Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 36 h
Yield: 24 %

Procedure:
A mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (WO 03/089412, p22), (2 g, 9.33 mmol), 2-bromopyridine (1.35 mL, 13.99 mmol) and N,N-diisopropylethylamine (2.5 mL, 13.99 mmol) was heated at 130° C. for 3 hours. Potassium carbonate (2 g, 14 mmol) was added and the reaction mixture was heated at 130° C. for a further 8 hours. 2-Bromopyridine (1 mL, 10.36 mmol) was then added to the mixture and heating continued at 130° C. for 36 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and extracted with saturated citric acid solution (2×15 mL), and the combined aqueous solution was basified with sodium hydrogen carbonate and extracted with dichloromethane (2×30 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 0:100 to 50:50, to afford the title compound in 24% yield, 646 mg. 1H NMR(CDCl3, 400 MHz) δ: 1.45(s, 9H), 1.55-1.70(m, 4H), 2.78-2.90(m, 5H), 4.10-4.30(m, 2H), 4.65-4.80(m, 1H), 6.45-6.55(m, 2H), 7.40-7.45(m, 1H), 8.10-8.15(m, 1H); LRMS APCI m/z 292 [M+H]+
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[N:29][C:28]([CH3:31])=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1ncn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 65 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (100 mg, 0.149 mmol), DCM (4.0 mL) and TFA (1.0 mL, 13.0 mmol) for 3 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (50 mg, 65%) as a white powder. LCMS: m/z=514.7 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.4 Hz, 1H), 8.72 (br s, 1H), 6.78 (s, 1H), 5.25 (dd, J=8.8, 5.6 Hz, 1H), 4.61 (dd, J=14.4, 5.2 Hz, 1H), 4.47 (dd, J=14.4, 6.0 Hz, 1H), 4.33 (dd, J=6.0, 5.2 Hz, 1H), 2.30 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:15]1([NH2:19])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:19][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: NC1CCC1
Product: COc1cccc2cc(C(=O)NC3CCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and cyclobutylamine to give N-Cyclobutyl-7-methoxybenzofuran-2-carboxamide (Compound 289a). Successively, it was formylated to give N-cyclobutyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 289b), then compound 289b was reacted with methylamine hydrochloride to give Compound 289 as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH3:10])[C:5]([C:27]#[N:28])=[CH:4][N:3]=1.[OH-].[NH4+:30]>O1CCOCC1>[NH2:30][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH3:10])[C:5]([C:27]#[N:28])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: C[C@H](Nc1nc(Cl)ncc1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 100 °C
Yield: 24.9 %

