Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[N:61]=[C:62]=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:62]([NH:61][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[O:63])[CH2:51][CH2:52]1
Reactant: O=C=Nc1ccccc1F
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1F)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as the starting materials in 40% yield. LCMS for C31H32ClFN7O2 (M+H)+: m/z=588.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:6]([CH:33]=1)[CH2:7][N:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1.[OH-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:6]([CH:33]=1)[CH2:7][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH:15]=1)[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(C(=O)O)cc2)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (from example 16) was dissolved in a solution of methanol (10 ml) and tetrahydrofuran (10 ml). To this solution was added aqueous 2N sodium hydroxide (3 ml) and the solution stirred at ambient temperature for 18 hours. The volume of the reaction mixture was reduced by evaporation to half the original volume, water (20 ml) was added and the mixture acidified with acetic acid. The resulting solid was filtered and dried under vacuum at 60° C. to give the title compound (12 g) m.p. 110° C.
Reaction SMILES: CS[C:3](=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[CH:4]([CH3:6])[CH3:5].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:3]([CH:4]([CH3:6])[CH3:5])=[N:24][N:23]=2)=[CH:17][CH:16]=1
Reactant: NNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CSC(=Nc1ccccc1F)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)c1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-(2-Fluorophenyl)-2-methylthiopropionimidate methyl ester (7.84 g) prepared in the Reference Example 1 and biphenyl-4-carboxylic acid hydrazide (5.25 g) were dissolved in N,N-dimethylformamide (50 ml), followed by addition of p-toluenesulfonic acid.monohydrate (941 mg), and stirred at 120° C. for 59 hours. After the reaction solution was cooled to ambient temperature, the resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:chloroform-chloroform/methanol=100/1 to 50/1 to 20/1), to afford 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole as pale yellow solid (5.98 g, 68%). A part of the product was recrystallized from ethyl acetate, to afford the entitled compound as pale yellow crystal. The physico-chemical values are as follows.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=1[C:20]#[N:21])=[N+]=[N-].[H][H]>[C].[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=1[C:20]#[N:21]
Reactant: [H][H]
Reactant: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(N)c(C#N)c2)c1

Procedure:
Palladium-carbon was added to a methanol solution of methyl 2-(4-azido-3-cyanophenyl)isonicotinate, and the mixture was stirred in the presence of hydrogen gas at room temperature for 5 hours to obtain methyl 2-(4-amino-3-cyanophenyl)isonicotinate. AP: 254.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35]Cl)[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:30]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cc(Cl)ccn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Tetrahydrofuran (3 mL) and 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. Next, the reaction solution was concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature, and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36.6 mg, 83%).
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([OH:20])[CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:24][C:25]1([CH3:37])[CH:27]([CH:28]([Br:33])[C:29]([Cl:32])([Cl:31])[Br:30])[CH:26]1[C:34](Cl)=[O:35]>C1C=CC=CC=1>[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([O:20][C:34]([CH:26]1[CH:27]([CH:28]([Br:33])[C:29]([Cl:31])([Cl:32])[Br:30])[C:25]1([CH3:37])[CH3:24])=[O:35])[CH:18]=[CH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C1C(Br)C(Cl)(Cl)Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=CC(OC(=O)C1C(C(Br)C(Cl)(Cl)Br)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g of pyridine in 10 ml of benzene is added dropwise at 5° C., with stirring, to 8 g of 3-phenoxy-α-vinyl-benzyl alcohol in 30 ml of benzene. After the addition of 14 g of 2,2-dimethyl-3-(1-bromo-2,2-dichloro-2-bromoethyl)-cyclopropanecarboxylic acid chloride at 10° C., the mixture is stirred for 2 hours at room temperature, and is allowed to stand for a further 10 hours at this temperature. The reaction mixture is diluted with ice water; the organic layer is extracted three times with 100 ml of 3% HCl each time, and subsequently three times with 100 ml of 3% sodium bicarbonate each time; the organic phase is dried with sodium sulfate, and the benzene is distilled off. There is obtained the compound of the formula ##STR9## as colourless oil having a refractive index of nD40° =1.5776. In an analogous manner is also obtained the compound of the formula ##STR10##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)c(Cl)c1
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1ccc(F)c(Cl)c1
