Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Br:14][C:15]1[CH:16]=[C:17]([NH:18][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: O=C(Nc1cccc(Br)c1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 3-bromoaniline using the same procedure described in example 5.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(CCN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (150 mg, 0.51 mmol) in DCE (10 mL) was added 2-piperidin-4-ylpropan-2-ol (110 mg, 0.77 mmol), trimethyl orthoformate (0.55 mL, 5.02 mmol) and acetic acid (0.03 mL, 0.52 mmol). The reaction mixture was stirred at room temperature for 5 h, sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as an off white solid (109 mg, 51%). LCMS (Method H): RT=2.54 min, [M+H]+ 423.5
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20]Cl.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1c2ccccc2C(c2ccccc2F)=NCC1CNc1cccc(C(F)(F)F)c1

Procedure:
According to the method of Example 5, 1-methyl-2-chloromethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (200 mg, 0.66 mmole) and m-trifluoromethyl aniline (319 mg, 1.97 mmole) were combined in 2 ml of dry N,N-dimethylformamide, and potassium carbonate (273 mg, 1.97 mmole) and sodium iodide (198 mg, 1.32 mmole) were added to this mixture (which was heated at 65° C. for 18 hours). After solvent-removal, partitioning, separation, washing, drying and concentrating, the analytical product was obtained via chromatography on silica gel (ethyl acetate-hexane elution, 3:7 v/v) and was shown to be 96% pure by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:32]1[N:33]=[C:34]([NH2:38])[NH:35][C:36]=1[NH2:37]>C(O)(=O)C.C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][N:32]4[N:33]=[C:34]([NH2:38])[N:35]=[C:36]4[N:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1nnc(N)[nH]1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(N)nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 1 (250 mg, 0.59 mmol) and 4H-[1,2,4]Triazole-3,5-diamine (58.91 mg, 0.59 mmol) in acetic acid (0.4 mL) and ethanol (1.6 mL) was heated under reflux for 6 hours. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with NaHCO3 aq. and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 6-1. MS (ESI) m/e (M+H+) 457.3
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[N:20][C:21]#[N:22])OC2C=CC=CC=2)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3].[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>C(O)(C)C>[N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:20][C:21]#[N:22])=[N:28][C:23]([CH3:25])([CH3:24])[CH2:26][CH3:27])[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: N#CN=C(Nc1cc(I)cc(N=[N+]=[N-])c1)Oc1ccccc1
Reactant: CCC(C)(C)N
Solvent: CC(C)O
Product: CCC(C)(C)N=C(NC#N)Nc1cc(I)cc(N=[N+]=[N-])c1
Yield: 64.9 %

Procedure:
Step B-2. To a stirred suspension of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1, 1.09 g, 2.69 mmol) in isopropanol (20 mL) is added tert-amylamine (0.95 mL, 8.08 mmol). The reaction mixture is heated to reflux for 2.5 hour. The cooled reaction mixture is concentrated and the residue is diluted with ether (50 mL) and washed with 1 N aqueous sodium hydroxide (2×15 ml). The aqueous is extracted with ether (2×30 mL). The combined organics are dried (MgSO4), filtered and concentrated. The organic residue is purified by flash chromatography using 25% ethyl acetate in hexane as an eluent to afford 0.694 g of N-(3-azido-5-iodophenyl)-N'-cyano-N"-(1,1-dimethylpropyl)guanidine (B-2) as a foam. IR (mull) 3310, 3251, 3077, 2954, 2924, 2869, 2854, 2174, 2109, 1603, 1582, 1572, 1497, 1457, 1421, 1408, 1366, 1301, 1231, 844 cm-1 ; 1H NMR (CDCl3)δ8.29 (bs, 1 H), 7.33 (t, 1 H, J=2 Hz), 7.24 (t, 1 H, J=2 Hz), 6.83 (t, 1 H, J=2 Hz), 4.64 (bs I H), 1.70 (q, 2 H, J=7 Hz), 1.32 (s, 6 H), 0.84 (t, 3 H, J=7 Hz); 13C NMR (CDCl3) δ156.7, 142.7, 138.5, 129.0, 125.4, 116.9, 114.2, 94.8, 55.6, 32.9, 26.3, 8.1; Mass Spec (70eV, EI) m/z 397 (parent), 369, 328, 299, 258, 242, 232, 213, 172, 145, 130, 105, 71, 55, 43 (base); Exact mass calculated for C13H16IN7 : 397.0514. Found: 397.0532.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:27]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[N:28][O:29][C:30]=2[CH3:31])[OH:19])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:27]([CH2:32][O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)=[N:28][O:29][C:30]=2[CH3:31])=[O:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(COCc2noc(C)c2-c2ccccc2C(O)c2ccc(Cl)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COCc2noc(C)c2-c2ccccc2C(=O)c2ccc(Cl)cc2)cc1
Temperature: -78 °C