Procedure:
A mixture of (S)-2-chloro-4-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile (60 mg, 0.153 mmol) in dioxane (1 mL) and ammonium hydroxide (1 mL, 7.19 mmol) was heated at 100° C. in a microwave reactor for 1 hour. The reaction mixture was subsequently concentrated and purified by preparative HPLC (basic mode, 25% to 50% ACN/water gradient) to give the title compound as an off-white solid (14.2 mg, 24.9%). 1H NMR (500 MHz, CD3OD) δ ppm 1.41 (br s, 3 H), 3.59-3.74 (m, 3 H), 3.86-3.92 (m, 3 H), 5.16-5.36 (m, 1 H), 6.39-6.50 (m, 1 H), 6.63-6.73 (m, 1 H), 7.57-7.67 (m, 2 H), 7.77-7.88 (m, 1H), 8.04-8.13 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C19H19N9, 374.18; found 374.3.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:56])([F:55])[CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:52]2[CH2:53][CH2:54][CH:49]([C:48]([F:56])([F:55])[F:47])[CH2:50][CH2:51]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(C(F)(F)F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-trifluoromethylpiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[C:17]([N+:6]([O-:9])=[O:7])=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(NC(C)=O)c(C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of tin(IV)chloride (1 9.3 ml) and 69.5% nitric acid (10.3 ml) in methylene chloride (140 ml) was added dropwise to a solution of N-(4-methoxy-2-methylphenyl)acetamide (28 g, 0.14 mol) in methylene chloride (500 ml) cooled to and maintained at −30° C. The reaction mixture was stirred at −30° C. for 1.5 hours, allowed to warm to ambient temperature then poured on to ice/water. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined extracts were dried (MgSO4), the solvent removed by evaporation and the residue purified by column chromatography eluting with petroleum ether/ethyl acetate (2/8) to give N-(4-methoxy-2-methyl-5-nitrophenyl)acetamide (1 7.8 g, 51%)
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[NH:22][CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[N:22]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)[CH2:21]1)[C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:12][N:13]=1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cn1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
A mixture of [3,5-bis(trifluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]amine (45 mg, 0.09 mmol), 2-chloro-5-trifluoromethyl-pyridine (50 mg, 0.27 mmol) and iPr2EtN (45 uL 0.27 mmol) in THF (1.5 mL) is stirred at 120° C. under microwave irradiation. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: hexane/EtOAc) to give (3,5-Bis-trifluoromethyl-benzyl)-[(3S,5R)-5-ethyl-1-(5-trifluoromethyl-pyridin-2-yl)-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a colorless oil (38 mg, 66%). ESI-MS m/z: 643 [M+1]+, Retention time 2.45 min (condition A).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:24]=[O:25])[C:10]([CH3:14])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)n(Cc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccccc2)c(C)c1C=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Dissolve 1-benzyl-3,5-dimethyl-1H-pyrazole (3.088 g, 16.6 mmol) in N,N-dimethylformamide (12.8 mL) and heat the mixture to 95° C., then add phosphorus oxychloride (13.4 mL) dropwise. Stir the mixture for 3 hr. at 95° C. then cool and add ice water very slowly. Adjust the mixture to approximately pH=4 using 5 N sodium hydroxide, extract the black mixture with diethyl ether 3 times, dry (sodium sulfate) and filter to give the title preparation as a yellow solid (2.65 g, 75%). 1H-NMR (400 MHz, DMSO-d6) δ 2.282 (s, 3H); 2.433 (s, 3H); 5.233 (s, 2H); 7.13 (m, 2H); 7.21-7.34 (m, 3H); 9.800 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH2:6][CH2:5][N:4]([CH:9]([C:11]([OH:13])=[O:12])[CH3:10])[C:3]1=[O:14].O=[C:16]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:11]([CH:9]([N:4]1[C:3](=[O:14])[CH:2]([NH:1][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][S:7][CH2:6][CH2:5]1)[CH3:10])([OH:13])=[O:12]
Reactant: CC(C(=O)O)N1CCSCC(N)C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSCCN(C(C)C(=O)O)C1=O
Yield: 74.8 %

Procedure:
6-Amino-4-N-(1-carboxyethyl)perhydro-1,4-thiazepin-5-one (0.05 g) is suspended in 1 ml of methanol. Ethyl 2-keto-4-phenylbutyrate (0.24 g) and acetic acid (0.02 g) are added. A 1M solution of sodium cyanoborohydride (0.75 ml) is added dropwise over a period of twenty hours. After removal of methanol, the reaction mixture is taken up in water and loaded onto a column of Dowex-50 (on the proton cycle). After thorough washing with water, the column is developed with 5% pyridine solution. Lyophilization of the eluent afforded the crude product (0.08 g), which is purified by preparative thin layer chromatography on silica gel (9:1 chloroform-methanol containing 5% formic acid). The product is obtained as an oil (0.07 g). The NMR spectrum is consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:1]([NH:5][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.14 g of isobutylamine (56.6 mmol) and 2.86 g of triethylamine (28.3 mmol) in 40 mL of CH2Cl2 was slowly added 5.0 g of benzenesulfonyl chloride (28.3 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 hr. 150 mL of CH2Cl2 were added, and the organic layer was washed with saturated aqueous solution of NH4Cl and brine (30×2 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (CDCl3) δ 0.87 (d, J=6.6 Hz, 6H), 1.71 (tsept, J=6.7, 6.5 Hz, 1H), 2.76 (dd, J=6.5, 6.7 Hz, 2H), 4.61 (t, J=6.5 Hz, 1H), 7.49–7.88 (m, 5H). Mass Spectrum (CI+) m/e=214 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH:14](O)=O.C=O.[OH-].[Na+]>O.C(OCC)C>[CH3:14][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: O=CO
Reactant: CC1CC(C)(C)NC2CCCCC12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC1CC(C)(C)N(C)C2CCCCC12

