Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[CH:21])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27]>[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]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20]#[C:21][C:23]2[CH:24]=[C:25]([CH2:26][OH:27])[CH:28]=[CH:29][CH:30]=2)[CH:17]=[N:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1cccc(I)c1
Reactant: C#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#Cc2cccc(CO)c2)c1

Procedure:
A small resealable tube with stir bar was charged with 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-ethynylpyridine (168 mg, 583 μmol), copper(I) iodide (11 mg, 58 μmol, 0.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (43 mg, 58 μmol, 0.1 equiv.). To these reactants was added a solution of m-iodobenzyl alcohol (136 mg, 581 μmol, 1 equiv.). The mixture was purged with nitrogen through a needle, then the tube was capped, and the brown suspension was stirred at room temperature for 18.5 h. Solids were removed by suction filtration over celite and were washed with three portions of EtOAc (4 mL each). The solution was evaporated. TLC analysis (silica gel, EtOAc/hexane 3:1) showed, besides some PPh3 and baseline material, a single spot (Rf 0.3). The brown crude product was purified by CC on silica gel (24×2.5 cm, EtOAc/hexane 3:1 changing to 1:0 after appearance of the product). The product-containing fractions were evaporated and dried (50° C./oil pump) to yield 189 mg (82%) of a light-amber glass. 1H NMR (CDCl3, TMS, 250 MHz) δ 8.35 (d, 1H, J=1.4 Hz), 8.28 (d, 1H, J=2.7 Hz), 7.57 (narrow m, 1H), 7.49-7.43 (m, 1H), 7.43-7.32 (m, 3H), 4.73 (s, 2H), 4.53 (m, 1H), 4.35, 4.14 (ABq, 2H, J=10.1 Hz, low-field part br d, J=4.3 Hz, high-field part d, J=2.9 Hz), 3.90 (t, 2H, J=7.6 Hz), 2.47-2.21 (m, 3H, apparently including OH), 1.43 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 156.0, 154.4, 144.3, 141.8, 137.4, 130.3, 129.8, 128.3, 127.2, 123.0, 122.2, 120.5, 92.5, 85.4, 79.7, 68.5, 63.9, 59.8, 46.9 (br), 28.2, 18.8; MS (EI) m/z 394 (M+, 2.7%), 321 (3.8%), 294 (14%), 293 (11%), 265 (10%), 238 (22%), 100 (23%), 57 (100%), 56 (73%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccc2)cc1F
Temperature: 67.5 °C

Procedure:
4-Bromo-2-fluoro-phenylacetic acid (0.25 gm, 1.1 mmole), phenylboronic acid (0.15 gm, 1.2 mmole) and 50% water wet 10% Palladium carbon (0.07 gm, 0.033 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.14 gm, 1.3 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was acidified using 20% H2SO4, filtered and dried (0.2 gm, 83%) H1-NMR INOVA-500 (DMSO d6) δ 3.675 (s, 2H), 7.382-7.518 (m, 6H), 7.707 (d, J=7.5 Hz, 2H), 12.498 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:16][CH:17]=1
Reactant: OC(COc1ccc(Cl)cc1)Cn1cncn1
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(COc1ccc(Cl)cc1)Cn1cncn1

Procedure:
The 1-(4-chlorophenoxy) 3-(1,2,4-triazol-1-yl)propan-2 ol (3.0g) was dissolved in acetone (100ml) and treated with Jones reagent (3ml) for 3 h. To complete the oxidation, two subsequent additions of Jones reagent (0.5ml) were added. After cooling, ethyl acetate (150ml) was added and the reaction was neutralised by the addition of a saturated solution of sodium bicarbonate. The organic phase was separated, washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica using 2% by volume methenol in chloroform as eluent, to give 1-(4-chlorophenoxy)-3-(1,2,4-triazol -1-yl)propan-2-one as a gum, NMR in deuteriochloroform: δ4.7(2H,s), 5.38(2H,s), 6.85(2H,d), 7.3(2H,d), 8.01(1H,s), 8.17(1H,s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][NH:65][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:50]
Reactant: CN(C)CCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N,N-Dimethylethylenediamine (137 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.026 g, 22%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:16])[C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(OCc2ccccc2)cc1Br
Reaction time: 2 h

