Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2.[C:22]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)c2c(cnn2C2CCCCO2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of ethyl 7-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (1.45 g, 5.0 mmol) in acetone (20 mL) containing K2CO3 (760 mg, 5.50 mmol) was added iodomethane (781 mg, 0.34 mL, 5.5 mmo). The mixture was heated at reflux under N2 overnight. The mixture was cooled to room temperature, filtered, evaporated and partitioned between EtOAc and water. The aqueous phase was extracted with additional EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to provide crude product. The crude material was purified by chromatography (Isco, 0-40% EtOAc/heptane) to provide material which was dried under high vacuum overnight to afford ethyl 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (1.40 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12])=[CH:7][CH:8]=1
Reactant: NCCCNCCCCNCCCN
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: COc1ccc(CC(=O)NCCCNCCCCNCCCN)cc1
Reaction time: 48 h

Procedure:
According to the General Procedure using 4-methoxyphenylacetic acid (83 mg, 0.50 mMol), dicyclohexylcarbodiimide (56 mg, 0.27 mMol), and spermine (201 mg, 0.99 mMol) in DME (4 ml), activation during 2.5 h and coupling over 48 h. The product was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (4:1:1). The desired amide was in fractions 16-25 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH lower layer, 4:1:1), Rf =0.07, (30 mg, 32%), lyophilisation gave 21 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.4-1.8 (m, 8H, 4×CH2 --CH2), 2.4-2.9 (m, 10H, 5×CH2 --N), 3.3 (t, J=7, 2H, CON2H--CH2 --CH2), 3.5 (s, 2H, Ar--CH2 --CO), 3.83 (s, 3H, OCH3), 6.8-6.95 (m, 2H, 2×ArH 3,5), and 7.1-7.3 (m, 2H, 2×ArH 2,6)ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][C:3]=1[CH3:14].[Si](C=[N+]=[N-])(C)(C)[CH3:16]>CO.C1(C)C=CC=CC=1>[CH3:16][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([CH3:14])=[C:2]([F:1])[CH:10]=2)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc2cc(C(=O)O)[nH]c2cc1F
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(C)c(F)cc2[nH]1
Temperature: 25 °C

Procedure:
To a cooled solution of 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid in MeOH/toluene (1C) (200 mL, 1:1) was added TMS-diazomethane (2.0 M solution in diethylether, 1.05 eq.) dropwise and the reaction was allowed to warm up to room temperature over 1 h. The reaction mixture was concentrated and purified using triturating with CH2Cl2 and hexane and collecting the solids by filtration to obtain 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid methyl ester 1D (3.5 g). The concentrated filtrate was purified using chromatography over SiO2 using 0 to 40% ethyl acetate in hexanes to provide an additional amount of 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid methyl ester 1D (1.0 g). Overall yield (60%). 1H NMR (400 MHz, d6-DMSO): 2.26 (s, 3H), 3.83 (s, 3H), 7.07 (s, 1H), 7.08 (d, J=10.2 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 11.9 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[BrH:12].BrBr>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:7]([Br:12])[CH:8]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Br
Agent: BrBr
Solvent: O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 7 °C
Reaction time: 1 h

Procedure:
Mix 4-fluoro-2-nitroaniline (15.6 g, 0.1 mol) in water (400 mL) and add 48% hydrobromic acid (1kg). Add bromine (16 g, 0.1 mol) with stirring and stir for 1 hour. Dilute to 2L and cool to 7° C. Filter, wash with water and dry to give 4-fluoro-2-bromo-6-nitroaniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[N:7]([CH:27]1[CH2:30][N:29](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:28]1)[CH2:8][C@H:9]([OH:26])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6](=[O:44])[N:7]([CH:27]1[CH2:30][NH:29][CH2:28]1)[CH2:8][C@H:9]([OH:26])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccc(OCc2ccccc2)cc1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccc(O)cc1)C1CNC1
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a solution of (1-Benzhydryl-azetidin-3-yl)-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.55 g, 0.9 mmol) in methanol (20 ml) was added ammonium formate (2.0 g, 30 mmol), and 0.2 g of 10% Pd/C. The mixture was stirred at reflux for 18 h. After cooling to room temperature, it was filtered through Celite. The solvent was evaporated to give 0.31 g of a beige solid; m.p. 130-134° C.; MS (ES) m/z 339.1 (MH+); HRMS (EI) Calcd. for C37H42N2O5 (M+): 338.1841, Found: 338.1833.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(O)=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)Cl)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of benzyl (2R)-2-(carboxymethyl)-4-methylvalerate (500 mg) in dry dichloromethane (10 ml) was added oxalyl chloride (0.2 ml) at 0° C. After the solution was stirred at the same temperature for 1 hour, the solvent was evaporated in vacuo to give benzyl (2R)-2-(chloro-carbonylmethyl)-4-methylvalerate (522 mg) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[C:13]([O:17][C:18](=[O:35])[NH:19][C@@H:20]([C:29](=[O:34])N(OC)C)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:16])([CH3:15])[CH3:14].OS([O-])(=O)=O.[Na+]>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:29](=[O:34])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccccn1
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1F)C(=O)Cc1ccccn1
Temperature: 15 °C

