H), 6.79-6.97 (m, 2H), 6.56 (d, 1H, J=8.4 Hz), 5.01 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 2.74 (t, 2H, J=7.4 Hz), 2.66 (t, 2H, J=7.4 Hz), 1.88 (pentet, 2H); MS m/z 453 (M−1). Anal. Calc'd for C25H23ClO4S: C, 66.00; H, 5.10. found: C, 65.95; H, 4.97.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[NH:30][C:29]([C:31]5[CH:36]=[N:35][CH:34]=[CH:33][N:32]=5)=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].CO.[CH:45](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[NH:30][C:29]([C:31]6[CH:36]=[N:35][CH:34]=[CH:33][N:32]=6)=[N:28][N:27]=5)[CH2:22][CH2:21]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[CH:45]=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6cnccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5cnccn5)[nH]4)CC3)cc2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 10-3 (0.5 g, 0.9 mMol) in 16 mL of 3:1 toluene:methanol was added trimethyl orthoformate (0.3 g, 2.7 mMol) and p-toluenesulfonic acid monohydrate (0.017 g, 0.09 mMol). The reaction was heated to 100° C. in a microwave reactor for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The product was purified on a C18 reverse phase HPLC to give 10-4 as a solid. Mass (M+1) calculated: 565.2571 observed: 565.2523
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18](OCC)=[O:19]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[CH:1]1([N:7]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH:18]=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(NC2CCCCC2)CC(C)(C)N1
Reactant: CCOC=O
Agent: [Ti]
Solvent: CCCCO
Product: CC1(C)CC(N(C=O)C2CCCCC2)CC(C)(C)N1

Procedure:
80 g of 4-(N-cyclohexylamino)-2,2,6,6-tetramethylpiperidine and 32 g of tetrabutyl orthotitanate in 175 ml of ethyl formate were refluxed for 11 hours. Fractional distillation gave a fraction of boiling point 143°-144° C. under 0.4 mmHg. After solidification, this fraction was recrystallized from n-hexane. 4-(N-cyclohexyl-N-formylamino)-2,2,6,6-tetramethylpiperidine was isolated as a colorless solid of melting point 105° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1)#[N:2].[H][H]>N.C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1
Reactant: N#CCCn1cnc(N)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCCn1cnc(N)c1
Yield: 73.7 %

Procedure:
1-(2-Cyanoethyl)-4-aminoimidazole (1 g, 6 mmol) was suspended in 3% ammonia/ethanol (50 ml), and Raney nickel was added to the solution. The mixture was stirred at 80° C. for 5 hours in a hydrogen atmosphere. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (chloroform:methanol:aqueous ammonia=5:1:0.5) to obtain 620 mg of the title compound (oil).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[CH:6]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:35]([O:37][CH3:38])=[O:36])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1
Reactant: COC(=O)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(=O)OC)C2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(indan-2-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([SiH:11]([CH3:13])[CH3:12])[C:7](Br)=[N:8][CH:9]=1)[CH:2]=[CH2:3].C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[CH2:1]([C:4]1[CH:5]=[C:6]([SiH:11]([CH3:13])[CH3:12])[C:7]([CH:22]=[O:23])=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc(Br)c([SiH](C)C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCc1cnc(C=O)c([SiH](C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution of 5-allyldimethylsilyl-2-bromopyridine (7 Scheme 27, 14.5 g, 56 mmol) in dry THF (400 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 22.5 mL, 56 mmol) over a period of 20 min. After stirring 30 min at this temperature, anhydrous DMF (6.5 mL, 84 mmol) was added over a period of 5 min, and the reaction mixture was stirred for 30 min then warmed to room temperature. Saturated NCl (10 mL) was added to the reaction mixture. The layers were separated, and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:7 ethyl acetate/hexanes) to afford an oil (4.2 g, 36%); 1H NMR (300 MHz, CDCl3) δ 0.26 (s, 6 H), 1.71 (d, J=8.40 Hz, 2 H), 4.74 (m, 1 H), 4.79 (s, 1 H), 5.62 (m, 1 H), 7.80 (d, J=7.80 Hz, 1 H), 7.89 (m, 1 H), 8.75 (d, J=0.90 Hz, 1 h), 9.97 (s, 1 H); 13C NMR (75 MHz, CDCl3) 3.65 (2C), 23.1, 114.7, 120.7, 133.3, 139.9, 142.7, 153.0, 154.5, 193.8. HRMS (EI) calcd for C11H15NOSi 205.0923, found 205.0927.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:17]1(OC(N(C)C)=[N+](C)C)[C:21]2N=CC=[CH:25][C:20]=2N=N1.[C:34]([C:37]1[CH:42]=[C:41]([CH2:43][S:44][C:45]2[C:50]([C:51]([NH:53][C:54]3[CH:59]=[C:58]([CH3:60])[CH:57]=[C:56]([CH3:61])[CH:55]=3)=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:40]=[CH:39][N:38]=1)(O)=[O:35].C(N)CC>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:58]1[CH:59]=[C:54]([NH:53][C:51]([C:50]2[C:45]([S:44][CH2:43][C:41]3[CH:40]=[CH:39][N:38]=[C:37]([C:34]([NH:17][CH2:21][CH2:20][CH3:25])=[O:35])[CH:42]=3)=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:52])[CH:55]=[C:56]([CH3:61])[CH:57]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(C(=O)O)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
