Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][CH2:17][C:18]#[N:19])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[NH2:19][CH2:18][CH2:17][CH2:16][C:13]12[CH2:15][CH:6]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=31)[C:7]1[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCCC12CC(c3ccccc31)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: NCCCC12CC(c3ccccc31)c1ccccc12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of β-(9,10-dihydro-9,10-methano-9-anthryl)propionitrile (250 mg) and lithium aluminum hydride (100 mg) in dioxane (12 ml) was stirred at 60° C. for 5 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-aminopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted into its hydrochloride. M.P. 275° C. (decomp.).
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH2:25]([NH2:27])[CH3:26]>C1(C)C=CC=CC=1>[CH2:25]([NH:27][CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH3:26]
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CCN
Solvent: Cc1ccccc1
Product: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
A solution of (2RS)-2-(2-cyano-10-phenothiazinyl)-propyl methanesulphonate (50 g) and ethylamine (100 cc) in toluene (600 cc) is heated for 24 hours to a temperature in the region of 105° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with distilled water (250 cc) and the mixture is extracted successively with ethyl acetate (500 cc and 250 cc). The combined organic phases are extracted with N aqueous hydrochloric acid solution (2×500 cc). The aqueous phases are alkalinized with caustic soda (d=1.33) to pH 13 and extracted successively with ethyl acetate (500 cc and 250 cc). The combined organic phases are washed with saturated aqueous sodium chloride solution (250 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-Ethylamino-2-propyl]-2-phenothiazinecarbonitrile (30.4 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24]S(C5C=CC(C)=CC=5)(=O)=O)=[CH:20][CH:19]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)O1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:56]1[N:57]([CH3:61])[CH:58]=[CH:59][N:60]=1>CS(C)=O.CO>[CH3:61][N:57]1[CH:58]=[CH:59][N:60]=[C:56]1[C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(B5OC(C)(C)C(C)(C)O5)cc34)cc2)cc1
Reactant: Cn1ccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CS(C)=O
Product: Cn1ccnc1-c1cnc2[nH]cc(-c3ccc(O)cc3)c2c1
Yield: 52 %

Procedure:
50 mg (80 μmol) of toluene-4-sulfonic acid 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-phenyl ester and 7 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloride dichloromethane adduct were placed in a Smith® vial. 1 ml of acetonitrile, 1 ml of a 2 M aqueous solution of sodium carbonate and 16 μl of 2-bromo-1-methyl-1H-imidazole were added and the resulting mixture was irradiated in a Personal Chemistry microwave reactor to 165° C. for 20 min. The resulting mixture was diluted with 2 ml of DMSO and 1 ml of methanol and subsequently filtered over sodium sulfate and a 0.45 μm PTFE syringe filter. The filtrate is directly purified via mass-triggered reverse phase HPLC to afford 12 mg (41 μmol, 52% yield) of 4-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]phenol as a colorless solid. 1H-NMR (d6-DMSO): δ 11.97 (s, 1H), 9.40 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.14 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.30 (s, 1H), 7.02 (s, 1H), 6.86 (d, J=8.7 Hz, 2H), 3.78 (s, 3H); MS: m/z 291 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[Cl:21][CH2:22]I.C(=O)=O.CC(C)=O.C[Li]>CCOCC.C1COCC1>[Cl:21][CH2:22][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=2)[CH2:13][CH2:12]1)=[O:16]
Reactant: ClCI
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: O=C=O
Agent: [Li]C
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(C(=O)CCl)CC2)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A dry 3-neck, 250-mL round bottom flask was charged with ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (3.0 g, 10.07 mmol), anhydrous THF (50.4 mL) and chloroiodomethane (0.878 mL, 12.09 mmol). The flask was fitted with a rubber septum and pressure-equalized dropping funnel topped with an inert gas inlet and placed under a nitrogen atmosphere. The mixture was cooled to −78° C. (CO2/acetone bath). Methyllithium (7.56 mL of a 1.6 M solution in Et2O, 12.09 mmol) was added dropwise to the mixture from the dropping funnel over 10 min. The mixture was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl (10 mL) and warmed to RT. The mixture was adjusted to a pH=6 and extracted with Et2O (3×75 mL). The extract was washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using an 80 g silica gel cartridge and gradient elution from 20:1 Hex/EtOAc to 2:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone (1.3 g, 4.30 mmol, 43% yield) as a pale orange solid. LC/MS [M+H]+=302. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.50 (1 H, s), 6.44 (1 H, s), 4.18 (2 H, s), 3.87 (3 H, s), 3.62-3.71 (2 H, m), 2.75-2.86 (3 H, m), 1.97 (2 H, s), 1.84 (2 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18](O)=[O:19])=[CH:8][C:7]=1[O:6]2.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(OC(N(C)C)=[N+](C)C)C=2N=N1.[CH:45]([N:48](CC)[CH:49](C)[CH3:50])(C)[CH3:46].C(NCC)C>CN(C)C=O>[CH2:45]([N:48]([CH2:49][CH3:50])[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:17])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)=[O:19])[CH3:46]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(=O)c3ccc(C(=O)O)cc3oc2c1
