Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4](=[O:9])[C:5]=1[O:6]CC.Br.[NH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:9])[C:3]=1[NH:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1
Reactant: NCCn1oc(=O)[nH]c1=O
Reactant: CCOc1c(N)c(=O)c1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(NCCn2oc(=O)[nH]c2=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (0.56 g, 4.0 mmol) in ethanol (20 mL) was added to 2-(2-aminoethyl)-1,2,4-oxadiazolidine-3,5-dione hydrobromide (0.90 g, 4.0 mmol) in ethanol (100 mL). The reaction mixture was treated with 1N sodium hydroxide solution (8 mL, 8 mmol) and allowed to stir for 24 hours at room temperature. The resulting precipitate was filtered, dissolved in water and passed through an ion exchange column (AG 50W-X2, 100-200 mesh, H+ form), eluting with water. The eluent was freeze dried yielding the title compound as a cream colored solid, partial hydrate (0.45 g, 45%, mp 225° C. (dec)); IR (KBr, cm-1) 3300, 3140, 1820, 1740, 1720, 1640; MS (+FAB) 241 (MH+); 1H NMR (DMSO, 400 MHz): δ12.4 (br s, NH), 7.5 (br s, 3 NH), 4.0-3.5 (m, 4H); 13C NMR (DMSO, 400 MHz): ppm 183.72, 183.63, 170.06, 168.96, 158.17, 152.72, 50.41, 41.68.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[CH2:44]([O:51][C:52]1[CH:61]=[CH:60][C:55]([C:56]([NH:58][NH2:59])=[O:57])=[CH:54][CH:53]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:59][NH:58][C:56](=[O:57])[C:55]3[CH:60]=[CH:61][C:52]([O:51][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:53][CH:54]=3)=[O:19])=[CH:21][CH:22]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:10])=[CH:27][CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(C(=O)NN)cc1
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirring solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1 (260 mg, 0.68 mmol) in THF (5 mL) were added 4-methylmorpholine (0.15 mL, 1.36 mmol) and isobutyl carbonochloridate (0.09 mL, 0.71 mmol). After stirring at room temperature for 2 h, 4-(heptyloxy)benzohydrazide (187 mg, 0.75 mmol) was added and stirring continued for another 2 h. The reaction mixture was poured onto NaHCO3 (50 mL) and extracted with DCM (3×20 mL). The combined organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (100% EA in iso-hexanes) to afford 297 mg (71%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 as an off-white foam. LCMS-ESI (m/z) calculated for C36H45N3O6: 615.8 found 616.0 [M+H]+, tR=2.89 min. (Method 4).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.[Cl-].[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) are dissolved in glacial acetic acid (50 mL) and a solution of sodium chloride (8.2 g, 75 mmol) in water (15 mL) is added. The reaction mixture is stirred at room temperature for 1 hour, then water (300 ml) is added to obtain the precipitation of the desired product that is filtered and dried at 40° C. under vacuum (12 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[C:10]([OH:17])[N:11]=[CH:12]3)[CH:4]=[N:3]1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[S:19]([O:17][C:10]1[N:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[N:16]=[CH:15][CH:14]=2)(=[O:20])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2nccc3cnc(O)cc23)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2nccc3cnc(OS(=O)(=O)C(F)(F)F)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-ol (Preparation 89, 15 mg, 0.066 mmol) in DCM (0.5 mL) was added Tf2O (0.013 mL, 0.080 mmol) and triethylamine (9.3 uL, 0.066 mmol). The reaction mixture was stirred at room temperature under 1 hour. The reaction mixture was concentrated in vacuo. The residue was passed through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (14 mg, 59%).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:57])[CH2:56][CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][CH2:56][C:52]([F:57])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as colorless gum (13.3 mg, 69%). MS (m/e): 407.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH3:11][N:12]([CH3:20])[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1O>>[CH3:11][N:12]([CH3:20])[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: CN(C)[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cc(O)no1
Product: COC(=O)c1cc(O[C@@H]2CCCC[C@H]2N(C)C)no1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield by essentially following the procedures outlined in Example 20, Part B from methyl 3-hydroxyisoxazole-5-carboxylate and (±)-trans-2-(dimethylamino)cyclohexanol (Example 79, Part A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:7]=2[CH:15]=1.[Cl:16][CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][Cl:16])=[CH:26][CH:25]=3)=[N:8][C:7]=2[CH:15]=1
Reactant: Nc1ccc(OCCCl)cc1
Reactant: COc1ccc2sc(S(C)(=O)=O)nc2c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2sc(Nc3ccc(OCCCl)cc3)nc2c1
Reaction time: 2 h

Procedure:
A mixture of 5-methoxy-2-methylsulphonylbenzothiazole (1,105 g.), 4-(2-chloroethoxy)aniline (780 g.) and toluene (5 liters) is boiled for 2 hours under reflux with simultaneous removal of water. A further quantity of 4-(2-chloroethoxy)aniline (156 g.) is then added and the mixture boiled under reflux for 4 hours. The mixture is cooled, the solid filtered off, washed with ethanol (about 3 liters) and dried to give 5-methoxy-2-[4-(2-chloroethoxy)anilino]benzothiazole m.p. 176°- 178°C.
