Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:50])([F:49])[C:41]1[N:42]=[C:43]([C:46](O)=[O:47])[S:44][CH:45]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:11][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:46]([C:43]5[S:44][CH:45]=[C:41]([C:40]([F:49])([F:39])[F:50])[N:42]=5)=[O:47])[CH2:5][CH2:6]4)[CH2:13]3)[CH:15]=2)=[N:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: Cl
Product: N#CCC1(n2ccc(-c3ncnc4[nH]ccc34)c2)CN(C2CCN(C(=O)c3nc(C(F)(F)F)cs3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 4-trifluoromethylthiazol-2-ylcarboxylic acid following the procedure described for Example 261, followed by purification with HPLC (method B) provided the title compound. LC-MS: 541.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.92 (brs, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 7.78 (s, 1H), 7.43 (d, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 4.45 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.55 (d, 2H), 3.45 (d, 2H), 3.37 (s, 2H), 3.20 (m, 2H), 1.80-1.60 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C=O)C.[Cl-].[NH4+].C(OCC)(=O)C>[C:31]([N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:19]1[C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:28])=[O:10])[CH2:12][CH2:13]1)=[O:18])(=[O:33])[CH3:32]
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)n1c(C(=O)N2CCC(C(=O)N(C)Cc3ccccc3)CC2)cc2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) in 1 mL of DMF was added to a suspension of sodium hydride (11.72 mg, 0.293 mmol) in 2.0 mL DMF. The reaction was stirred at 80° C. for 10 minutes before adding acetic anhydride (0.050 ml, 0.533 mmol). The reaction was allowed to stir for 5 hours before it was cooled to room temperature and diluted with ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride twice, followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via silica gel chromatography for 50% ethyl acetate/hexanes to 100% ethyl acetate. Purification afforded white solid as the product. (Yield: 13 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.12-8.06, 7.65-7.59, 7.41-7.13, 6.91-6.84, 4.65, 4.49, 3.96-3.83, 3.06-2.94, 2.76, 2.61-2.55, 1.87-1.49
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][OH:32])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCNCCO
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 455 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH2:11][CH2:10][NH:9][CH2:8][C:6]=2[N:7]=1.[C:18]([O:23][C@@H:24]([C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(O)(C)C>[C:18]([O:23][C@@H:24]([C:26]1[N:27]=[C:28]([N:9]2[CH2:10][CH2:11][C:5]3[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3][C:2]([CH3:1])=[N:7][C:6]=3[CH2:8]2)[CH:29]=[CH:30][N:31]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: Cc1nc2c(c(-c3ccccc3)n1)CCNC2
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(nc(C)nc3-c3ccccc3)C2)n1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine (prepared according to the method of Example 86, Step D, 6.8 g, 30.0 mmol) in isopropanol (125 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 30 mmol) followed by triethylamine (12.5 mL, 89.9 mmol). This mixture was stirred at reflux for 8 h, cooled to room temperature overnight, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/ethyl acetate) to give 11.0 g (88%) of the title compound of Example 86, Step E, as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.62-7.40 (c, 5H), 6.45 (d, 1H), 5.69 (q, 1H), 4.78 (s, 2H), 3.93 (app s, 2H), 2.95 (t, 2H), 2.77 (s, 3H), 2.40 (t, 2H), 1.77-1.63 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 418 (MH+).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)=O)=CC=1[N+]([O-])=O.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:46]([O-:48])=[O:47])=[C:30]([CH:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[OH:33])[CH:31]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:46]([O-:48])=[O:47])=[C:30]([C:32]([C:34]2[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=2)=[O:33])[CH:31]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(O)c2cc(OC)c(OC)c(OC)c2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: COc1ccc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: c1cc[nH+]cc1
Product: COc1ccc([N+](=O)[O-])c(C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Yield: 77.2 %