Agent: CN(C)C(Oc1cccc2[nH]nnc12)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccc(OC)cc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of compound 6i (0.707 g, 2.62 mmol) and O-benzotriazol-yl-N,N, N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowed to stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added and the resultant mixture was stirred for 2 h. The mixture was poured into ice water. A solid was collected by filtration, washed with water and air dried to give the title compound (0.445 g). MS: m/z 326.0 (MH+). 1H NMR (DMSO-d6): δ 1.07 (br t, 3 H), 1.19 (br t, 3 H), 3.20 (br q, 2 H), 3.48 (brt, 2 H), 3.95 (s, 3 H), 7.08 (m, 1 H), 7.17 (d, 1 H, J=2.1 Hz), 7.40 (d of d, 1H, J=1.3 &8.1 Hz), 7.59 (d, 1 H, J=1.2 Hz), 8.12 (d of d, 1 H, J=1.3 & 8.9 Hz) and 8.21 (d, 1 H, J=8.1 Hz).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Phenyl chloroformate (0.474 mL, 3.77 mmol) was added dropwise to 4-[4-[(4-fluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.67 g, 3.77 mmol) and sodium bicarbonate (476 mg, 5.66 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give crude product which was triturated with diethyl ether to give the desired product (1.90 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(NC(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.[Na+].[I-]>CN1C(=O)CCC1.O>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])=[CH:32][CH:31]=1
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
Hexadecandioic acid (2 g, 7 mmol) was dissolved in dry NMP (25 mL). Diisopropylamin (1.2 mL, 7 mmol) and 4-methoxybenzyl chloride (0.95 mL, 7 mmol) was added, followed by NaI (0.52 g, 3.5 mmol). The mixture was heated to 80° C. for 1 hour, poured into water (100 mL) and filtered. The precipate was washed with dichloromethane (150 mL), the dichoromethane phase was dried (Na2SO4) and solvent removed in vacuo to yield the crude product, which was recrystallized several times from heptane to yield hexadecanedioic acid mono-(4-methoxy-benzyl)ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>CS(C)=O.C(#N)C>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[F:29])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Fc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CS(C)=O
Product: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(N)sc12
Reaction time: 1 h
Yield: 62.3 %

Procedure:
The product from step (a) (20 mg, 67 μmol) was suspended in dimethyl sulphoxide (450 μL) and Hunig's base (13 μL, 74 μmol) was added. 2-Fluorobenzyl bromide (8.0 μL, 67 μmol) was quickly added to the stirred solution. The reaction was stirred for 60 minutes to give a homogeneous solution The crude solution was diluted to 1 mL with acetonitrile and chromatographed on a reverse phase column using a gradient (40–70% acetonitrile) to give the title compound as a white solid (17 mg, 61% yield).
Reaction SMILES: [NH2:1][C:2](=[S:12])[C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:6][CH:7]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CC(C)=O>[C:17]1([C:15]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:6][CH:7]=3)[S:12][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(C(N)=S)cs1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)cs1
Temperature: -10 °C
Yield: 90 %

Procedure:
To a solution of 150 mg (0.745 mmol) of methyl 4-(aminothioxomethyl)-thiophene-2-carboxylate (as prepared in the previous step) in 6 mL of acetone was added 148 mg (0.745 mmol) of 2-bromoacetophenone. After refluxing for 2 h, the mixture was concentrated by boiling to a volume of ca. 2 mL. The resulting mixture was cooled (−10° C.) and filtered washing with cold acetone (2×0.5 mL). A second crop was obtained from the mother liquors and the combined crops dried to afford the title compound as a beige solid (202 mg, 90%). 1H-NMR (300 MHz, DMSO-d6) δ8.56 (d, 1H, J=1.5 Hz), 8.25 (d, 1H, J=1.5 Hz), 8.18 (s, 1H), 8.04 (d, 2H, J=7 Hz), 7.48 (t, 2H, J=7 Hz), 7.38 (t, 1H, J=7 Hz), and 3.89 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C15H11NO2S2: 302.0 (M+H). Found: 301.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][N:13]([CH3:30])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)c(CO)c4)c3c2cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2ncc3c(c(-c4ccc(C#N)c(CO)c4)nn3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (78 mg, 216 μmol) is dissolved in N,N-dimethylformamide (1.0 ml) under argon, and methyl iodide (34 μl, 541 μmol) and potassium carbonate (60 mg, 433 μmol) are subsequently added. The suspension is stirred at room temperature for 1 h. For purification, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are lyophilised, giving 4-(7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (41 mg, 110 μmol) as a solid. MS: 375.2 (M+H+).
