Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)([C:21](OCC)=[O:22])=[O:20]>O1CCCC1>[CH:9]([N:8]1[C:19](=[O:20])[C:21](=[O:22])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2)([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)Nc1ncccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)c(=O)[nH]c2cccnc21
Reaction time: 2 h

Procedure:
To a stirred solution of 3-amino-2-isopropylamino-pyridine (2.0 g, 10.6 mmole) and triethylamine (4.8 ml, 34.6 mmole) in tetrahydrofuran (30 ml) was dropwise added ethoxalyl chloride (2.68 ml, 24 mmole). Stirring was continued for two hours after the addition. The mixture was filtered through a glass filter funnel and the filtrate was evaporated to give the title compound as white crystals. M.p. 246°-247° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1C=CC2C(=CC=C(O)C=2)C=1)C.[C:18]([O-])([O-])=[O:19].[K+].[K+].[I-].[Na+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>CC(C)=O>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][CH:4]([C:3]([O:2][CH3:1])=[O:17])[CH3:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCCCCBr
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OC(C)C(=O)OC
Yield: 83.7 %

Procedure:
To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid methyl ester 6 (150 g, 652 mmol), anhydrous K2CO3 (480 gr, 3.473 mol) and sodium iodide (22.5 grams, 150 mmol) in anhydrous acetone (2000 ml) was added methyl 6-bromohexanoate (216 g, 1.033 mol) and refluxed for 60 hours. Acetone was distilled off and water (1500 ml) was added. Crude 9 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 2 (130 g, 55.6%) as a light yellow syrup. The structure was confirmed with NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)=[O:5].[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:8]=1)=[O:5]
Reactant: Nc1cc(NC(=O)c2ccc(F)cc2Cl)ccc1F
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN1CCC(Nc2cc(NC(=O)c3ccc(F)cc3Cl)ccc2F)CC1
Product: Cl
Reaction time: 1 h
Yield: 125.2 %

Procedure:
Under an inert atmosphere, stir a mixture of 2-chloro-4-fluoro-N-(3-amino-4-fluorophenyl)benzamide (Preparation 14, 481 mg, 1.7 mmol), 1-methyl-4-piperidone (384 mg, 0.42 mL, 3.4 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g) for 15 min. Add glacial acetic acid (306 mg, 0.3 mL, 5.1 mmol). After 1 hr., add sodium triacetoxyborohydride (900 mg, 4.25 mmol). Allow the reaction to go overnight. Pour the reaction mixture into ethyl acetate (200 mL), and wash once with aqueous NaOH (2N, 30 mL). Separate the organic layer, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure. Further purify the residue by chromatography on silica gel using a 4%-6% gradient of (2M NH3 in methanol) in CH2Cl2 to obtain the free base of the title compound (443 mg, 69% yield). Convert the product to its HCl salt by dissolving it in CH2Cl2 and treating with excess 1.0M HCl in diethyl ether. Add more ether to precipitate the title compound as a white solid: mass spectrum (ion spray): m/z=380.2 (M+1); Analysis calculated C19H20ClF2N3O.HCl.H2O: C, 52.54; H, 5.34; N, 9.68. Found: C, 52.93; H, 5.29; N, 9.65; LY 653915: 1H NMR δ (methanol-d) 7.72 (dd, 1H), 7.60 (m, 1H), 7.37 (dd, 1H), 7.14 (m, 3H), 3.74 (m, 1H), 3.62 (d, 2H), 3.30 (dd, 2H), 2.88 (s, 3H), 2.36 (d, 2H), 1.93 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30]([NH:33][C:34](=[O:38])[CH:35](Br)[CH3:36])(=[O:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30]([NH:33][C:34](=[O:38])[CH:35]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[CH3:36])(=[O:31])=[O:32]
Reactant: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Br)c1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)c1
Temperature: 45 °C
Yield: 83.7 %