Procedure:
To a solution of 5-(benzyloxy)pyridin-2-amine (10.2 g) in acetic acid (50 mL) was added bromine (2.61 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.50 g).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=CC=1.[NH2:28][C:29]1[C:37]([CH3:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:30]=1[C:31](O)=[O:32]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:31](=[O:32])[C:30]3[CH:34]=[C:35]([Cl:39])[CH:36]=[C:37]([CH3:38])[C:29]=3[N:28]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, Step D) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (1.86 g, 10 mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes at a temperature of −5 to 0° C. The reaction mixture was stirred 15 minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a light yellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13](Cl)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][CH3:22]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13]([N:21]([CH3:22])[CH3:20])[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18]
Reactant: CNC
Reactant: Cn1c(-c2nnc3ccc(Cl)nn23)cnc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)c1ccc2nnc(-c3cnc([N+](=O)[O-])n3C)n2n1

Procedure:
0.5 g. 3-(1-methyl-2-nitro-5-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were dissolved, with heating, in 10 ml. dimethyl formamide and gaseous dimethylamine passed in at 60° C. over the course of 15 minutes. The resultant suspension was then diluted with 6 ml. water, filtered with suction, first washed with aqueous dimethyl formamide, then with water and finally with methanol. There was thus obtained 0.4 g. (78 percent of theory) of the desired 3-(1-methyl-2-nitro-5-imidazolyl)-6-dimethylamino-s-triazolo[4,3-b]pyridazine in the form of yellow crystals which melt, with decomposition, at 261° - 263° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:36])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:78]1[CH:82]=[CH:81][CH:80]=[C:79]1[C:83](O)=[O:84]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:36])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:12][NH:13][C:83]([C:79]1[S:78][CH:82]=[CH:81][CH:80]=1)=[O:84]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
To a solution of (S)-3-Amino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester trifluoro-acetic acid salt (0.16 mmol) in anhydrous DMF (4 mL) was added triethylamine (0.07 mL, 0.48 mmol), HBTU (0.091 g, 0.24 mmol), HOBT (0.026 g, 0.19 mmol), and 2-Thiophenecarboxylic acid (0.025 g, 0.19 mmol). The mixture was stirred at room temperature 1.5 h, treated with EtOAc (30 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (0-100% EtOAc in hexane) to give 0.040 g (47%) white foam product. MS m/e 530.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CN(C=O)C>[NH2:1][C:2]1[C:3](/[CH:11]=[CH:10]/[C:9]([O:13][CH3:14])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Br
Reactant: C=CC(=O)OC
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ncccc1N
Temperature: 145 °C
Yield: 133.5 %

Procedure:
The following reaction was performed in duplicate: A glass microwave reaction vessel was charged with 3-amino-2-bromopyridine (2.00 g, 11.56 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.250 g, 0.353 mmol). DMF (10 mL) was added followed by methyl acrylate (4.00 mL, 44.3 mmol) and triethylamine (4.00 mL, 28.7 mmol). The reaction mixture was sealed under argon and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 145° C. for 40 min. The reaction mixtures were combined and the solvent was removed in vacuo. The residue was dissolved in DCM, evaporated onto silica gel and purified by flash chromatography (ISCO, (120 gram HP)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1-1:39) to give 2.75 g (69%) of a yellow amorphous solid. ESI-MS 179.0 [M+1].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[N:11]([OH:19])[C:10]2=[O:20])=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:19][N:11]1[C:12](=[O:18])[C:13]2[S:17][CH:16]=[CH:15][C:14]=2[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=2)[C:10]1=[O:20]
Reactant: O=c1c2sccc2n(Cc2ccc(Cl)nc2)c(=O)n1O
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=c1c2sccc2n(Cc2ccc(-c3ccccc3C(F)(F)F)nc2)c(=O)n1O