N,N-Diisopropylethylamine (40 μL, 0.23 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (51 mg, 0.14 mmol) were added to a solution of 2-(2-carboxypyridine-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (42 mg, 0.11 mmol, Compound No. 6-1) and n-propylamine (34 μL, 0.41 mmol) in N,N-dimethylformamide (1 mL) at room temperature, this mixture was stirred at 40° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL), then the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (40 mL) and brine (30 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether. This solid was dried at 50° C. under reduced pressure to give 21 mg of the target compound as a white solid. (Yield 46%)
Reaction SMILES: Br.C(O)(=O)C.C(O)(=O)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:29])[CH:23]([CH3:28])[C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1>CS(C)=O>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22]([CH3:29])=[C:23]([CH3:28])[C:24](=[O:27])[NH:25][N:26]=2)=[CH:19][CH:20]=1
Reactant: CC1C(=O)NN=C(c2ccc(CCCCN)cc2)C1C
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(CCCCN)cc2)n[nH]c(=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
44 ml of a 25% hydrogen bromide-acetic acid solution was added to 44 ml of an acetic acid solution containing 2.20 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dihydro-4,5-dimethylpyridazin-3(2H)-one, and the mixture was stirred at room temperature for 5 minutes. Then, 0.75 ml of dimethylsulfoxide was added to the mixture, and the resulting mixture was stirred for 6 hours. The solvent was removed, and the residue was dissolved in 150 ml of water. The solution was made alkaline with ammonia and extracted with chloroform. After the chloroform layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-28% aqueous ammonia (10:1:0.1)) to obtain 1.52 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dimethylpyridazin-3(2H)-one.
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][S:2][C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Sodium thiomethoxide (91 mg; 1.3 mmol; 1.3 equiv) was dissolved in water (0.34 mL). Tetrabutylammonium bromide (48 mg; 0.15 mmol; 0.15 equiv) was added. Methyl 2-nitro-4trifluoromethylbenzoate (5a; 249 mg; 1.0 mmol) was dissolved in toluene and added to the mixture. The reaction mixture was stirred at ambient temperature for 1 h to completely consume 5a according to gas chromatography (GC) analysis. The reaction mixture was diluted with ethyl acetate and water and the layers were thoroughly mixed and then separated. The organic layer was dried over Na2SO4 and concentrated to afford 0.26 g of 6a which contained a small amount of tetrabutylammonium bromide. The crude product was filtered through a pad of flash silica gel to afford 226 mg (90%) of 6a.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([F:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].C1C(=O)N([Br:31])C(=O)C1.Br>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([F:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:31])=[CH:18][C:17]=1[Cl:22]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
A mixture of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (251 mg, 0.739 mmol), NBS (139 mg, 0.781 mmol), and catalytic amount of HBr (48%) in DMF (3 mL) was stirred for 19 hours at room temperature. The reaction mixture was diluted with EtOAc, and washed with water (5×). The organic layer was dried over MgSO4, filtered, and concentrated to give the desired product (269 mg, 87%) that was used directly without further purification.
Reaction SMILES: Cl.[N:2]([CH2:5][C@H:6]([NH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:3]=[N-:4].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>ClCCl>[N:2]([CH2:5][C@H:6]([NH:12][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:3]=[N-:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)CN=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CN=[N+]=[N-])NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of ethyl 3 azido-2(S)-aminopropionate hydrochloride (0.3 g) in dichloromethane (3 ml) was added triethylamine (0.47 ml) and benzoyl chloride (0.2 ml) under stirring at 0° C. After stirring at ambient temperature for 2 hours, the mixture was poured into water and extracted with dichloromethane. The extract was washed with water, saturated aq. NaHCO3, water and brine, and dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give ethyl 3 azido-2(S)-(benzoylamino)propionate (0.35 g).