Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:20])[C:10](=O)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:21].Cl[CH2:23][CH:24]=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:10]1[NH:21][CH:23]=[CH:24][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: O=CCCl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OC(C)(C)C
Product: C[C@@H](NC(=O)OC(C)(C)C)c1[nH]ccc1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
(R)-tert-butyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (702a; 34.3 g, 119 mmol) was treated with NH4OAc (Fluka; 92 g, 1194 mmol), NH3 (2 M in MeOH; Aldrich; 597 mL, 1194 mmol). To the resulting slurry was added chloroacetaldehyde (50% in water; Aldrich; 154 mL, 1194 mmol) in portions. The temperature of the reaction rose to 42° C. and the reaction was cooled with ice briefly, to 38° C. When no further exotherm was noted, the clear light yellow reaction was placed on a rotovap in a 50° C. water bath. After 40 min, the reaction was dark brown. The reaction was heated for an additional 100 min. The reaction was concentrated in vacuo and treated with DCM and sat'd aq. NaHCO3 with rapid stirring (CAUTION GAS EVOLUTION). The reaction was transferred to a 5 L bottle and solid NaHCO3 was added. When gas evolution was no longer observed and the material was transferred to a separatory funnel. (Noted a lot of chunky material that did not dissolve in DCM, used some MeOH to dissolve.) The water layer was extracted with 3×250 mL of DCM, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting thick brown oil was dissolved in ˜150 mL of DCM, filtered, and purified by silica gel chromatography (1500 g ISCO Redisep gold column) using 0-30% EtOAc/hexanes to elute product. The product-containing fractions were concentrated to afford (R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate (23.41 g, 75 mmol, 63% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (1H, br. s.), 6.53 (2H, dt, J=13.9, 2.8 Hz), 6.10 (1H, br. s.), 5.15 (1H, br. s.), 1.57 (9H, s), 1.53 (3H, d, J=6.8 Hz), 1.43 (9H, s). m/z (ESI, +ve) 333.1 (M+Na)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:33][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:32]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 417.22 g/mol.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([NH:25][CH2:26][C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:22]([N:25]([CH2:26][C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:21]
Reactant: Cc1nnc(CNC(C)(C)C)o1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C(C)(C)C)o1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine in the presence of TBTU and DIEA to obtain the title compound as yellow solid; MS (EI): m/e=436.4 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(Cn1ncc2cc(I)ccc21)OC
Temperature: 40 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a solution of 5-iodio-1H-indazole (8.28 g, 33.9 mmol) in DMSO (104 mL) was added 2-bromoacetaldehyde dimethyl acetal (7.9 mL, 68 mmol) and Cs2CO3 (44.1 g, 136 mmol). The reaction mixture was stirred at 40° C. for 18 h; then the reaction mixture was diluted with H2O (100 mL) and EtOAc (175 mL). The partitioned material was extracted with EtOAc (4×175 mL). The organics were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (silica gel, hexanes with 0.1% Et3N/EtOAc with 0.1% Et3N, 100:0 to 90:10) gave the title compound (4.49 g, 46%) as a light orange powder. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=1.0 Hz, 1H), 7.92 (d, J=0.5 Hz, 1H), 7.60 (dd, J=9.0, 1.5 Hz, 1H), 7.28 (d, J=9.0 Hz, 1H), 4.71 (t, J=5.5 Hz, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.33 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(C)(C)CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
A solution of methyl 3-hydroxy-2,2-dimethylpropanoate (5.00 g, 38 mmol), N,N-diisopropylethylamine (7.30 g, 57 mmol) and tert-butyldimethylchlorosilane (6.80 g, 45 mmol) in dry DMF (70 mL) was stirred at room temperature for 12 h. The reaction solution was quenched with water (225 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), then dried over MgSO4. Concentration under reduced pressure afforded methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate as colorless oil (9.36 g, 100%). It was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.64 (s, 3H), 3.55 (s, 2H), 1.13 (s, 6H), 0.85 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:16]1([S:26](Cl)(=[O:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.[Li+].[OH-]>C(Cl)Cl>[C:16]1([S:26]([NH:1][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)(=[O:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCOC(=O)c1c(N)ccc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1c(NS(=O)(=O)c2cccc3ccccc23)ccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 6-amino-1H-indole-7-carboxylate (prepared as described in Showalter, H. D. et al., J. Org. Chem., 1996, 61, 1155-1158, 0.05 g, 0.25 mmol) in CH2Cl2 (5 mL) was treated with 1-naphthalenesulfonyl chloride (0.066 g, 0.29 mmol) and pyridine (0.040 mL, 0.50 mmol), shaken for 16 hours at ambient temperature, filtered, and concentrated. The concentrate was dissolved in 9:1 methanol/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 60° C. for 16 hours. The mixture was concentrated and the concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 384 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.43 (br s, 1H), 10.77 (s, 1H), 8.62 (d, 1H), 8.30 (dd, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.69 (m, 1H), 7.64-7.60 (m, 3H), 7.20 (d, 1H), 7.17 (t, 1H), 6.35 (dd, 1H).