Procedure:
To a solution of 2-picoline (0.54 mL, 5.5 mmol) in 20 mL of THF at −52° C. is slowly added a 1.5 M solution of n-butyllithium in hexanes (3.6 mL, 5.5 mmol). The reaction is then warmed to 15° C. and is then immediately re-cooled to −52° C. To the reaction is added a solution of [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.6 g, 1.8 mmol) in 4 mL of THF. The reaction is then is poured into 8 mL of a 2M solution of NaHSO4 in water. The solution is adjusted to pH7 by addition of pH7 buffer and the product is extracted into ether. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[O:18]=[C:19]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][N:20]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:39]=[C:38]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)[CH2:37][N:20]1[CH2:21][CH2:22][CH2:23][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:18]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(4-(trifluoromethyl)benzyl)piperazine (0.046 g, 0.188 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.053 g, 0.171 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.257 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.56-7.60 (m, 2H), 7.42-7.46 (m, 2H), 7.27-7.33 (m, 8H), 7.18-7.25 (m, 2H), 4.23 (s, 2H), 3.66 (t, J=4.7 Hz, 2H), 3.55 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 3.44-3.49 (m, 2H), 2.62-2.66 (m, 2H), 2.35-2.50 (m, 4H), 1.79-1.88 (m, 2H); MS (ESI+) m/z 536 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:20][C:21]([CH3:31])([CH2:26][C:27](=O)[CH2:28][CH3:29])[C:22]([O:24]C)=[O:23]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:28]([CH3:29])=[C:27]2[CH2:26][C:21]([CH3:31])([CH3:20])[C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxohexanoate as the starting materials and tert-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C:21](=[O:23])[NH:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[S:8]2(=[O:10])=[O:9])=[N:13][C:14]=1[CH3:19]
Reactant: Cc1ccc(NS(=O)(=O)c2cccnc2N)nc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(N2C(=O)Nc3ncccc3S2(=O)=O)nc1C
Yield: 60.6 %

Procedure:
The title compound (0.4 g, 1.31 mmol) was prepared from 2-amino-N-(5,6-dimethylpyridin-2-yl)pyridine-3-sulfonamide (0.6 g, 2.16 mmol) and triphosgene (0.7 g, 2.36 mmol) in 1,4-dioxane (15 mL) at 80° C. using the methods of (IntA1), step 3.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([C:45]1([C:48](O)=[O:49])[CH2:47][CH2:46]1)=[O:44].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43](=[O:44])[NH:42][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[F:35])[CH2:46][CH2:47]4)=[O:49])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Reactant: O=C(O)C1(C(=O)Nc2ccccc2F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4F)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (410 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(2-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (223 mg), triethylamine (0.139 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (442 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound as white powder (90.6 mg).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN[C@H]1CCN(Cc2ccccc2)C1
Yield: 102.4 %

Procedure:
A mixture of (S)-1-(phenylmethyl)-3-pyrrolidinamine, (0.115 mol) and 2-propenenitrile (0.115 mol) in ethanol (250 ml) was stirred and refluxed for 2 hours. 2-Propenenitrile (1 g) was added and the reaction mixture was stirred and refluxed for another 2 hours. The solvent was evaporated, yielding 27.0 g of (S)-3-[[1-(phenyl-methyl)-3-pyrrolidinyl]amino]propanenitrile (interm. 5).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH2:24]([OH:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C

Procedure:
To butan-1-ol (76 mL) was added portion wise sodium tert-butoxide (15.2 g) (Note: reaction mixture gets warm). The above was stirred until homogeneous (˜15 min) before 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (10.0 g) was then added to the resultant pale yellow solution. The reaction mixture was then heated to 100° C., overnight. The reaction mixture was stripped to remove as much butan-1-ol as possible before being partitioned between diethyl ether and water. The diethyl ether phase was separated and the aqueous re-extracted further with diethyl ether. Combined organic layers dried over magnesium sulphate (anhydrous). Magnesium sulphate was filtered off and filtrate stripped to give brown viscous oil which was azeotroped with toluene (3 times) and placed under high vacuum overnight, transferred to new flask with dichloromethane and stripped, placed under high vacuum to give the title compound as a brown glass (9.45 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CN(C)C=O.C[O:11][C:12]1[CH:29]=[C:28]([O:30]C)[CH:27]=[CH:26][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=1[O:24]C)=[O:15]>O>[OH:11][C:12]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:24])=[O:15]
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2OC)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Temperature: 30 °C
Reaction time: 4.5 h

