Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O:14][C@@H:15]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[CH2:26][S:25][C@H:16]1[O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=1)(=O)C>>[O:17]([C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]=1)[C@@H:16]1[S:25][CH2:26][C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:15]1[OH:14]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(Cl)cc3)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 4-chlorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(4-chlorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of off-white crystals (yield=74%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:22][CH2:21]1)[CH2:3][O:4][C:5]1[C:10]2[O:11][C:12]([C:14]([O:16]CC)=[O:15])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CO>[OH:1][C@@H:2]([CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:24][CH2:25]1)[CH2:3][O:4][C:5]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc2cccc(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2cccc(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)c2o1
Yield: 81.8 %

Procedure:
To a solution of ethyl (S)-7-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)benzo(b)furan-2-carboxylate (5.2 g) in methanol (50 ml) was added 10% saturated aqueous sodium hydroxide solution (50 ml) and the mixture was refluxed under heating for 1 hr. The reaction mixture was made acidic (pH 1) with conc. hydrochloric acid and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.0 g) as a brown oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:2]3[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1783.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].[C:9](Cl)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CCOCC>ClCCl>[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:9](=[O:11])[CH3:10]
Reactant: COC(=O)CCN
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCNC(C)=O
Reaction time: 48 h

Procedure:
A 10.0 g portion of β-alanine methyl ester hydrochloride was slurried in 200 ml of dichloromethane. A 20 ml portion of acetyl chloride and 20 g of anhydrous potassium carbonate were added and the mixture was stirred vigorously for 48 hours. The mixture was poured into 400 ml of ether, 20 g of fresh anhydrous potassium carbonate added and the solids allowed to settle for 15 minutes. Suction filtration through celite and concentration gave an oil. This oil was concentrated four times from 50 ml portions of toluene, giving 4.73 g of the desired compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.O>O1CCCC1.CN(C)C=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
3.2 g (78.9 mmol) of 60% sodium hydride are added to a solution of 10 g (65.7 mmol) of methyl 4 hydroxybenzoate in 50 ml of tetrahydrofuran and 50 ml of dimethylformamide. The reaction medium is stirred at ambient temperature for 20 minutes then 8.3 g (72.3 mmol) of 2-methoxyethoxymethyl chloride are added. After stirring for 24 h at ambient temperature, the mixture is poured over water then extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. 16 g (100%) of methyl 4-(2-methoxyethoxymethoxy)benzoate are obtained in the form of a colourless oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.CN(C)C1C=CC=CC=1.[Cl:40][C:41]([Cl:46])([Cl:45])[C:42](Cl)=[O:43]>ClCCl>[Cl:40][C:41]([Cl:46])([Cl:45])[C:42]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:43]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2′-dimethyl-biphenyl-4-yl)-methanone of Step C (12.4 g, 31.6 mmol) and N,N-dimethylaniline (6.4 mL, 50.5 mmol) in dry dichloromethane (90 mL) at 0° C. under nitrogen, was added trichloroacetyl chloride (5.3 mL, 47.5 mmol). The reaction was then allowed to warm slowly to room temperature while stirring overnight. The reaction mixture then was washed with 2N hydrochloric acid (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by filtration through a plug of silica gel (60 g) eluting with dichloromethane afforded the title compound (15.9 g, 94%) as a light orange solid, m.p. 212-214° C. MS [(+)ESI, m/z]: 537 [M+H]+.
Reaction SMILES: C[Al](C)C.CCCCCC.[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([S:18]([NH:21][C:22]2[S:26][CH:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])[CH:12]=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]([C@H:38]1[CH2:42][CH2:41][O:40][C:39]1=[O:43])[CH2:33][CH2:32][CH2:31]2.Cl>ClCCl.C(OC(=O)C)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]([C@@H:38]([CH2:42][CH2:41][OH:40])[C:39]([NH:17][C:16]1[CH:11]=[CH:12][C:13]([S:18](=[O:20])(=[O:19])[NH:21][C:22]3[S:26][CH:25]=[CH:24][N:23]=3)=[CH:14][CH:15]=1)=[O:43])[CH2:33][CH2:32][CH2:31]2
Reactant: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)[C@H](CCO)N1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 29.4 %