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(CCOc3ccccc3)C2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (500 mg), (2-bromoethoxy)benzene (347 mg), and DMF (5 mL) was added Na2CO3 (488 mg). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (516 mg).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[NH:34][CH:35]=[C:36]([CH:38]=O)[N:37]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:36]4[N:37]=[C:33]([CH3:32])[NH:34][CH:35]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cc1nc(C=O)c[nH]1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]c(C)n4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-methyl-1H-imidazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl (3-fluoro-4-hydroxyphenyl)carbamate (17.2 g, 75.7 mmol) in dimethyl sulfoxide (100 mL) were added 2-chloro-5-nitropyridine (10 g, 63.1 mmol) and cesium carbonate (30.8 g, 94.6 mmol), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=5/1) and collected by filtration to give the title compound (17.0 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]([NH:29][OH:30])=[NH:28])=[N:19]3)[CH:12]([CH3:32])[CH2:11]2)=[C:4]([F:33])[CH:3]=1.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]4[N:28]=[CH:34][O:30][N:29]=4)=[N:19]3)[C@@H:12]([CH3:32])[CH2:11]2)=[C:4]([F:33])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(C(=N)NO)c4cccnc43)C(C)C2)c(F)cc1Cl
Solvent: COC(OC)OC
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncon4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 248.1 %

Procedure:
A mixture of 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (1.2 g), trimethyl orthoformate (20 mL) and para-toluene sulfonic acid (PTSA) (0.1 g) was stirred at 100° C. overnight. The reaction mixture was concentrated in vacuo to provide a crude residue which was purified by flash chromatography to provide 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-[1,2,4]oxadiazol-3-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (0.7 g). LCMS Retention time: 2.61 min (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile). LCMS observed for (M+H)+: 486.
Reaction SMILES: COC(=O)C1C=CC([CH:10]2C[N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][C:25]5[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=5[O:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)=CC=1.N1[CH2:38][CH2:37][CH2:36][CH:35]([C:39]([OH:41])=[O:40])CC1>>[O:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22][C@@H:21]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:12]2[CH2:38][CH2:37][CH2:36][CH:35]([C:39]([OH:41])=[O:40])[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C2CN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)C2)cc1
Reactant: O=C(O)C1CCCNCC1
Product: O=C(O)C1CCCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1

Procedure:
Compound 266 is synthesized from Intermediate A and azepane-4-carboxylic acid according to General Method B. (LC/MS method 16: ES+ m/z 368.3 [M+H]+, Rt=2.76 min)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([C:10](OCC)=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([NH:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(SC)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1CO
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 4-(ethylamino)-2-(methylthio)pyrimidine-5-carboxylate (19.5 g, 81.9 mmol) in anhydrous THF (100 mL) was added LiAlH4 (12.3 g, 327.6 mmol) in portions at 0° C. under N2 atmosphere. After stirring for 30 min, the reaction was quenched with water and then 2N aqueous NaOH as added. The suspension was filtered and the filtrate was concentrated to afford (4-(ethylamino)-2-(methylthio)pyrimidin-5-yl)methanol (15 g, 92.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.78 (s, 1 H), 6.74 (t, J=4.8 Hz, 1 H), 5.05 (t, J=5.2 Hz, 1 H), 4.26 (d, J=5.2 Hz, 2 H), 3.36 (m, 2 H), 2.37 (s, 3 H), 1.10 (m, 3 H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[CH:20]=[CH:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>C(O)CC(C)C>[CH3:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[CH:20]=[CH:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccccc1C=CC(=O)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccccc4C)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 479 mg. of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 461 mg. of 2-methylcinnamoylpiperazine in 10 ml. of isoamyl alcohol was heated under reflux for 4 hours. After ice-cooling, the reaction mixture was filtered and the product thus obtained was washed with ethanol to yield 812 mg. of the desired product as the hydrochloride.