Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](O)([C:22]([F:25])([F:24])[F:23])=O.[BH4-].[Na+].[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:20][C:22]([F:25])([F:24])[F:23])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (500 mg, 1.5 mmol) and TFA (15 ml), was added NaBH4 (1.0 g, 26 mmol) portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and then heated to 50° C. for 3 hours and treated with a further aliquot of NaBH4 (300 mg) over 25 minutes. The reaction mixture was then heated to 60° C. for 2 hours and left to stir at room temperature for 17 hours. The reaction mixture was treated with TFA (5 ml) and NaBH4 (200 mg) and heated back up to 60° C. for 3.5 hours. A further aliquot of NaBH4 (200 mg) was added over 15 minutes, along with TFA (5 ml) and heating continued for a further 3 hours, before being left to stand at room temperature overnight. The reaction mixture was poured over ice (75 ml) and stirred until the ice had melted. The reaction mixture was then basified by the addition of 6M NaOH (aq) (40 ml) and re-adjusted to pH 7 using 1M HCl (aq) (40 ml). The resulting white suspension was collected by filtration, the solid washed with water (20 ml) and dried in-vacuo at 40° C. for 3 hours to give the title compound (577 mg, 91%) as a white solid. LC-MS 98%,), m/z=409.90, 410.9, 411.90, 412.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.80 (d, J=1.73 Hz, 1H) 7.41 (d, J=1.73 Hz, 1H) 4.01 (dd, J=11.51, 4.10 Hz, 2H) 3.91 (s, 3H) 3.64 (d, J=5.20 Hz, 2H) 3.32 (t, J=11.82 Hz, 2H) 2.99 (tt, J=11.43, 3.63 Hz, 1H) 2.48 (s, 3H) 1.80 (dd, J=12.53, 1.50 Hz, 2H) 1.54-1.62 (m, 2H).
Reaction SMILES: S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O=[C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][C:29]#[N:30]>C1C=CC=CC=1>[C:29]([CH:28]=[C:27]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=CC#N)c2ccccc2)CC1
Temperature: 115 °C

Procedure:
TsOH—H2O (1 g) was added into a solution of N-Boc piperazine (50 g) and 3-oxo-3-phenylpropanenitrile (19.49 g) in benzene (200 ml). The reaction mixture was heated up to 115° C. for 16 hours and resultant water was collected by Dean-Stark trap. After the solution was concentrated, a residue was obtained and further purification using silica gel chromatography provided tert-butyl 4-(2-cyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, CD3OD) δ7.91 (m, 5H), 5.24 (s, 1H), 3.89-3.50 (m, 8H), 1.88 (s, 9H); 13C NMR (125 MHz, CD3OD) δ167.6, 155.7, 135.4, 130.6, 129.4, 121.8, 81.1, 67.1, 45.4, 28.0. MS m/z: (M+H)+ calcd for C18H24N3O2 314.19, found 314.25. Retention time 1.81 min (column D).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[CH:23]1([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH:23]1([CH2:26][N:27]([CH3:28])[C:18]([CH:16]2[CH2:17][C:14]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][N:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)=[C:2]([Cl:1])[CH:3]=3)([OH:21])[CH2:15]2)=[O:19])[CH2:25][CH2:24]1
Reactant: CNCC1CC1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(CC1CC1)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added cyclopropylmethyl-methyl-amine hydrochloride (61 mg, 0.51 mmol) triethylamine (0.18 ml, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.9 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (71 mg, 29% yield). Rf=0.50 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29ClN2O2, 376.9, found, 377.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, diagnostic peaks, δ 3.75 (s, 2H), 3.02 & 3.01 (2 singlets, 3H total), 2.62-2.54 (m, 6H), 1.82-1.74 (m, 4H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, peak list δ 175.9, 175.7, 146.4, 146.3, 135.2, 134.0, 130.9, 130.8, 126.5, 126.4, 123.7, 73.7, 73.5, 56.7, 54.6, 54.3, 52.4, 41.3, 41.0, 35.5, 34.5, 29.0, 28.5, 23.7, 10.5, 9.5, 3.8, 3.6.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([NH:19][CH3:20])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1NN=[N:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[N:19]([CH3:20])[C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28]([F:27])([F:41])[F:40])=[N:36][N:37]=3)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2]