Procedure:
(5-Methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone using (5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.9 g, 8.2 mmol) and pyridinium chlorochromate (2.6 g, 12.2 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 95:5) to afford (5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (2.2 g, 76%) as a white solid: 1H NMR (CDCl3) δ 8.22 (d, J=9 Hz, 1H), 7.11-7.06 (dd, J=3, 9 Hz, 1H), 7.00 (s, 2H), 6.89 (d, J=2 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.82 (s, 6H); 13C NMR (CDCl3) δ 191.95, 164.01, 153.25, 143.37, 139.57, 138.57, 130.85, 126.93, 115.30, 113.49, 106.78, 60.93, 56.32, 56.25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O)(=O)C.[Br:13]Br>>[Br:13][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: BrBr
Reactant: Nc1ccc(F)cn1
Solvent: CC(=O)O
Product: Nc1ncc(F)cc1Br

Procedure:
To a solution of 5-Fluoro-pyridin-2-ylamine (3.00 g, 26.8 mmol) in acetic acid (30.0 mL, 528 mmol) at 80° C. was added bromine (5.50 mL, 107 mmol) in acetic acid (5.50 mL, 96.7 mmol). The temperature was maintained for one hour. The reaction was poured over ice, neutralized, and extracted with EtOAc. The organic layer was purified with ISCO silica gel chromatography to afford 3-bromo-5-fluoro-pyridine-2-ylamine. 6-Fluoro-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-fluoro-pyridine-2-ylamine in a manner analogous to Steps 2a-b to afford a white solid (80%). MP=243-246° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.97 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 6.28 (bs, 2H). MS=231.0 (MH)+. 105b) 6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine prepared from 8-Bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and (4-Methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford a tan solid (45%). MP=226-234° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.00 (s, 1H), 8.43 (d, J=7.8 Hz, 2H), 8.06-8.00 (m, 3H), 6.27 (bs, 2H), 3.28 (s, 3H). MS=307.0 (MH)+. 105c) [6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-bis-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was formed from 6-fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (14% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.32 (m, 2H), 8.10 (d, J=7.8 Hz, 2H), 7.70 (d, J=9.4 Hz, 1H), 7.55 (s, 1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 2H), 7.17-7.13 (m, 2H), 7.01 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 3.31 (bm, 4H), 3.18 (bm, 4H), 3.12 (s, 3H), 2.62 (bm, 4H), 2.58 (bm, 4H), 2.40 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([NH:14][NH2:15])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16](OC(=O)C)(=O)[CH3:17].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[O:13][C:16]([CH3:17])=[N:15][N:14]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CCN(C(=O)NN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1CCN(c2nnc(C)o2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.1 %

Procedure:
To a solution of 1-hydrazinocarbonyl-piperidine-4-carboxylic acid ethyl ester (215 mg, 0.999 mmol) in THF (2 ml) was added acetic anhydride (188 μl, 2.00 mmol). After stirring for 5 minutes at rt phosphorus oxychloride (182 μl, 2.00 mmol) was added and the reaction mixture was stirred for 5 days at RT. The reaction mixture was added dropwise onto a 1 M solution of sodium carbonate (10 ml). The mixture was diluted with EtOAc (15 ml). The aq. layer was extracted with EtOAc (15 ml). The organic layers were washed with brine (15 ml) and dried over Na2SO4. A column chromatography (SiO2, EtOAc/Hept 1/1 to Hept/MeOH 9/1) yielded 48 mg (20%) of the title product as a light brown oil. MS m/e: 240.3 [M+H]+
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A mixture of 4-boronobenzoic acid (200 mg, 1.2 mmol), 2-bromopyridine (208 mg, 1.3 mmol), K2CO3 (497 mg, 3.6 mmol) and Pd(dppf)Cl2 (10 mg) in dioxane (4 mL) and H2O (1 mL) was stirred at 125° C. for 30 min with microwave heating under N2. The catalyst was filtered, and the filtrate was acidified with 2N HCl to pH 5-6. The solution was concentrated, and the residue was dissolved in MeOH and filtered. The filtrate was concentrated, and the residue was purified by prep-TLC to give the title compound (100 mg, Yield 41.8%). LCMS (m/z): 200.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[C:12]([OH:14])=[O:13].N(C(OCC)=O)=NC(OCC)=O.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[C:12]([O:14][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:13]
Reactant: OCc1ccccc1
Reactant: CC(Sc1cc2ccccc2[nH]1)(C(=O)O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Sc1cc2ccccc2[nH]1)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution (5 ml) of 2-(1H-indol-2-yl)thio-2-phenylpropionic acid (1.5 g) and diethyl azodicarboxylate (0.96 g) in anhydrous tetrahydrofuran, a solution (5 ml) of benzyl alcohol (0.81 g) and triphenylphoshine (1.44 g) in anhydrous tetrahydrofuran was added dropwise under an argon atmosphere, and the mixture was stirred at room temperature overnight. The solvent was evaporated off under reduced pressure. Benzene was added to the residue, and deposited crystalline matter was filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (diluting solvent: n-hexane/ethyl acetate=9:1), and was further recrystallized from ethyl acetate/n-hexane to give 1.37 g (yield 71 %) of the product compound as a colorless scale-like crystal. The melting point was 102°-103° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:26][C:25]1[CH:24]=[C:23]([CH3:27])[NH:22][C:21](=[O:28])[C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=2[CH:10]=[C:2]([C:37]2[CH:42]=[N:41][C:40]([N:43]3[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:17]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3ccc(N4CCNCC4)nc3)cc21
Yield: 75.9 %