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]1[CH2:15][C@@H:14]([CH2:16][O:17][Si](C(C)C)(C(C)C)C(C)C)[C@H:13]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=O)=[CH:30][CH:29]=2)[C@@H:12]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]3[O:48][CH2:47][C:46](=O)[N:45]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:44]=3[CH:55]=2)[CH2:11]1)=O)(C)(C)C.[CH2:56]1[CH2:60][O:59][CH2:58][CH2:57]1>O>[CH2:60]([O:59][C@H:58]([CH3:57])[CH2:37][O:36][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:13]2[C@@H:12]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]4[O:48][CH2:47][CH2:46][N:45]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:44]=4[CH:55]=3)[CH2:11][NH:10][CH2:15][C@H:14]2[CH2:16][OH:17])=[CH:29][CH:30]=1)[CH3:56]
Reactant: COCCCN1C(=O)COc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H]3c3ccc(C(=O)OC)cc3)cc21
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4.30 mmol of NaOH are added to a solution of 1.05 mmol of (3R,4R,5S)-4-(4-methoxycarbonyl-phenyl)-3-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilanyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester in 10 ml of THF and 10 ml of H2O. The resulting reaction mixture is stirred at 90° C. for 16 h and then cooled to RT. After dilution with H2O and acidification (pH 3) with 4N aqueous HCl, the mixture is extracted with TBME (2×)—the combined organic phases are washed with brine, dried over Na2SO4 and concentrated by evaporation. The crude title compound is obtained as a viscous brown oil. Rf=0.24 (EtOAc/heptane 2:1+a drop of formic acid); Rt=6.71 (gradient I).
Reaction SMILES: [NH2:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10][C:11]1[CH:12]=[N:13][C:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=2)=[C:15]([CH:19]=1)[C:16](O)=[O:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[F:10][C:11]1[CH:12]=[N:13][C:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=2)=[C:15]([CH:19]=1)[C:16]([NH:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:17]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: NC1(CO)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)NC2(CO)CCCCC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 62.7 %

Procedure:
A solution of (1-aminocyclohexyl)-methanol (R. J. W. Cremlyn et al J. Chem. Soc Perkins I, 1972, 1727) (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 64 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-(1-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (191 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17](O)=[O:18].S(Cl)([Cl:23])=O>C=CC(=C)C>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17]([Cl:23])=[O:18]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: C=CC(=C)C
Product: CC1(C)[C@H](C(=O)Cl)[C@@H]1/C=C\C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1.6 g of (1R,cis)2,2-dimethyl-3[(Z)3-oxo-3-benzyloxy-1-propenyl]-cyclopropane carboxylic acid, 10 ml of isoprene and 1 ml of thionyl chloride was stirred for 5 hours under a current of nitrogen and then was concentrated to obtain 2 g of (1R,cis)2,2-dimethyl-3[(Z)3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylic acid chloride which was concentrated to obtain 2 g of (1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylic acid chloride which was used as is in the following step.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([NH:22][NH2:23])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:21][C:34](=[O:36])[NH:23][N:22]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)NN)c3c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
To a solution of 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carbohydrazide (1 g, 3.2 mmol) in DCM (100 mL) and DIPEA (1.19 mL, 19 mmol) was added a solution triphosgene (1.1 g, 3.7 mmol) in DCM (3 mL) dropwise. The reaction was stirred at RT for 2 h, then the solution was concentrated in vacuo. The residue was purified with silica gel chromatography (eluting with 0-10% MeOH in DCM) to give 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (50 mg, 5%) as a white solid. MS (ESI, pos. ion) m/z: 338.0 (M+1); 1H NMR (DMSO-d6) δ ppm: 12.32 (s, 1H), 12.1 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.00-8.17 (m, 3H), 7.6 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 1.49 (d, J=6.0 Hz, 6H).