Reactant: FC(F)(F)c1ccccc1-c1nnn[nH]1
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)NC)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl amide 11-9 (0.470 g, 1.56 mmol) was dissolved in anhydrous methylene chloride (5 mL) and treated with oxalyl chloride (2M in methylene chloride, 1.56 mL, 3.12 mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 h, then solvent removed by evaporation under reduced pressure. The residue was redissolved in anhydrous toluene (7 mL) and treated with 5[2-(trifluoromethyl)phenyl]1H-tetrazole (368 mg, 1.72 mmol). The mixture was refluxed for 18 h. The reaction was cooled to room temperature and the precipitate was filtered and washed to give 300 mg of crude product as the HCl salt. The salt was taken up in methylene chloride/1N HCl and the aqueous layer was washed with two additional portions of methylene chloride. The organic layers were combined and evaporated and the residue was chromatographed by flash silica gel chromatography. Elution was carried out with a gradient ranging from 0 to 5% methanol/methylene chloride. The appropriate fractions were combined and evaporated to give 3-{4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (11-10) as a white powder. MS (ESI+)=470.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.87 (1H, m), 7.72 (2H, m), 7.56 (1H, m), 3.49 (3H, s), 3.05 (2H, q, J=7.2 Hz), 2.96 (2H,m), 2.18 (6H, m), 1.86 (2H, m), 1.62 (6H, m), 1.46 (3H, t, J=7.3 Hz), 1.36 (2H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[C:37]([CH2:39][C:40](O)=O)#[N:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:21]2[NH:20][C:19](=[O:31])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:8]4[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]5[CH:32]=[C:33]([CH3:36])[C:34]6[N:35]=[C:40]([CH2:39][C:37]#[N:38])[NH:1][C:2]=6[CH:3]=5)[CH:7]=4)[CH2:17][CH2:16]3)[CH2:24][CH2:23][C:22]=2[CH:25]=1
Reactant: N#CCC(=O)O
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC#N)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 40 mg (0.46 mmol) cyanoacetic acid, 0.15 g (0.47 mmol) TBTU and 0.14 mL (1.00 mmol) TEA in 2.00 mL DMF were stirred for 4 h at RT. Then 2.00 mL glacial acetic acid was added and the mixture was stirred overnight at RT. The reaction mixture was also stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH3:13].C1COCC1.C(N(CC)CC)C>C(OCC)(=O)C.[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>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: COCOc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc(C#Cc2ccc(OCOC)cn2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
To a solution of 2-bromo-5-(methoxymethoxy)pyridine (2.50 g, 11.5 mmol), 1-ethoxy-4-ethynylbenzene (2.57 mL, 17.2 mmol) and copper(I) iodide (220 mg, 1.15 mmol) in a mixed solvent of THF-triethylamine (20 ml-10 mL) was added bis(triphenylphosphine)palladium(II) chloride (807 mg, 1.15 mmol), and the mixture was stirred under an argon stream at 60° C. for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:7) to give the title compound (3.21 g, yield 98%) as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([C:23](Cl)=[O:24])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>>[CH2:2]([NH:4][C:23]([C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][Br:5])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:24])[CH3:3]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCN
Agent: Cl
Product: CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from ethylamine hydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:59][CH3:60])[C:48]([N:50]([CH3:58])[CH2:51][CH2:52][C:53]2[S:54][CH:55]=[CH:56][CH:57]=2)=[O:49])=[CH:42][CH:41]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:59]([C@@H:47]([C:48](=[O:49])[N:50]([CH3:58])[CH2:51][CH2:52][C:53]1[S:54][CH:55]=[CH:56][CH:57]=1)[CH2:46][C:43]1[CH:42]=[CH:41][C:40]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:45][CH:44]=1)[CH3:60])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N(C)CCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
A solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (202 mg, 0.83 mmol) and 1-hydroxy-7-azabenzotriazole (113 mg, 0.83 mmol) in N,N-dimethyformamide (3 ml) and dichloromethane (3 ml) was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (159 mg, 0.83 mmol) was added. The reaction mixture was stirred for 10 min at 0° C. A solution of (2R)-3-(biphenyl-4-yl)-N-methyl-2-(methylamino)-N-(2-(2-thienyl)ethyl)propionamide (314 mg, 0.83 mmol) in dichloromethane (3 ml) and ethyldiisopropylamine (0.14 ml, 0.83 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (100 ml). The aqueous solution was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified on silica (80 g), using ethyl acetate/heptane (1:1 (500 ml), then 2:1) as eluent, to give 374 mg of (3E)-4-(N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[CH3:11][C:12]1(C)[C:16](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:12]([CH3:16])=[CH2:11])[CH:7]=[C:6]([Cl:8])[C:5]=1[Cl:9]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc(Br)cc(Cl)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)c1cc(Cl)c(Cl)c(Cl)c1
Yield: 80.6 %

Procedure:
To a mixture of 5-bromo-1,2,3-trichlorobenzene (3.64 g, 14 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.5 g, 15 mmol) and Pd(PPh3)2Cl2 (983 mg, 1.4 mmol) in THF (50 ml) and H2O (5 ml) at rt was added K2CO3 (5.8 g, 42 mmol). The mixture was refluxed overnight and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (5:1 to 2:1) to give the desired intermediate (2.5 g, yield 81%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 7.44 (s, 2H), 5.39 (s, 1H), 5.19-5.18 (t, 1H), 2.10 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: O=C(O)CO
Product: OCc1nc2cc(Cl)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.67 g of 5-chloro-2,3-diaminopyridine (prepared as described in Preparation 62) and 18.6 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 8.83 g of the title compound, melting at 209°-211° C.
Reaction SMILES: [CH:1]1([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:7]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:26])=[CH:23][CH:22]=1
Reactant: c1ccc([C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(c1ccc(Cl)cc1)N(C1CCCCC1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-cyclohexyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 164°-166° C.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Sc1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1nc(Sc2ccccc2)c2[nH]cnc2n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution of 2-fluoro-6-chloropurine (10.0 g, 57.9 mmol) in methanol (200 mL) is added diisopropylethylamine (25.2 mL, 144.7 mmol). The mixture is cooled to 0° C. and followed by slow addition of thiophenol (11.9 mL, 115.8 mmol) via an addition funnel over one hour. The reaction is stirred at 0° C. for 12 hours. The solvent is then removed under reduced pressure and the solid is collected by filtration and washed twice with hexanes. The collected solid is further purified by re-crystallization from methanol to afford desired product (11.8 g, 83% yield). 1H NMR (400 MHz, (CD3)2SO) δ 7.54 (m, 3H), 7.66(m, 2H), 8.49(s, 1H); MS C11H7FN4S [MH+] 246.04, found: 247.05.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][C:27]2[CH:39]=[CH:38][C:30]3[C:31](=[O:37])[N:32]([CH3:36])[CH2:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:59][O:60][CH2:61][C@H:62](O)[CH3:63]>C1COCC1>[CH3:63][C@H:62]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][C:27]2[CH:39]=[CH:38][C:30]3[C:31](=[O:37])[N:32]([CH3:36])[CH2:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:61][O:60][CH3:59]
Reactant: COC(=O)c1cc(O)cc(Oc2ccc3c(c2)OCCN(C)C3=O)c1
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 116 %

Procedure:
DIAD (1.18 mL, 6.0 mmol) was added to a stirred solution of methyl 3-hydroxy-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoate (1.72 g, 5.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) in THF (50 mL) at 0° C.-5° C. The mixture was stirred for 30 minutes, then treated with (R)-1-methoxy-2-propanol (675 mg, 7.5 mmol) and the mixture stirred at RT for 18 hours. The mixture was evaporated in vacuo to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane. The residue was slurried in ether (25 mL), filtered, and the filtrates evaporated in vacuo to give the desired compound (2.41 g) with a small amount of contaminating triphenylphosphine present. The material was used in the next steps without further purification. 1H NMR δ (CDCl3): 1.25 (d, 3H), 3.15 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 3.5 (t, 2H), 3.8 (s, 3H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (d, 1H), 6.7 (d, 1H), 6.75 (d, 1H), 7.2 (d, 1H), 7.35 (d, 1H), 7.8 (d, 1H); m/z 416 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[C:19]([Cl:20])=[C:18](/[CH:21]=[C:22](/[N+:25]([O-:27])=[O:26])\[CH2:23][CH3:24])[CH:17]=[CH:16][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>O1CCCC1>[Cl:6][C:7]1[C:19]([Cl:20])=[C:18](/[CH:21]=[C:22](/[N+:25]([O-:27])=[O:26])\[CH2:23][CH3:24])[CH:17]=[CH:16][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC/C(=C\c1ccc(OCCCC(=O)Cl)c(Cl)c1Cl)[N+](=O)[O-]
Reactant: NCC(=O)O
Solvent: C1CCOC1
Product: CC/C(=C\c1ccc(OCCCC(=O)NCC(=O)O)c(Cl)c1Cl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a stirring suspension of finely ground glycine (6.01 g, 0.08 mole) in tetrahydrofuran (50 ml) is added, dropwise, the solution of E-4-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]butyryl chloride over a period of 15 minutes. The mixture is stirred at ambient temperature for 2.25 hours and then at reflux for one hour. The mixture is cooled, filtered and washed with tetrahydrofuran. The solid is suspended in water (60 ml), filtered, washed with water and dried to give 7.45 g of N-{(E)-4-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]butyryl}glycine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:28][CH3:29])=[C:13]([C:19]2[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:31][N:32](C(C)C)[CH:33](C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.CNC>CCOC(C)=O.CN(C=O)C>[Cl:17][C:15]1[C:14]([CH3:18])=[C:13]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([N:32]([CH3:33])[CH3:31])=[O:26])[N:24]=2)[C:12]([O:28][CH3:29])=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:10])[CH:16]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1cccc(C(=O)O)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
The 6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylic acid (0.07 g, 0.2 mmol) was combined with DMF (3.0 mL) and DIPEA (0.14 mL, 0.83 mmol) at room temperature and the N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.13 g, 0.33 mmol) was added. The reaction stirred for 10 min and dimethylamine hydrochloride (0.041 g, 0.50 mmol) was added. The reaction was stirred at room temperature for 3 h and was complete by LC/MS. The reaction mixture was diluted with EtOAc and washed with water, saturated ammonium chloride, brine, dried over magnesium sulfate and concentrated to give the desired product as an oil (0.06 g, 83%). LCMS calculated for C23H31ClN3O4 (M+H)+: m/z=448.2. found: 448.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([OH:21])=O)=[CH:5][N:4]=1.C(Cl)CCl.[OH-].[NH4+:27].O>CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([NH2:27])=[O:21])=[CH:5][N:4]=1
Reactant: CSc1ncc(C(=O)O)c(NC2(c3ccccc3)CC2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CSc1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
To a solution of 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylic acid (646 mg, 2.15 mmol) and HOBtH2O (395 mg, 2.58 mmol) in DMF (3.5 mL), EDC (515 mg, 2.69 mmol) was added. The mixture was stirred at room temperature for 20 min. Ammonium hydroxide (244 mg, 4.30 mmol) was added. It was stirred at room temperature for 1 h. Water was added to induce precipitation, the solids were collected by filtration to give 2-(methylthio)-4-(1-phenylcyclopropylamino) pyrimidine-5-carboxamide (636 mg). MS 301.2 (M+H).