Procedure:
To a 30 mL microwave vial were added (R)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.225 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCl2(dppf)-CH2Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140° C. for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25% ACN/H2O, 0.1% NH4OH to 60% ACN/H2O, 0.1% NH4OH) to give 90 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.11 (s, 3H), 2.15-2.20 (m, 3H), 2.24 (s, 3H), 2.77-2.83 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54-4.68 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.52 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.27 Hz, 1H); LCMS: 527.7 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>C(Cl)Cl>[Cl:17][C:16]1[CH:15]=[CH:14][C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:3][C:2]=1[N:1]=[C:18]=[S:19]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 3-amino-4-chlorobenzylcarbamate (2.57 g, 10.0 mmol) was added to a mixture of 1,1′-thiocarbonyldi-2-pyridone (2.55 g, 11.0 mmol) and DCM (90 mL) and it was stirred at rt for 4 h. The mixture was diluted with DCM and filtered over silica gel. The organic layer was concentrated to give the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N:28]([CH3:52])[CH:29]2[C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][C:32]=3[CH2:31][CH2:30]2)[N:39]=[C:38]([CH3:42])[N:37](COC(=O)C(C)(C)C)[C:36]4=[O:51])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH2:13][C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]C)=[O:21])[N:18]=1)[C:8]([O:10]C)=[O:9])=[O:5].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:27]=[C:26]([N:28]([CH3:52])[CH:29]2[C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][C:32]=3[CH2:31][CH2:30]2)[N:39]=[C:38]([CH3:42])[NH:37][C:36]4=[O:51])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH2:13][C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)Cn1nnc(CC[C@H](NC(=O)c2ccc(N(C)C3CCc4cc5nc(C)n(COC(=O)C(C)(C)C)c(=O)c5cc43)cc2F)C(=O)OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)N[C@@H](CCc2nnn(CC(=O)O)n2)C(=O)O)c(F)c1)CC3
Reaction time: 1 h