Yield: 84 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 84% yield (yellow solid) after purification by flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.70 (m, 1H), 7.56 (d, 2H, J=8.6 Hz), 7.51 (m, 1H), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 7.05 (s, 1H), 3.46 (s, 2H), 2.46 (bs, 8H), 2.28 (s, 3H), 2.25 (s, 3H); MS (ESI): 426.3 [M+H]+, 213.7 [M+2H]2+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:13]([CH:12]([F:11])[C:16]([F:19])([F:18])[F:17])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (2.03 g; 11.5 mmoles) and 2,3,3,3-tetrafluoro-propionic acid (1.99 g; 13.6 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (60 mL) and with ethyl acetate (60 mL), then sodium bicarbonate (4.02 g; 47.9 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light orange solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[NH4+].[Cl-].[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1>CCOCC>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:13][CH2:12][CH2:11][CH2:15][CH2:15][CH2:11][CH2:12][CH2:13][CH2:7][CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccccc1Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccccc1Cl
Yield: 47.4 %

Procedure:
To 0.05 g (0.065 mmoles) of [NitriphosCl]PF6 and 2.00 g (13.61 mmoles) of o-dichlorobenzene in 20 mL of ether at 0° C. was added 19.65 g (13.70 mmoles) of 0.697 mmoles/g of n-dodecylMgBr in THF. The mixture was refluxed overnight, poured into NH4Cl solution, extracted with ether, dried over MgSO4, and the solvent was removed by rotary evaporation. The residue was distilled (101° to 105° C./0.14 mm) to give 1.806 g (6.44 mmoles, 47.4%) of 1-chloro-2-dodecylbenzene. 1H NMR (200 MHz, CDCl3): δ7.4-7.0 (m, 4H), 2.70 (t, J=8 Hz, 2H), 1.6 (m, 2H), 1.3 (br s, 18H), 0.9 (m, 3H). High resolution mass spectrum: calculated for C18H29Cl: 280.1957; Found: 280.1954. Elemental analysis: Calculated for C18H29Cl: C, 76.97; H, 10.41; Found: C, 77.11; H, 10.47. IR(neat): 2935s, 2860s, 1478m, 1470m, 1460sh, 1445m cm-1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reaction time: 16 h
Yield: 89 %

Procedure:
Palladium on charcoal (10%, 50% w/w water, 8 g) was treated with ethanol (200 mL) followed by a solution of 5-(azidomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (39.94 g, 121 mmol) in ethanol (1200 mL). The mixture was stirred under an atmosphere of hydrogen for 16 h. The catalyst was then removed by filtration and the filtrate removed of solvent in vacuo to reveal 41.24 g of a black oil. The product was purified by flash chromatography on 1 kg of silica using a step gradient from 5-20% methanol in dichloromethane to afford 32.66 g of the title compound. LC-MS m/z 304 (M+H)+, 1.71 min (ret time).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[CH:15]1([CH2:27][CH2:28][N:29]=[C:30]=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:15]1([CH2:27][CH2:28][NH:29][C:30]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1COC(=O)C1
Reactant: O=C=NCCC1CCCCCCCCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCC1CCCCCCCCCCC1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry flask containing 40 mL of chloroform was added 1.87 g (18.7 mmol) of tetronic acid, 2.29 g (18.7 mmol) of 4-N,N-dimethylaminopyridine, 2.6 mL (18.7 mmol) of triethylamine followed by 4.4 g (18.7 mmol) of 2-cyclododecylethyl isocyanate. The reaction mixture was allowed to stir overnight at room temperature, after which time a small amount of starting materials was still evident by TLC. The reaction mixture was quenched with 1N HCl, the layers separated, the organic fraction dried over MgSO4, filtered, and stripped of solvent. The residue was flash chromatographed using acidic silica gel eluting with 25% EtOAc/hexane to give a yellow solid. M.P. 135°-137° C. Spectral data follow: 1H NMR (DMSO-d6) δ 8.05 (bs, 1H), 4.6 (s, 2H), 4.2 (bs, 10 H), 3.25 (t, 2H), 2.5 (s, 3H), 1.2-1.4 (bm,>20 H); IR (KBr) 3340, 2920, 2850 (C-H), 1750, 1650 cm-1 (C=O).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH2:9]2)=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:15]2[C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH2:9][N:8]([C:6]([NH:5][CH:3]4[CH2:2][N:1]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:4]4)=[O:7])[CH2:13][CH2:12][N:11]3[N:14]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CNC1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CN(CC(F)(F)F)C1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
To a stirred solution of Intermediate 339B (100 mg, 0.255 mmol) in THF (10 mL) was added DIPEA (0.222 mL, 1.273 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (118 mg, 0.509 mmol) and stirred at RT for 16 h. The reaction mixture was quenched with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (2×20 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 339 as an off-white solid (15 mg, 12%). HPLC retention times 10.73 min. and 11.90 min (Methods C and D). MS(ES): m/z=475 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84 (dd, J=7.37, 2.08 Hz, 1H), 7.62-7.72 (m, 1H), 7.41-7.50 (m, 1H), 7.36 (br. s., 1H), 7.27 (d, J=6.80 Hz, 1H), 7.18 (br. s., 1H), 4.73 (s, 2H) 4.19-4.31 (m, 1H), 4.06-4.17 (m, 2H), 3.84 (d, J=5.67 Hz, 2H), 3.57-3.69 (m, 2H), 3.09-3.23 (m, 4H).