Procedure:
To a stirred solution of 0.75 g (0.0026 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.89 g (0.0026 mole) of N-(2,5-dimethoxyphenylsulfonyl)-2-bromopropionamide in 50 mL of acetone was added 1.04 g (0.0026 mole) of potassium carbonate. After complete addition the mixture was heated at 45° C. for two days. The resultant mixture was cooled and the solvent was removed by evaporation under reduced pressure to leave a residue. The residue was dissolved in 100 mL of water. The aqueous solution was acidified by the dropwise addition of concentrated hydrochloric acid producing a precipitate. The precipitate was collected by filtration. The filter cake was washed with water and then dried under reduced pressure to leave 1.23 g of N-(2,5-dimethoxyphenylsulfonyl)-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide (mp 168°-172° C.) Compound C90.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9](=[O:10])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:7]=1
Reactant: C1CCNC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)N2CCCC2)c1
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and pyrrolidine (0.5 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (28 mg, yield 7%). MS calcd for (C19H22BN3O5S): 415.1. MS found (ESI negative): (M−H)−=414.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.77 (s, 1H), 9.17 (bs, 1H), 7.44 (m, 2H), 7.23 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.37 (m, 2H)), 4.87 (s, 2H), 3.82 (s, 2H), 3.32 (m, 4H), 1.81 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:7])(F)[C:3](O)=O.FC(F)(F)C(O)=O.[O:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[N:29]=[C:28]([C:30]4[CH:31]=[N:32][N:33]([C:35]5([CH2:39][C:40]#[N:41])[CH2:38][NH:37][CH2:36]5)[CH:34]=4)[N:27]4[CH:42]=[CH:43][N:44]=[C:26]4[CH:25]=3)[CH:21]=[N:20]2)[CH2:16]1.FC(F)(F)S(OCC(F)F)(=O)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][CH:2]([F:7])[CH2:3][N:37]1[CH2:36][C:35]([CH2:39][C:40]#[N:41])([N:33]2[CH:34]=[C:30]([C:28]3[N:27]4[CH:42]=[CH:43][N:44]=[C:26]4[CH:25]=[C:24]([C:22]4[CH:21]=[N:20][N:19]([CH:17]5[CH2:16][O:15][CH2:18]5)[CH:23]=4)[N:29]=3)[CH:31]=[N:32]2)[CH2:38]1
Reactant: O=C(O)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CNC1
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CN(CC(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
2-(3-(4-(7-(1-(Oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile bis(2,2,2-trifluoroacetate) (0.080 g, 0.089 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.038 g, 0.178 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.093 mL, 0.534 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2.5-3.5% (9:1 MeOH:NH4OH)/DCM to provide 2-(1-(2,2-difluoro ethyl)-3-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (0.005 g, 0.011 mmol, 12% yield). MS (apci) m/z=466.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[N:44]1([CH2:49][CH2:50][NH2:51])[CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:51][CH2:50][CH2:49][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: NCCN1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NCCN4CCCC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (68 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-tetrahydro-1H-1-pyrrolyl-1-ethanamine (26 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (26 mg, yield 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:13]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)c2ncccc2c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 3.3 g of 8-chloro-6-hydroxyquinoline (Step 1, 3.3 g) in dimethylformamide was added K2CO3 (3.8 g), followed by iodomethane (5.2 g). The mixture was stirred at room temperature overnight. Water was then added and the aqueous mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2, to give 2.2 g of the desired product as a beige solid; MP=74-75° C.; MS (ES) m/z (relative intensity): 194 (M+H)+ (100).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([CH2:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24](=O)[CH3:25])=[CH:17]4)[N:11]=[N:12][C:7]2=[N:6][CH:5]=1)(=O)[CH3:2].[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO.C(O)(=O)C>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:24](/[C:18]1[CH:19]=[N:20][C:21]2[C:16]([CH:17]=1)=[CH:15][C:14]([CH2:13][N:10]1[C:8]3=[N:9][C:4](/[C:1](=[N:27]/[O:28][CH2:29][CH2:30][OH:31])/[CH3:2])=[CH:5][N:6]=[C:7]3[N:12]=[N:11]1)=[CH:23][CH:22]=2)\[CH3:25]
Reactant: NOCCO
Reactant: CC(=O)c1cnc2ccc(Cn3nnc4ncc(C(C)=O)nc43)cc2c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2ccc(Cn3nnc4ncc(/C(C)=N/OCCO)nc43)cc2c1
Yield: 16.2 %