Procedure:
440 g (3.30 mol) of AlCl3 were stirred into 120 g (1.64 mol) of dimethylformamide in such a way that the temperature remained below 160° C. After cooling to 30° C., 60.5 g (0.20 mol) of 2,2',4,4'-tetramethoxybenzophenone were introduced into the mixture, which was easily stirrable. The mixture was stirred at about 50°-52° C. for 4.5 hours and then added to 1.8 l of water to which 3 g of active carbon had been added. The hydrolyzate was filtered at about 95° C., and then 65 g of concentrated hydrochloric acid were added to the filtrate. The precipitate was filtered off with suction at 25° C., washed with water and dried at 125° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:24])[N:7]([C:13]3[C:22]4[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=4[CH:16]=[N:15][CH:14]=3)[C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[BH3-]C#[N:27].[Na+].CC([O-])=O.[NH4+]>C(O)(C)C>[NH2:27][CH:18]1[C:17]2[CH:16]=[N:15][CH:14]=[C:13]([N:7]3[C:8]([CH3:12])([CH3:11])[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[C:6]3=[O:24])[C:22]=2[CH2:21][CH2:20][CH2:19]1
Reactant: [BH3-]C#N
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2N
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 4-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-isoquinolin-8-one (408 mg, 1.2 mmol), NaBH3CN (75 mg, 1.2 mmol) and CH3COONH4 (1.0 g, 12 mmol) in isopropanol (10 mL) was heated to reflux for 3 hours. After cooling to room temperature, it was concentrated to afford a yellowish oil which was extracted between water with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford the crude title compound (327 mg, 80%) as a brown solid. MS: 342.1 & 325.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CNC2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a mixture of methyl 4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.18 mmol), benzoyl chloride (28 mg, 0.20 mmol), and triethylamine (36 mg, 0.36 mmol) in DCM (10 mL) was stirred at 20° C. for 1 hour. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get a crude product (70 mg, 99%) which was used in the next step without further purification. LCMS (ESI) m/z: 384.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[H-].[Na+].Br[C:28]1[S:32][C:31]([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[CH:39]=[N:38][CH:37]=[CH:36]3)=[N:30][N:29]=1>CN1CCCC1=O>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][C@H:3]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH2:2][O:1][C:28]2[S:32][C:31]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[N:38][CH:37]=[CH:36]4)=[N:30][N:29]=2)=[CH:6]1
Reactant: Brc1nnc(-c2ccc3cnccc3c2)s1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1c[nH]c2ccccc12

Procedure:
(S)-2-(1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl)isoindoline-1,3-dione (150 mg, 0.47 mmol) and 60% sodium hydride in mineral oil (37.6 mg, 0.94 mmol) was mixed in 2 ml N-methylpyrrolidinone. After stirring for ten minutes, compound 1b suspended in 2 ml N-methylpyrrolidinone was added and the reaction mixture was stirred at 20° C. for an hour. The reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride. The ethylacetate phase was washed with more saturated aqueous ammonium chloride and dried over anhydrous sodium sulfate. After removing the ethylacetate, the remaining residue was subjected to a silica gel column chromatography separation to yield the intermediate 2-((S)-3-(1H-indol-3-yl)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-yl)isoindoline-1,3-dione (3a). Compound 3a was dissolved in 4 ml ethyl alcohol, 0.5 ml water and 0.5 ml hydrazine monohydrate in a microwave heating tube. The tube was heated at 100° C. under microwave for five minutes. After removing all the solvent, the residue was subjected to a C18 reverse phase HPLC separation to yield (2S)-1-(1H-indol-3-yl)-3-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-amine (3) (2.4 mg) as a TFA salt. 1H NMR (400 MHz, Methanol-d4): δ 3.08 (m, 1H), 3.12 (m, 1H), 3.58 (m, 2H), 3.74 (m, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.32 (m, 2H), 8.46 (d, J=8.8 Hz, 1H), 8.53 (m, 2H), 8.72 (s, 1H), 9.60 (s, 1H); MS (API-ES) m/z (%): 402 (95%, M++1), 424 (100%, M+Na+); HRMS (ESI): calculated for C22H19N5OS [M+1]: 402.1388; found: 402.1394.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10]2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.O.NN>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
To a solution of crude 2-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (1.7 g, 3.42 mmol) in THF (30 ml) was added hydrazine monohydrate (0.83 ml, 17.1 mmol, Aldrich). The resulting yellow solution was stirred at ambient temperature under nitrogen for 5 h. The resulting suspension was filtered using a hydrophobic frit and the residue washed with ether (approximately 25 ml). The filterate was concentrated in vacuo and the residue loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-dichloromethane+0-20% methanol (+1% Et3N). The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (0.624 g); LCMS: (System 4) MH+=368, tRET=2.54 min.