Procedure:
Prepared using general procedure 58. Under an N2 atmosphere at RT, 2M-trimethylaluminium in hexane (19.2 mL, 38.4 mmol) was added drop wise to a stirring solution of sulfathiazole (9.81 g, 38.4 mmol) in dichloromethane (90 mL) in 30 minutes. Upon completion of addition, the mixture was stirred at RT for an hour. Added (S)-3-(6-chloro-3,4-dihydroquinolin-1-(2H)-yl)dihydrofuran-2-(3H)-one (10.7 g, 42.7 mol) in dichloromethane (90 mL) to above solution over 30 minutes. The mixture was stirred for 16 hrs at RT. The reaction mixture was diluted with 500 mL of ethylacetate were added. The aqueous phase was acidified to pH 2 with an (1N) aqueous HCl solution. The ethyl acetate layer was washed with (1N) aqueous HCl (3×200 mL) till LCMS showed disappearance of sulfathiazole. The organic layer was dried over MgSO4, filtered, concentrated. Purification via silica gel chromatography using 2-10% methanol in dichloromethane gave the (S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl) butanamide as a white solid (5.73 g, 30% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=507.3; tR=1.53 min. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.78 (s, 4H), 7.24 (d, J=4.6 Hz, 1H), 7.01-6.96 (m, 2H), 6.82-6.76 (m, 2H), 4.68 (s, 1H), 4.59 (t, J=7.1 Hz, 1H), 4.03 (dd, J=14.2, 7.1 Hz, 1H), 3.47 (s, 2H), 3.35-3.21 (m, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.14-2.06 (m, 1H), 1.93-1.78 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:44]([N:51]1[CH2:55][C@H:54]2[C@H:56]([NH2:59])[CH2:57][CH2:58][C@H:53]2[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:44]([N:51]1[CH2:55][C@H:54]2[C@H:56]([NH:59][C:8](=[O:10])[C@@H:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:57][CH2:58][C@H:53]2[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Reaction time: 0.25 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid (359 mg, 1.526 mmol) was combined with triethylamine (0.387 mL, 2.77 mmol) in dichloromethane (10 mL). 1-Hydroxybenzotriazole (234 mg, 1.526 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.270 mL, 1.526 mmol) were added, and the reaction mixture was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with 10 mL of aqueous sodium bicarbonate and extracted with 3×20 mL of dichloromethane. The solvent was removed in vacuo. The crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.76 (d, J=6.9, 1H), 7.46-7.39 (m, 2H), 7.40-7.33 (m, 2H), 7.26 (dd, J=9.9, 17.2, 1H), 4.52 (t, J=7.7, 1H), 4.44-4.34 (m, 1H), 3.93 (dt, J=7.0, 14.5, 1H), 3.57 (dd, J=5.4, 13.1, 1H), 3.49-3.36 (m, 2H), 3.30-3.20 (m, 2H), 2.83-2.74 (m, 1H), 2.62-2.45 (m, 2H), 2.44-2.37 (m, 1H), 2.33-2.17 (m, 4H), 2.11 (qd, J=6.5, 12.5, 1H), 1.92-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.45-1.32 (m, 1H), 0.88 (d, J=6.6, 3H), 0.83 (dd, J=2.5, 6.5, 3H); MS (ESI+) m/z 434 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1.[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCc2ccc(-c3cccc(N4CCNCC4)n3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCCN1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CC4)n2)CC1

Procedure:
The preparation is carried out analogously to FS401 starting from 142 mg (0.46 mmol) of 1-[6-(3,3-dimethylindan-5-yl)pyridin-2-yl]piperazine and 90 μl of bromobutyl acetate using 2 equiv. of potassium carbonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Oc1ccc(I)c2cccnc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12
Reaction time: 8 h
Yield: 80.5 %