Procedure:
A solution of 1-(6-((6-acetyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanone (74 mg, 0.213 mmol) and 2-aminooxy-ethanol (35 mg, 0.45 mmol) in 5 mL of methanol and 0.1 mL of acetic acid was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was diluted with DCM and methanol. The precipitate was collected, washed with DCM, dried to afford the title compound (16 mg, 15%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 9.23 (d, 1H), 8.52 (d, 1H), 8.03 (d, 1H), 7.98 (s, 1H), 7.86 (dd, 1H), 6.22 (s, 2H), 4.76 (d, 2H), 4.31 (t, 2H), 4.22 (t, 2H), 3.72-3.69 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H). LCMS (method E): [MH]+=465, tR=4.85 min.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]2[C:23]([NH:24][CH2:25][C:26]([O:28]CC)=O)=[CH:22][CH:21]=[C:20]([O:31][CH3:32])[N:19]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC.[O-2].[O-2].[Mn+4]>[CH3:32][O:31][C:20]1[CH:21]=[CH:22][C:23]2[N:24]=[CH:25][C:26](=[O:28])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]3)[C:18]=2[N:19]=1
Reactant: CCOC(=O)CNc1ccc(OC)nc1NCCN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Yield: 43.1 %

Procedure:
A solution of ethyl N-[2-({2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]ethyl}amino)-6-(methyloxy)-3-pyridinyl]glycinate (1.2 g, 2.7 mmol) in toluene (400 ml) was heated to reflux under argon for 24 hours. This solution was treated at rt with manganese dioxide (2.0 g, 23 mmol). After 7 h the mixture was filtered, washing with warm toluene then evaporated affording a dark oil. Chromatography on silica eluting with 0-100% ethyl acetate in hexane afforded a yellow solid (470 mg, 43%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:13]=[C:12]([N:22]4[CH2:26][C@@H:25]([O:27][CH3:28])[CH2:24][C@H:23]4[C:29](O)=[O:30])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]1.O.N1(O)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:13]=[C:12]([N:22]4[CH2:26][C@@H:25]([O:27][CH3:28])[CH2:24][C@H:23]4[C:29]([NH:44][C@@H:45]4[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]4)=[O:30])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(c2nc(Nc3cc(C4CC4)[nH]n3)nc(N3CCOCC3)n2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1C[C@@H](C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)N(c2nc(Nc3cc(C4CC4)[nH]n3)nc(N3CCOCC3)n2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a solution of 112B (900 mg, 1.653 mmol) in DMF (10 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (951 mg, 4.96 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (993 mg, 4.96 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (253 mg, 1.653 mmol), and Et3N (1.382 ml, 9.92 mmol). The reaction mixture was stirred at RT for 14 h. The crude reaction mixture was purified by prep. HPLC to give 112C (800 mg, 79%). LC/MS [M+H]+: 613; Ret time (Method F): 2.99 min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][CH:7](O)[C:8]([OH:10])=[O:9])=[O:5].[Br:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>CS(O)(=O)=O>[Br:17][C:18]1[S:19][C:20]([CH:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])[C:8]([OH:10])=[O:9])=[CH:21][CH:22]=1
Reactant: Brc1cccs1
Reactant: O=C(NC(O)C(=O)O)c1c(F)cccc1F
Agent: CS(=O)(=O)O
Product: O=C(NC(C(=O)O)c1ccc(Br)s1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 52.3 %

Procedure:
A solution of 4.76 g (20.6 mmol) of the product of Step A in 140 mL of methanesulfonic acid was immersed in an ice-water bath (temperature between 5°-10° C.). Then, 4.0 g (24.6 mmol) of 2-bromothiophene was added dropwise. It was stirred at the same temperature until a deep blue-black color formed. It was poured into ice-water and the resulting precipitate was filtered. The solid was triturated with methylene chloride to give 4.05 g of a tan solid: mp 198°-199° C. (dec.). 1H-NMR (DMSO-d6) δ9.80 (d,1H), 7.55 (m, 1H), 7.20 (m,3H), 7.00 (d, 1H), 5.80 (d, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.O.[NH2:24][NH2:25]>CO>[Cl:10][C:9]1[C:4]([C:3]([NH:24][NH2:25])=[O:2])=[N:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
3-chloro-6- [3-(trifluoromethyl)phenoxy]-2-picolinic acid methyl ester (0.72 g, 0.00217 mol) was dissolved in methanol (10 ml), and then mixed with hydrazine monohydrate (1.087 g, 0.00217×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated, and the obtained residues were distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCCC1.O.C(OCC)(=O)C>[CH2:23]([O:22][C:20]([NH:5][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 86 %