Procedure:
To a round bottomed flask was added DCM (4 mL) and oxalyl chloride (28.0 μl, 0.320 mmol) before the solution was cooled to −78° C. To this solution was added DMSO (37.9 μl, 0.533 mmol) and the reaction stirred at −78° C. for 15 min before addition of (4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanol (120 mg, 0.267 mmol) dissolved in DCM. The solution was stirred for an additional 15 min before addition of Et3N (112 μl, 0.800 mmol) and the reaction warmed to room temperature. Water was added and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanone. LC/MS m/z 448 [M+H]+.
Reaction SMILES: Cl.[OH:2][NH3+:3].[C:4]([O:13]CC)(=O)[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7]>[OH-].[Na+].O1CCOCC1>[C:4]([NH:3][OH:2])(=[O:13])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7]
Reactant: CCOC(=O)c1ccccc1O
Reactant: [NH3+]O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NO)c1ccccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
Hydroxylammonium hydrochloride (15 g) was dissolved in 10% aqueous sodium hydroxide solution (220 mL), and a solution of ethyl salicylate (24 g) in 1,4-dioxane (70 mL) was gradually added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated until the amount thereof became almost the half, and acidified with conc. hydrochloric acid. The precipitated solid was collected by filtration, which was then recrystallized from methanol to give salicylhydroxamic acid (12 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I-].C[N+]1C=CN([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1OC
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCOCC4)cc3oc2=O)cc1OC
Yield: 56.4 %

Procedure:
The title compound (120 mg, 56% yield) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O>ClCCl>[Br:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:8](=[O:10])[CH3:9]
Reactant: Nc1cccc(F)c1Br
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(F)c1Br
Reaction time: 72 h

Procedure:
2.7 ml of triethylamine and then 1.2 ml of acetyl chloride are added to a solution of 3 g of 2-bromo-3-fluoroaniline in 30 ml of dichloromethane. The reaction mixture is stirred for 72 hours and then treated with a mixture of water and dichloromethane. The phases are separated and the organic phase is concentrated so as to give 3.75 g of N-(2-bromo-3-fluorophenyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1)#[N:33]
Reactant: CN(C)C=O
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)nc1

Procedure:
To a solution of (S)-5-bromo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)picolinamide (Example 205) (0.100 g, 0.198 mmol) in DMF (1.3 mL) was added zinc cyanide (0.050 mL, 0.793 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.020 mmol). The resulting mixture was subjected to a microwave irradiation at 140° C. for 20 min. The mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.95-9.06 (m, 2H), 8.39 (dd, J=8.1, 2.1 Hz, 1H), 8.21-8.32 (m, 2H), 7.57-7.70 (m, 5H), 6.89 (s, 1H). MS (ESI pos. ion) m/z: 451.1 (M+H).
Reaction SMILES: [S:1]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19][OH:20].C(N(CC)CC)C.[Cl-].ClC1N(C)C=C[N+]=1C>C(Cl)Cl>[S:1]([N:11]([CH2:13][C:14]([N:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19][OH:20])=[O:16])[CH3:12])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: OC[C@@H]1CCCN1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N2CCC[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
N-tosylsarcosine (60 g, 247 mmol) and L-prolinol (24.9 g, 247 mmol) are dissolved in methylene chloride (800 ml), and triethylamine (102.5 ml, 741 mmol) is added thereto. To this mixture is added dropwise, over a period of one hour under water-cooling, a solution of 2-chloro-1,3-dimethylimidazolium chloride (DMC) (62.6 g, 371 mmol) in methylene chloride. The mixture is further stirred for 2 hours at room temperature and then the reaction liquid is washed successively with water (1 l, a saturated aqueous solution of sodium hydrogen carbonate (1 l, 1N hydrochloric acid (1 l) and water (1 l). The organic layer is dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated to dryness under reduced pressure to give N-tosylsarcosyl-L-prolinol (82.1 g, 102%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1.[BH4-].[Na+]>CO>[CH3:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: NCCc1cccnc1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCc2cccnc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2 carboxamide (Example 404, part D) (0.600 g, 2.33 mmol), 2-pyridin-3-ylethylamine (0.285 g, 2.33 mmol) and 3 Å molecular sieves in a vial. Add methanol (11.7 mL), cap and stir overnight. Add NaBH4 (0.088 g, 2.33 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 25% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2× 25 mL), dry it over Na2SO4 and concentrate it to give the title compound (0.315 g, 37.2%): TOF MS ES+ 364.2 (M+H)+, HRMS calcd for C20H22N5O2 364.1773 (M+H)+, found 367.1774, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=6.1 min, 100% purity.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17][C:16](=O)[O:15][C:13]2=[O:14]>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:13](=[O:14])[C:12]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCCCn1ccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCCn1ccnc1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture of 1.53 g of 1H-imidazole-1-pentanamine, 1.63 g of isatoic anhydride and 15 ml at ethanol was stirred for 20 hours and concentrated. The viscous residue was mixed with 10 ml of ethyl chloroformate and heated for 1.5 hours in an oil bath at 95° C. The mixture was dissolved in ethanol, reconcentrated, mixed with 2.0 g of potassium hydroxide and 50 ml of ethanol and heated at reflux temperature for 3 hours. The reaction mixture was concentrated, dissolved in water and treated with acetic acid to pH 6-7. The insoluble material was collected by filtration and recrystallized from ethanol to obtain the desired product, mp 160°-162° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]2[CH2:14][NH:13][CH2:12][C@@H:11]2[OH:15])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]2[CH2:14][N:13]([CH3:19])[CH2:12][C@@H:11]2[OH:15])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1CNC[C@@H]1O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CN1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 103.4 %