Procedure:
8-Hydroxy-5-iodoquinoline (7.0 g, 25.8 mmol), imidazole (1.85 g, 27.2 mmol) and tert-butyldimethylsilyl chloride (4.28 g, 28.4 mmol) are dissolved in anhydrous CH2Cl2 (40 ml) under N2. The mixture is stirred vigorously overnight, then diluted with CH2Cl2 (60 ml) and washed with 5% aqueous HCl (2×30 ml) and water (40 ml). The organic phase is dried over sodium sulfate, and the solvent is distilled off under reduced pressure, leaving a brown liquid. This crude product is purified by flash chromatography on silica (heptane:ethyl acetate 5:1). The end product is isolated as pale-yellow solid (8 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[C:25](O)(=[O:29])[CH2:26][CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in DMF (4 ml), butyric acid (0.36 mmol), water soluble carbodiimide (0.45 mmol) and 1-hydroxybenzotriazole hydrate (0.45 mmol) are added at 0° C. and then the reaction mixture is stirred at room temperature for 1 day. The reaction mixture is quenched with ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuo to give 129 mg of crude product. Purification of the residue by silica gel column chromatography affords the title compound in 96% yield. Rf=0.46 (n-hexane:AcOEt=1:1)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](O)=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18]([NH:14][C:11]1[CH:12]=[C:13]2[C:5]([C@@H:3]3[CH2:4][C@@H:2]3[CH3:1])=[N:6][NH:7][C:8]2=[N:9][CH:10]=1)=[O:19]
Reactant: C[C@H]1C[C@H]1c1n[nH]c2ncc(N)cc12
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc([C@@H]4C[C@@H]4C)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
3-(cis-2-Methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0399 g, 0.212 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.0651 g, 0.233 mmol), EDCI (0.0488 g, 0.254 mmol), and HOBt (0.0344 g, 0.254 mmol) were dissolved in DMF and stirred overnight at room temperature. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, which was purified by column chromatography (1:2 hexanes/EtOAc) to give 2,6-difluoro-N-(3-((1R,2S)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (66 mg, 69%) as a solid. 1H NMR (400 MHz, d6-DMSO) 13.16 (s, 1H), 11.07 (s, 1H), 9.81 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 7.53-7.59 (m, 1H), 7.26-7.31 (m, 1H), 3.11-3.15 (m, 2H), 1.99-2.03 (m, 1H), 1.75-1.80 (m, 2H), 1.32-1.34 (m, 1H), 1.14-1.22 (m, 3H) 0.99-1.02 (m, 3H), 0.78-0.83 (m, 3H); m/z (APCI-pos) M+1=450.1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.[I-].[Na+].C(#N)C.C(=O)(O)[O-].[Na+]>>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:26][C:25]4[CH:27]=[CH:28][C:22]([O:21][C:20]([F:19])([F:29])[F:30])=[CH:23][CH:24]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 59.6 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.103 g, 0.000366 mol), 4-(trifluoromethoxy)aniline (0.0983 mL, 0.000733 mol) and sodium iodide (0.020 g, 0.00013 mol) in Acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 180° C. for 15 minutes. After cooling to room temperature, the mixture was added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentrated to leave an oil. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.092 g of an off-white solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:29])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:28])[C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl.C(O)(=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5](=[O:29])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:23](=[O:27])[N:24]([CH3:25])[CH3:26])[NH:28][S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=3)(=[O:47])=[O:46])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(N)C(=O)N(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NS(=O)(=O)c3ccc(C)cc3)C(=O)N(C)C)cc2)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Hydrochloride compound 23 (1.5 g, 3.69 mmol) was dissolved in CH2Cl2 (50 mL) and cooled to 0-5° C. N,N′-Diisopropylethylamine (1.28 mL, 7.74 mmol) was added to the above solution followed by addition of p-toluenesulfonyl chloride (0.58 g, 3.06 mmol) in small portions. The reaction mixture was then warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residual oil was taken up in EtOAc (75 mL). The organic layer was washed with 2.0 M HCl (1×10 mL), water (1×50 mL), and brine (2×50 mL). The resulting EtOAc layer was dried and concentrated under reduced pressure to yield oil. Flash chromatography (hexanes:ethyl acetate—3:2 containing 1% acetic acid) yielded the desired sulfonamide 24 (0.9 g, 47%). 1H NMR (400 MHz, DMSO-d6): 7.54 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.39 (m, 1H), 3.58 (s, 3H), 2.72-2.92 (m, 4H), 2.69 (s, 3H), 2.57-2.64 (m, 4H), 2.47 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][N:4]=1)#[N:2].Cl>C(OCC)C.C(Cl)(Cl)Cl>[NH:2]=[C:1]1[C:3]2[C:12]3[C:7]([CH:6]=[CH:5][N:4]=2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:13]2[C:17]1=[CH:16][CH:15]=[CH:14]2
Reactant: N#Cc1nccc2cccc(-n3cccc3)c12
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N=c1c2nccc3cccc(c32)n2cccc12
Yield: 80.1 %

Procedure:
A solution of 1-cyano-8-(pyrrol-1-yl)isoquinoline (279 g.) in diethyl ether (7 liters) and pure chloroform (7 liters) saturated with anhydrous hydrogen chloride is kept at a temperature of between 0° and 5° C. for 72 hours. After extraction with ice-water (15 liters) followed by alkalinisation of the blood red acid solution thus obtained, 7-imino-7H-indolizino[5,6,7-ij]isoquinoline (223.4 g.) is obtained in the form of green-yellow needles melting at 201° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CCCCO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, butanol and DBU in DME. EI-MS m/e (%): 278 (M+, 24), 249 ([M—C2H5]+, 28), 193 (70), 177 (100), 150 (48), 108 (86), 94 (62), 70 (48), 69 (46), 43 (68), 41 (62), 29 (45).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[C:40]([CH3:45])[N:41]=[C:42]([CH3:44])[CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (320 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (530 mg, 93%).