Procedure:
To a stirred solution of 2-methoxy-5-nitroaniline (5.0 g, 30 mmol) and potassium carbonate (12 g, 90 mmol) in tetrahydrofuran (200 mL) and water (100 mL) was added benzyl chloroformate (6.1 g, 36 mmol). After 12 h, the mixture was diluted with ethyl acetate (200 mL) and the layers were separated. The organic phase was washed twice with 1 N aqueous hydrochloric acid, once with saturated aqueous sodium chloride solution, twice with saturated aqueous sodium bicarbonate solution, twice with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The resulting solid was suspended in diethyl ether and after sonication, the solid was filtered, washed with diethyl ether, and dried in vacuo to give 7.8 g (86%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH:14]=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCc1ccc2c(c1)cc(C=O)n2C
Temperature: 150 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of 5-butyl-1H-indole-2-carbaldehyde (75 mg, 0.37 mmol) and methyl iodide (57 mg, 0.40 mmol) in 0.75 mL dimethylformamide was added potassium carbonate (57 mg, 0.41 mmol). The resulting suspension was stirred vigorously at 150° C. in a sealed vial under argon for 1 h. Solids were filtered and the liquor concentrated before being subjected to chromatography on silica gel (40% ethyl acetate in hexanes) to give 5-butyl-1-methyl-1H-indole-2-carbaldehyde (15 mg, 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>C(O)(=O)C.S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:10]=1[NH:11][C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 2-(benzyloxy)-4-bromo-6-nitroaniline (33.0 g, 102 mmol, WO 2004054984) and acetic anhydride (14.5 mL, 153 mmol) in acetic acid (90 mL) was added concentrated sulfuric acid (2 drops) at 70° C. The mixture was stirred at 70° C. for 20 minutes. After cooling to room temperature, water (800 mL) was added, and the formed precipitate was collected by filtration and washed with diisopropyl ether to afford the title compound as a brown solid (30.9 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]3[C:45](=[O:46])[C:44]4[S:43][C:42]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=5[C:36]=4[CH:35]=[N:34]3)[C:28]=2[CH:47]=[O:48])=[CH:3]1.[BH4-].[Na+].O>CO.ClCCl>[OH:48][CH2:47][C:28]1[C:29]([N:33]2[C:45](=[O:46])[C:44]3[S:43][C:42]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=4[C:36]=3[CH:35]=[N:34]2)=[N:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 4-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-2-{6-oxo-8-thia-4,5-diazatricyclo-[7.4.0.02,7]-trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 191k (118 mg, 0.18 mmol) in methanol/dichloromethane (10/10 mL) was added NaBH4 (21 mg, 0.54 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was completed. Then the mixture was poured into water (20 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (20 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 191 (71 mg, 60%) as white solid. MS-ESI: [M+H]+ 667. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48-8.46 (m, 2H), 7.86 (d, J=3.0 Hz, 1H), 7.54 (d, J=5.5 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.37 (dd, J=3.0, 9.0 Hz, 1H), 7.25 (d, J=9.5 Hz, 1H), 4.86-4.85 (m, 1H), 4.58-4.55 (m, 2H), 4.48-4.46 (m, 2H), 4.42-4.40 (m, 2H), 3.65-3.64 (m, 1H), 3.61 (s, 3H), 3.41-3.99 (m, 1H), 3.05-3.04 (m, 1H), 2.97-2.95 (m, 3H), 2.87-2.86 (m, 2H), 2.52-2.51 (m, 1H), 2.34-2.32 (m, 2H), 2.21-2.20 (m, 1H), 1.89-1.87 (m, 4H), 0.94 (d, J=6.0 Hz, 3H).