Procedure:
To a solution of methyl (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzamido}-4-(2-methoxycarbonylmethyltetrazol-5-yl)butyrate (87 mg) in methanol (2 ml) was slowly added an aqueous solution of NaOH (1N, 0.72 ml). The resultant solution was stirred at room temperature for 4 hours then more aqueous 1N NaOH (0.36 ml) was added and stirring was continued at room temperature for 1 hour. Next the solution was diluted with water (3 ml) and acidified to pH 4 with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water (15 ml), and dried in vacuo over phosphorus pentoxide. There was thus obtained (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-amino]benzamido}-4-(2-carboxymethyltetrazol-5-yl)butyric acid (57 mg) as a pale yellow solid, m.p. 196°-199° C.;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2cc(C)nc(C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
2,6-Dimethyl-4-chloro-pyrimidine (1.0 g) in ethanol (10 ml) was added slowly to a solution of ethyl isonipecotate (1.1 g) and triethylamine (2.0 ml) in ethanol (20 ml). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water, washed with water (2×50 ml), dried and evaporated to give 1-(2,6-dimethylpyrimidin-4-yl)-4-(ethoxycarbonyl)piperidine as an oil (1.71 g); NMR (CDCl3): 1.25 (t, 3H), 1.65-1.80 (m, 4H), 1.95-2.00 (m, 2H), 2.55 (s, 3H), 2.45 (s, 3H), 2.50-2.60 (m, 1H), 3.00 (dt, 2H), 4.15 (q, 2H), 4.35 (d, 2H), 6.2 (s, 1H).
Reaction SMILES: OCC(CO)O.C([O:14][CH2:15][CH:16]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:17][CH3:18])C1C=CC=CC=1>[Pd].CO>[Si:21]([O:20][CH2:19][CH:16]([CH2:15][OH:14])[O:17][CH3:18])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: OCC(O)CO
Product: COC(CO)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of the protected glycerol derivative Compound 41 (5.0 g, 16 mmol) and 10% palladium on activated carbon (wet Degussa type E101 NE/W) (0.43 g) in MeOH (50 mL) was evacuated using an aspirator pump and filled with hydrogen. After 2 hours, TLC analysis showed the reaction to be complete, the mixture was filtered through Celite and the filtrate was evaporated to dryness to give 1-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (Compound 42) (99%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=O.FS(OC)(=O)=O.[C:14]1([NH:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[NH:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(Cl)Cl.C(O)(C)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[N:22][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[N:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCOC1=O
Reactant: N=C(Nc1ccccc1)N1CCCC1
Agent: COS(=O)(=O)F
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CN1CCOC1=NC(=Nc1ccccc1)N1CCCC1
Reaction time: 3 h

Procedure:
To a solution of 3-methyloxazolidin-2-one, 2.02 g (0.02 mole), in dry methylene chloride under dry nitrogen is added 2.28 g (0.02 mole) of methyl fluorosulfonate in one portion. After stirring 3 hrs, 0.02 mole of N-phenyl-1-pyrrolidinecarboximidamide free base in dry methylene chloride is added. After stirring at room temperature overnight, the solution is shaken with excess cold 3 N NaOH. The organic layer is separated and dried over K2CO3, filtered, and the solvent removed in vacuo to afford the crude base. Addition of an equimolar amount of fumaric acid to a solution of the free base in isopropanol, followed by recrystallization from isopropanol/ether affords pure N-(3-methyl-2-oxazolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide fumarate; m.p. 160°-162° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18](=[O:21])[O:19][CH3:20])=O)(C)(C)C.C(OCC)(=O)C.Cl>C(O)C>[ClH:16].[NH2:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18](=[O:21])[O:19][CH3:20]
Reactant: COC(=O)Nc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(Cl)cc1CN
Reaction time: 8 h
Yield: 170.5 %

Procedure:
(Step 3) To a solution (2 ml) of methyl (2-{[(t-butoxycarbonyl)amino]methyl}-4-chlorophenyl)carbamate obtained in Step 2 (1.25 g) in ethanol was added 4N hydrogen chloride-ethyl acetate solution (2 ml) at room temperature, and the mixture was stirred overnight. The resulting crystals were collected by filtration, and recrystallized from ethanol and ethyl acetate to give methyl [2-(aminomethyl)-4-chlorophenyl]carbamate hydrochloride (0.85 g) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CO1
Product: OC(CCl)CNCc1ccccc1

Procedure:
reacting epichlorohydrin with benzylamine to form the addition product, N-benzyl-3-amino-1-chloropropan-2ol (I);