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.C([O:14][C:15](=[O:31])[CH2:16][C:17](=[N:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)C.Cl>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:16]([C:15]([OH:14])=[O:31])=[C:29]2[CH2:28][CH2:27][CH2:26][N:25]2[N:24]=1
Reactant: CCOC(=O)CC(=NN1CCCC1=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Add sodium ethoxide (145 g, 2.03 mol), followed by toluene (7 L) and 3-(2-oxo-pyrrolidin-1-ylimino)-3-(pyridin-2-yl)-propionic acid ethyl ester (Preparation 3, Part B; 280 g, 1.02 mol) to a 22 L flask equipped with mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture at 100° C. for 21 h. Cool to room temperature, add water (6 L), and adjust to pH 5 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous layer with 10% isopropyl alcohol in chloroform (2×9 L). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 218 g (93%) of the title compound as a yellow solid MS (ES) m/z=230 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=O)[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:22][C:23]4[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of the hydrochloride salt of 7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.99 g), tert-butyl [3-amino-5-(trifluoromethyl)-benzyl]carbamate (1.98 g, 6.82 mmol), and DMAP (0.834 g, 6.82 mmol) in DMF (60 mL) was added EDCI (1.31 g, 6.82 mmol). The reaction mixture was allowed to stir at rt overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give tert-butyl [3-[({7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)-amino]-5-(trifluoromethyl)benzyl]carbamate (2.45 g, 71%). LCMS: (FA) ES+ 557.9, ES+ 554.6.
Reaction SMILES: [O:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[C:6](=[O:10])[NH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]ccc2ccoc12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Br)c2ccoc12
Temperature: 15 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of 6H-furo[2,3-c]pyridin-7-one (1.0 g, 7.4 mmol) in DMF (30 mL) was treated with NBS (1.32 g, 7.4 mmol) in three equal portions at 0° C. After the resulting mixture was stirred at 15° C. for 2 h, it was treated with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc=3:1) to give the title compound (600 mg, 38%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 11.92 (s, 1H), 8.23 (s, J=2.0 Hz, 1H), 7.47 (s, 1H), 6.88 (m, 1H), 6.88 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[Si:13]([O:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH:22]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Nc2ccnc3ccc(Br)cc23)c1
Yield: 80.2 %

Procedure:
6.26 g (25.8 mmol) of 6-bromo-4-chloroquinoline are reacted by method A with 7.5 g (33.6 mmol) of 3-(tert-butyldimethylsilanyloxy)phenylamine. 8.9 g (20.7 mmol, 80%) of the desired product are obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C@H:7]([NH:19][C:20](=[O:23])[CH2:21][NH2:22])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([Br:18])[CH:9]=1)[CH3:3].[C:25]([O-:28])(O)=[O:26].[Na+]>O1CCOCC1>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C@@H:7]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([Br:18])[CH:9]=1)[NH:19][C:20](=[O:23])[CH2:21][NH:22][C:25]([O:28][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:26])[CH3:3]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C[C@H](NC(=O)CN)c1cc(Br)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product from example H (2 gm, 5.204 mmol) in 1,4-Dioxane (20 ml) was added saturated aq. NaHCO3 solution (2.5 ml) and stirred for 5 min at RT. Boc-anhydride (1.36 ml, 6.245 mmol) was then added to it at 0 C and the reaction mixture was allowed to stir at room temperature for 2 hrs. Reaction mixture was concentrated, dissolved in EtOAc (60 ml) and washed with water (60 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude which was purified by silica gel (100-200 mesh) column chromatography eluting with 10% EtOAc to afford the desired compound (1.7 g) as a colorless liquid.
Reaction SMILES: C([O:4][CH2:5][C@:6]1([O:28][C@H:27]([CH2:29][OH:30])[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][C:6]1([O:28][C@H:27]([CH2:29][OH:30])[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][OH:8]
Reactant: CC(=O)OC[C@@]1(CO)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OC[C@H]1OC(CO)(CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 1.7 g portion of 2-C-[(acetyloxy)methyl]-2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-diacetate was treated with 1.6 g of potassium carbonate, 10 ml of water and 8.5 ml of methanol and the mixture heated at reflux for 40 minutes and then evaporated. The residue was taken up in ether/water. The water layer was extracted twice with ether. All ether layers were combined, washed with brine, dried and evaporated. The residual oil was flash chromatographed, eluting with 4% methanol in dichloromethane, giving 1.0 g of the desired compound.