Reaction SMILES: OC1C=C2C(=CC=1)[C:8](=[O:12])[N:7]([CH3:13])[CH2:6]C2.COC1C(CCN2CCC(N3C4C(=CC=C(C(N)=O)C=4)C=C3)CC2)=C2C(C(=O)C(C)(C)CO2)=CC=1.C(C1C(OC)=CC2COC(=O)NC=2C=1)C=C.[CH3:65][O:66][C:67]1[C:78]([CH2:79][CH2:80][N:81]2[CH2:86][CH2:85][CH:84]([N:87]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([C:96]([NH:98][CH3:99])=[O:97])[CH:94]=4)[CH:89]=[CH:88]3)[CH2:83][CH2:82]2)=[CH:77][C:70]2N(C)C(=O)O[CH2:74][C:69]=2[CH:68]=1>>[CH3:65][O:66][C:67]1[CH:68]=[C:69]2[C:70](=[CH:77][C:78]=1[CH2:79][CH2:80][N:81]1[CH2:86][CH2:85][CH:84]([N:87]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([C:96]([NH:98][CH3:99])=[O:97])[CH:94]=4)[CH:89]=[CH:88]3)[CH2:83][CH2:82]1)[C:8](=[O:12])[N:7]([CH3:13])[CH2:6][CH2:74]2
Reactant: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)COC(=O)N5C)CC3)c2c1
Reactant: CN1CCc2cc(O)ccc2C1=O
Agent: C=CCc1cc2c(cc1OC)COC(=O)N2
Agent: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OCC(C)(C)C2=O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)CCN(C)C5=O)CC3)c2c1

Procedure:
The subject compound was synthesized from 6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one (CAS#: 308110-07-8) according to the methods described in Example 22, (1), (2) and (3), and Example 23, (5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH3:15]
Reactant: CC(=O)c1ccccc1
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccccc1)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with acetophenone (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=75 cm) was 3.46 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 1-(2-bromophenyl)-1-phenylethanol (GC retention time: 23.5 min) was obtained in 81% yield. 1H NMR (400 MHz, CDCl3) δ: 1.95 (s, 3H), 3.49 (s, 1H), 7.16 (dt, J=7.6, 1.6 Hz, 1H), 7.20-7.30 (m, 5H), 7.38 (dt, J=7.6, 1.2 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.80 (dd, J=7.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 30.4, 77.4, 122.2, 125.4, 126.7, 127.2, 128.0, 128.3, 129.0, 134.7, 144.7, 147.4. HRMS (EI) m/z: calcd. for C14H13BrO 276.0150, found 276.0155.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[C:8]([CH3:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:8]([CH3:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[CH2:1]
Reactant: Cc1c(Cl)cccc1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1cccc(Cl)c1C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (6.9 g, 0.019M) was suspended in dry tetrahydrofuran (100 ml) at -40° C. under an atmosphere of dry nitrogen. n-Butyllithium (13.5 ml. of a 1.55M solution in hexane, 0.021M) was added dropwise during 10 minutes and the mixture was stirred at -40° C. for 30 minutes. 3-Chloro-2-methylbenzaldehyde (3.0 g, 0.019M) in dry tetrahydrofuran (10 mls) was then added. The mixture was maintained at -40° C. for 30 minutes and then allowed to warm to room temperature. Hexane (150 ml) was added and the mixture was filtered. The hexane was evaporated to give crude 3-chloro-2-methylstyrene which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](Cl)=[O:41])[CH:35]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([C:19]([NH:18][C:14]2[CH:13]=[C:12]([N:11]([CH3:32])[C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:40]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[O:41])[S:3][C:4]=4[N:5]=3)[CH:17]=[CH:16][CH:15]=2)=[O:31])[CH:25]=[CH:24][CH:23]=1)([CH3:27])[CH3:28])#[N:30]
Reactant: O=C(Cl)c1cccnc1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)c3cccnc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl)-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D5(i) in pyridine (4 mL) was added pyridine-3-carbonyl chloride hydrochloride (362 mg, 2.03 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=35/65→15/85), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from methanol, ethyl acetate and hexane to give the title compound (78 mg, 42%) as a orange crystal.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([NH2:15])=[O:14]>C1COCC1>[N+:19]([C:18]1[CH:10]=[CH:11][C:12]([C:13]([NH2:15])=[O:14])=[CH:16][C:17]=1[O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)([O-:21])=[O:20]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1ccc([N+](=O)[O-])c(OC2CCOC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of 3-hydroxytetrahydrofuran (2.57 ml, 1.2 eq, 23.0 mmol) in THF (50 ml) was added sodium hydride as a 60% dispersion in oil (0.84 g, 1.1 eq, 20.91 mmol) this mixture was then stirred at 0° C. for 30 minutes. The preceding mixture was added dropwise to a solution of 3-fluoro-4-nitrobenzamide (3.5 g, 1.0 eq, 19.01 mmol) in THF (30 ml) and stirred at room temperature for 3.5 hours. The reaction was quenched with water and extracted with DCM (3×50 ml), the organics were combined, dried over sodium sulphate, filtered and the solvent removed in vacuo to give the title compound as a yellow solid (4.77 g, 18.9 mmol, 96% corrected). LCMS: [M+H]+=253, Rt=1.41 min, 100% purity