Procedure:
The title compound was prepared from 1-(6-chloro-pyridin-3-ylmethyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione and 2-trifluoromethyl phenylboronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.78 (bs, 1H), 8.68 (d, 1H, J=2.1 Hz), 8.18 (d, 1H, J=5.4 Hz), 7.85 (d, 1H, J=8.1 Hz), 7.80 (dd, 1H, J=2.1, 8.1 Hz), 7.75 (t, 1H, J=7.5 Hz), 7.66 (t, 1H, J=7.8 Hz), 7.56-7.46 (m, 3H), 5.39 (s, 2H); Electrospray MS: 420 (M+H); retention time; 2.44 min.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][NH:29][CH2:30][CH3:31]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:29]([CH3:28])[CH2:30][CH3:31])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCNC
Solvent: CC#N
Product: CCN(C)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-methylethanamine (0.5 ml), ACN (1 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.5), 84 (2), 73 (4), 72 (bp), 69 (2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1.C(O)C>[Pd].C1COCC1>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a mixture of tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Preparation Example 412) (2.21 g), ethanol (40 mL) and THF (20 mL), 10% palladium on carbon (1.0 g) was added and stirred at room temperature for 3 hours under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was distilled off under reduced pressure to give tert-butyl 4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (1.97 g) as a gray solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[N:13]=[C:12]2[S:14][C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])=[N:16][C:11]2=[CH:10][CH:9]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:20]1([C:18]([NH:17][C:15]2[S:14][C:12]3[C:11]([N:16]=2)=[CH:10][CH:9]=[C:8]([O:7][C:6]2[CH:23]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=4)[CH:3]=[CH:4][C:5]=2[O:24][CH3:25])[N:13]=3)=[O:19])[CH2:21][CH2:22]1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
To a solution of N-[5-(5-amino-2-methoxyphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (93.0 mg, 261 μmol) in pyridine (2 mL) were added a solution of 3-(trifluoromethyl)benzoyl chloride prepared above in pyridine (3 mL) and N,N-dimethylpyridine-4-amine (28.9 mg, 237 μmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with 0.1N hydrochloric acid (30 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), and dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20) to give the title compound (79 mg, 58%) as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])=[CH:21][CH:20]=2)[CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O.O>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])=[CH:23][CH:24]=2)[CH:18]=1)=[O:13])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CC(=O)OC(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a solution of N-{2-(tert-butyldimethylsilyloxy)ethyl}-1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide prepared in Example 67-(1) (0.700 g) in N,N-dimethylformamide (5.0 mL), sodium hydride (55% in mineral oil, 0.058 g) was added and stirred at room temperature for 20 minutes. To the reaction mixture, tert-butyl 2-bromoacetate (0.281 g) was added and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.220 g) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22]>CCO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:21](=[O:22])[C:20]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH2:25])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1C(=O)NNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (2.105 g, 14.76 mmol) was suspended in EtOH (25 ml), treated with di-isopropylethylamine (2.253 ml, 12.93 mmol) and stirred for 30 minutes. Isatoic anhydride (1.918 g, 11.76 mmol) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and stirred overnight. The material was concentrated to dryness and the resulting residue was partitioned between EtOAc (˜25 ml) and 50% saturated NaCl (3×30 ml). The organic layer (also containing a small amount of emulsion which would not dissipate over 3 extractions) was dried over MgSO4 and concentrated to an orange solid. The material was triturated with EtOAc, filtered and rinsed with additional EtOAc. The filtrate was concentrated to dryness and treated with DCM (dichloromethane). The mixture was stirred overnight. The mixture was filtered, rinsed with DCM and the solid dried to provide 1.538 g (50%) of 2-amino-benzoic acid N′-(4-chloro-phenyl)-hydrazide (Intermediate 40) as a mauve-colored solid. MS (APCI): (M+1)=262.1, (M−1)=260.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH:20]([CH3:22])[CH3:21])[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH:20]([CH3:22])[CH3:21])[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:17])[CH3:18])[NH2:8]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C

Procedure:
N-tert-butoxycarbonyl L-valyl L-valine methyl ester (16.47 g, 49.85 mmol) was treated with a 50% (v/v) solution of TFA in CH2Cl2 (130 mL). The reaction mixture was stirred for 2 h at room temperature before the solvent and bulk of excess TFA were evaporated. Portions of CH2Cl2 (3×100 mL) and purified CHCl3 (6×200 mL) were added and evaporated. The residue (19.17 g) was washed with Et2O (2×80 mL) and the Et2O decanted off. An additional 80 mL Et2O was added and the suspension filtered. The collected solid was washed with Et2O (80 mL) and dried; δH (300 MHz; d6-DMSO) 8.62 (1H, d, J 7, NH), 8.17 (3H, br s, NH3+), 4.19 (1H, dd, J 7 and 6, CαH(Val2)), 3.75 (1H, br d, J 5, CαH(Val1)), 3.64 (3H, s, OCH3), 2.16-2.01 (2H, m, CH(CH3)2), 0.96-0.90 (12H, m, CH(CH3)2); δC (75 MHz; d6-DMSO) 171.4, 168.4, 158.4 (q, JCF 31), 117.1 (q, JCF 297) 57.7, 56.9, 51.7, 29.9, 29.6, 18.8, 18.1, 18.1, 17.4
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:23]=[C:24]=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([NH:23][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C=NCCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Yield: 29 %

Procedure:
Prepared as in example 9-6b from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine and phenethyl isocyanate. Yield: 29%. 1H NMR (DMSO-d6, 400 MHz): δ2.10 (s, 3H), 2.36 (s, 3H), 2.69 (t, J=7.2 Hz, 2H), 3.25 (q, J=7.4 Hz, 2H), 5.02 (s, 2H), 6.00 (t, J=5.8 Hz, 1H), 7.16-7.30 (m, 6H), 7.68 (s, 1H), 8.13 (s, 1H). LC/MS; [M+H] calculated for C18H21N5O2; expected 340.17. Found 340.20.