Procedure:
1,2,2,4-tetramethyl decahydroquinoline was prepared. 36.3 grams (0.2 mole) of 2,2,4-trimethyl decahydroquinoline of about 58% cis structure was placed in a reactor vessel equipped for agitation. Formic acid, 20.2 grams (0.44 mole) was added dropwise to the reactor vessel followed by the slow addition of 17.4 grams of 38% by weight formaldehyde in water solution. After addition, the mix was refluxed at for 4 hours. A 5N sodium hydroxide solution was then added until the mix was basic. Diethyl ether was added and the mix separated out and the ether fraction obtained. The fraction was concentrated and then distilled using a 3 inch Vigreaux column to yield 5.4 grams of a product boiling at 70° C. at 0.6 mm Hg. The NMR spectra of the product was consistent with the desired product, 1,2,2,4-tetramethyl decahydroquinoline. The theoretical carbon, hydrogen, nitrogen analysis for the formula C13H25N is 79.92% carbon, 12.90% hydrogen, and 7.17% nitrogen while measured values were 77.23% carbon, 13.13% hydrogen, and 6.56% nitrogen.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([CH3:32])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:30]#[N:31])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH3:29])[CH:14]=2)=[O:9])C.[OH-].[Na+]>O1CCCC1.CO>[C:30]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][CH3:29])[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:33])[C:4]([OH:34])=[O:3])=[O:9])[N:11]=1)#[N:31]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3CC)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccccc1Oc1ccc2c(O)c(C(=O)NCC(C)(C)C(=O)O)nc(C#N)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.5 %

Procedure:
A mixture of 3-{[1-Cyano-7-(2-ethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (20.3 mg, 0.04 mmole) and 1N NaOH (0.4 ml, 0.4 mmole) in a mixture of tetrahydrofuran (0.5 ml) and methanol (1 ml) was stirred room temperature for three days before it was concentrated and acidified with 1N HCl to pH=3. The precipitated was filtered, dried to give the title compound as a white solid (15 mg): MS: (+) m/z 434.21 (M+1), (−) m/z 432.15 (M−1).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:10](O)[CH2:11]CC.CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:5]1([O:4][CH2:1][CH2:2][CH2:10][CH3:11])[CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: CCCCO
Reactant: CC(=O)OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC(C)=O
Product: CCCCOC1C=CCC1

Procedure:
2-Cyclopentenyl acetate (0.30 g) and n-butanol (0.40 g) were mixed and stirred vigorously at 40° C. for 4 hours with a solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water. At the end of the reaction period acetone was added to give a single phase, and the solution was analyzed by gas chromatography using an Apiezon column programmed at 60-220° C. Peaks for the cyclic compounds had the following relative areas.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:37])[C:9]2[N:10]=[C:11]([C:27]3[C:28]([CH3:36])=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](COCC[Si](C)(C)C)[N:15]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1.O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:37])[C:9]2[N:10]=[C:11]([C:27]3[C:28]([CH3:36])=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1nn2ccccc2c1-c1nc(N(C)c2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn2ccccc2c1-c1nc(N(C)c2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Yield: 84 %

Procedure:
N-(4-chlorophenyl)-N-methyl-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-amine (0.0566 g, 0.102 mmol) was treated with 4 M of Hydrochloric acid in 1,4-dioxane (6.0 mL, 24 mmol) and Water (1.0 mL, 56 mmol) at 35° C. to r.t. for 42 hours. The reaction solution was rotavaped, azeotroped with MeOH to give a crude residue. The material was dissolved in small amount of MeOH, diluted with Et2O, filtered to give a solid product. (0.037 g, 84% yield). LCMS: (FA) ES+ 422. 1H NMR (400 MHz, d1-chloroform & d4-methanol) δ 8.89 (0, 1H), 8.41 (d, J=6.78 Hz1-H8.26 (d, J=6.78 Hz, 1H), 7.36 (m, 1H), 7.10-7.12 (d, J=8.78 Hz, 2H), 6.87-6.90 (m, 3H), 3.51 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: C([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([OH:17])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.[ClH:18]>O>[ClH:18].[NH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([OH:17])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: Cl
Solvent: O
Product: NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Temperature: 95 °C
Yield: 78 %