Procedure:
To (3S,4S)-4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-3-ol hydrochloride (0.104 mol, 35.0 g) in acetonitrile add sodium triacetoxyborohydride (0.37 mol, 78.0 g) at 0° C. To this mixture, add slowly 37% aqueous formaldehyde (30 mL) over 10 min and stir at room temperature for 10 h. Add saturated aqueous sodium bicarbonate and stir for one hour. Extract with ethyl acetate, and wash with water and brine. Dry over anhydrous sodium sulfate, filter, and evaporate the solvent to obtain the title compound as a yellow solid (34.0 g, 98%). APCI MS m/z 302 [M+H]+; [α]23D +58.6° (c, 0.50, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:29][CH3:30].C1(=O)C=CC(=O)C=C1>C1COCC1.C(OCC)(=O)C.CC#N.CC#N.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12](=[O:14])[C:11]3[C:10]([CH:9]=2)=[CH:18][CH:17]=[C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:15]=3)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1ccc(COc2ccc(/C=C/c3ccc(F)c(OC)c3)c(C(=O)O)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)oc(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
A solution of (E)-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid (600 mg, 1.47 mmol) in anhydrous THF (5 mL) was sparged with nitrogen for 5 min, then PdCl2(MeCN)2 (39 mg, 0.15 mmol), p-benzoquinone (175 mg, 1.62 mmol), and molecular sieves (10 mg) were added and the mixture stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N NaOH (aq.). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by chromatography on silica gel with hexanes:EtOAc (2:1, v/v) as eluent to afford 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (300 mg, 0.74 mmol, 50%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[BH4-].[Na+]>C(Cl)Cl.CO.CC(O)=O>[N:38]1([CH2:1][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:28])=[O:29])[CH2:25][CH2:26]3)[CH:6]=[CH:7][CH:8]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reactant: C1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2cccc(CN3CCCC3)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reaction time: 2 h
Yield: 8.1 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (45.0 mg/0.086 mmol) in DCM/MeOH (1.0 ml/1.0 ml) was added pyrrolidine (0.043 mL, 0.517 mmol) and 1 drop of AcOH. The reaction mixture was stirred for 2 hr at r.t and then NaBH4 (17.0 mg, 0.086 mmol) was added. The reaction mixture was stirred for 30 min and concentrated and redissolved in 1.5 ml of DMSO. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (4 mg, 8%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([C:25]([NH:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])[CH2:13]1)(=[O:11])=[O:10]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:29]([O:28][NH:27][C:25]([C@H:14]1[CH2:13][N:12]([S:9]([CH2:8][CH2:7][NH:6][C:2]([O:4][CH3:5])=[O:3])(=[O:11])=[O:10])[CH2:17][CH2:16][N:15]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:26])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)ONC(=O)[C@H]1CN(S(=O)(=O)CCN)CCN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)NCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NOC(C)(C)C)C1
Temperature: 0 °C
Yield: 102.9 %

Procedure:
Methyl chloroformate (132 mg) in CHCl3 (3 ml) was added dropwise to (2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide (400 mg) in pyridine (2.5 ml) with cooling on an ice bath. After stirring on the ice bath for 3 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 3.6% HCl. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 470 mg of (2R)-N-tert-butoxy-1-tert-butoxycarbonyl-4-[2-(methoxycarbonylamino)-ethanesulfonyl]-2-piperazinecarboxamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20]#[N:21])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl>[C:20]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[NH:15][CH:14]=1)#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 4-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX (377 mg, 1.36 mmol) in THF/DCM (1/1, 22 ml) was added MsCl (105 μl, 1.36 mmol) dropwise. The mixture was stirred at 0° C. for 10 minutes, and TEA (226 μl, 1.62 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2.5 hours, poured into ice/water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated affording methanesulfonic acid 3-(3-cyano-1H-indol-4-yl)-3-phenyl-propyl ester(not shown in above scheme) as a yellow oil. A solution of this crude mesylate in MeNH2 (33% in EtOH, 8.5 ml) was placed in a sealed tube and stirred at 100° C. for 45 minutes. The reaction mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) affording 4-(3-methylamino-1-pheny-propyl)-1H-indole-3-carbonitrile LXI as a white foamy solid (346 mg). MS (M+H)=290.