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].[CH3:50][C:51]1([CH3:57])[O:56][CH2:55][CH2:54][NH:53][CH2:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:53]2[CH2:54][CH2:55][O:56][C:51]([CH3:57])([CH3:50])[CH2:52]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: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC1(C)CNCCO1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC1(C)CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)CCO1

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 2,2-dimethylmorpholine and isolated as colorless gum (13.7 mg, 70%). MS(m/e): 415.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N+:4]([O-])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C(OCC)(=O)C>CN(C)C=O.CO.[Pd]>[NH2:1][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2ccc(O)cc2[n+]([O-])n1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nnc2cc(O)ccc2n1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
4.6 g (25.82 mmol) of 3-amino-benzo[1,2,4]triazine-7-ol-1-oxide was dissolved in 200 mL of 1:1 mixture of dimethylformamide and methanol. 0.5 g of 10% Pd/C was added to this solution and H2 gas was bubbled through the solution for 3 hours. The progress of the reaction was monitored by TLC, using a 9:1 mixture of dichloromethane/methanol as an eluent and a UV lamp. The starting material is highly fluorescent under UV, while the product is not. When the reaction was complete, the resulting dark solution was filtered through a short pad of silica gel and solvent was removed in vacuum to produce a dirty-brown solid. 40 mL of ethyl acetate and 40 mL of methanol were added to the solid and the resulting suspension was heated to reflux for about 10 min. Then the suspension was allowed to cool down to ambient temperature. The solid was collected by filtration, washed with 40 mL of ethyl acetate, 40 mL of diethyl ether and dried in vacuum to yield 3.2 g of the product in a form of a greenish solid. Yield: 76%.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: COc1cccc(CCl)c1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(CN2Cc3ccccc3C2=O)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 1-chloromethyl-3-methoxy-benzene (0.094 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.053 g, 42%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.80 (s, 3H), 4.26 (s, 2H), 4.80 (s, 2H), 6.88 (d, 3H), 7.22-7.52 (m, 4H), 7.90 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[C:37](C)=[C:36]([CH:39]=O)[NH:35][C:34]=2[CH3:41])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:37]=[C:36]([CH3:39])[NH:35][C:34]=2[CH:41]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl) 1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (96.8 mg, 72%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:38]=[CH:37][C:24]([CH2:25][N:26]5[CH2:29][CH:28]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:27]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.CO>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:38]=[CH:37][C:24]([CH2:25][N:26]5[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A solution of tert-butyl 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (518 mg, 0.956 mmol) in trifluoroacetic acid (15 mL) was allowed to stand at room temperature for 1.5 h. The volatiles were removed under reduced pressure, and the residue was co-evaporated from ethyl acetate/hexanes. (2×10 mL). The residue was suspended in water (10 mL) and the pH was adjusted to ˜11 with 1N aqueous sodium hydroxide. To this solution was added sufficient 1N aqueous hydrochloric acid to adjust the pH ˜4.5. The resulting suspension was stirred at room temperature overnight. The white suspension was filtered through a medium porosity sintered glass filter, and the filter cake was washed thoroughly with water. The solid was dried, the white powder was suspended in methanol, and the suspension was sonicated until it was uniform. The methanol was removed under reduced pressure, and the procedure was repeated twice more to afford a white solid that was stirred as a suspension in methanol (−30 mL) overnight. Vacuum filtration and drying afforded 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylic acid (345 mg, 0.707 mmol, 74% yield) as a white powder. HPLC ret. time=3.45 min. (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=486.12. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.39-3.45 (m, 2H), 3.64 (s, 2H), 7.50 (d, J=8.28 Hz, 2H), 7.58 (m, 5H), 8.02 (d, J=8.28 Hz, 2H), and 8.26 (d, J=1.25 Hz, 1H). Elemental Analysis: Calc. for C24H18N3O3SF3.0.1H2O: C 59.22; H, 3.76; N, 8.63, S 6.59, F 11.71. Found: C24H18N3O3SF3-0.1H2O: C 59.06; H, 3.45; N, 8.60, S 6.61, F 11.42; KF (Found)=0.25% water.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCCCNC1=C(c2ccccc2)S(=O)(=O)N(CCOC)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and hexane-1-amine in a similar manner as described for Example 1. 1H NMR (400 MHz, CD3CN): δ 7.48-7.56 (m, 5H), 5.83-5.99 (m, 1H), 3.83 (t, 2H), 3.67 (t, 2H), 3.35 (s, 3H), 2.84-2.90 (m, 2H), 1.13-1.32 (m, 4H), 0.92-1.09 (m, 4H), 0.82 (t, 3H); Mass Spectrum: M−H+ 365.