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:4]=1)=[O:8])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=[O:12].[CH3:14]O>>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(O)c1cnccn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnccn1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To methanol (8.0 mL), thionyl chloride (2.08 mL) was added dropwise under a nitrogen atmosphere at −10° C. and the mixture was stirred at the same temperature for 30 minutes. To this, 2-pyrazinecarboxylic acid (1.00 g, 8.06 mmol) was added at the same temperature and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added to the residue, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 19/1) to give methyl 2-pyrazinecarboxylate (969 mg, yield: 87%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.[CH:23]1([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CCOC(C)=O.[Cu]I>[CH:23]1([CH2:27][O:28][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Reactant: OCC1CCC1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OCC3CCC3)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 115 °C
Yield: 24.5 %

Procedure:
3-Iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.100 g, 0.244 mmol), cyclobutylmethanol (1.05 mL, 12.19 mmol), 1,10-phenanthroline (0.044 g, 0.244 mmol), copper (I) iodide (0.046 g, 0.244 mmol), and 40% KF/Al2O3 (0.248 g, 1.71 mmol) were combined in a reaction vial and heated to 115° C. for 24 hours. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and filtered through GF/F filter paper. The filtrate was then concentrated and passed through a 10 g SepPak cartridge, eluting with DCM. The fractions were collected and then purified by preparative TLC (2×0.5 mm plates, 15% EtOAc/hexanes) to give 3-(cyclobutylmethoxy)-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (22 mg, 24.5%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C(=O)C>[CH2:16]([S:28][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCCCCCSc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A suspension consisting of 75.66 g (0.55 mol) of 4-chlorobenzonitrile, 106.42 g (0.77 mol) of potassium carbonate and 111.32 g (0.55 mol) of 1-dodecanethiol is heated, with stirring, under an inert gas atmosphere in 280 ml of N,N-dimethylacetamide to 130° C. and is then stirred at this temperature for 24 hours. After cooling the reaction mixture to room temperature, it is poured on a mixture of 700 g of ice and 750 ml of water. The mixture is filtered and the filter cake is washed with water. The product is recrystallised from methanol and dried at 50° C. under vacuum, affording 160.2 g (96% of theory) of 4-(dodecyl-thio)benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:13]1[C:21](=[O:22])[NH:20][C:19]2[C:14]1=[N:15][C:16]([CH:23]1[CH2:25][CH2:24]1)=[N:17][CH:18]=2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:34][N:35]1[C:43]2[C:38](=[C:39]([CH3:44])[CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:45][N+](C)(C)C)=[CH:36]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:13]1[C:21](=[O:22])[N:20]([CH2:45][C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])[N:35]([CH3:34])[CH:36]=2)[C:19]2[C:14]1=[N:15][C:16]([CH:23]1[CH2:24][CH2:25]1)=[N:17][CH:18]=2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C3CC3)nc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C3CC3)nc21
Temperature: 100 °C
Yield: 50.9 %

Procedure:
To a solution of (R)-3-(2-cyclopropyl-8-oxo-7,8-dihydro-purin-9-yl)-3-phenyl-propionic acid ethyl ester (313 mg, 0.89 mmol) in DMF (5 ml) were added K2CO3 (234 mg, 1.7 mmol) and (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (275 mg, 1.27 mmol). The reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was therefore diluted with ethyl acetate and washed with water (×4). The organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography, eluded with 3% methanol to 10% in CH2Cl2 to afford the titled compound (231 mg, 50%). LCMS, M++1, m/z: 509.59.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:29]4[CH2:28][CH2:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)([OH:32])[CH2:31][CH2:30]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Product: OC1(c2ccc(Cl)cc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 29 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-(4-chlorophenyl)-4hydroxypiperidine, the title compound hydrochloride salt was obtained in 29% yield as a white powder, mp 261°-263° C. elemental