Procedure:
To a 3-neck 5-L flask equipped with a reflux condenser, a mechanical stirrer and a temperature probe was added 3-acetylamino-adamantane-1-carboxylic acid (432 g, 1.82 mol), water (1.00 L) and concentrated hydrochloric acid (2.44 L), and the resulting mixture was heated at 95° C. for 6 days. During this time, solid material precipitated from the solution. After cooling at 0° C., the solids were filtered and washed with acetone. The solid was then dried under high vacuum at 50° C. for about 2 hours to afford 328 g (78%) of the title compound, 3-amino-adamantane-1-carboxylic acid hydrochloride, as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.35 (br s, 1H), 8.27 (br s, 3H), 2.22-2.12 (m, 2H), 1.92-1.85 (m, 2H), 1.83-1.71 (ml 6H), 1.69-1.48 (m, 4H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C=O)C>[O:3]=[C:2]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: NC(=O)CCl
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)C(=O)c2ccccc21
Temperature: 90 °C
Yield: 60.5 %

Procedure:
To a mixture of isatin (5.0 g, 35 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetamide (3.74 g, 40 mmol) in a 100 mL of flask was added DMF (25 mL). The resulting mixture was heated at 90° C. (oil temp.) for 2 h. After cooling to rt, it was poured onto ice/H2O (200 mL) δ 10 and the resulting precipitate was collected by suction filtration to give 2-(2,3-dioxoindolin-1-yl)acetamide (4.32 g) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.30 (s, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 4.25 (s, 2H).
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11](=[CH:14][CH2:15][CH3:16])[CH:12]=[O:13]>CC(C)=O>[CH2:15]([CH:14]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH:12]([OH:13])[CH:11]1[CH3:10])[CH3:16]
Reactant: CCC=C(C)C=O
Reactant: N=C(N)c1ccccc1
Solvent: CC(C)=O
Product: CCC1N=C(c2ccccc2)NC(O)C1C
Temperature: 25 °C

Procedure:
To an ice cooled mixture of 19.98 g (16.6 mmol) of benzamidine in 80 mL of acetone, was added dropwise over two hours, a solution of 16.35g (16.6 mmol) 2-methyl-2-pentenal and 0.055 g 1,4-hydroquinone, in acetone. The mixture was left to stir cold and warm to room temperature over 20 hours. The product was isolated by vacuum filtration and was washed with a minimal amount of acetone. 15.6 g (44%) of 6-ethyl-5-methyl-4-hydroxy-2-phenyl-3,4,5,6-tetrahydropyrimidine was collected, as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[C:24]([N:34]=[CH:35][N:36]([CH3:38])[CH3:37])=[C:23]([F:39])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:40])([CH3:4])([CH3:3])[CH3:2].CI.[C:46]([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([O:33][CH3:46])[C:29]([F:31])([F:32])[F:30])[C:24]([N:34]=[CH:35][N:36]([CH3:37])[CH3:38])=[C:23]([F:39])[CH:22]=3)[CH2:14][S:15](=[O:18])(=[O:19])[CH2:16]2)[O:11][C:10]1=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1C[C@H](O)C(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N=CN(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N′-[4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-6-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-phenyl]-N,N-dimethyl-formamidine (0.095 g, 0.144 mmol) in anhydrous DMF was added under argon NaH (0.008 g, 0.34 mmol, 95%) and after 20 min stirring methyliodide (0.028 mL, 0.44 mmol). The reaction mixture was stirred for 2 h at 25° C. After addition of saturated aq. NaHCO3 solution the title compound was extracted with EtOAc. The crude compound, a light yellow oil, was used as such in the next step: TLC (EtOAc) Rf=0.47; HPLC RtA=2.06 min; ESIMS [M+H]+=642.