Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:32])[NH:19][C:20]2([C:29]([OH:31])=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[CH2:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C:18]([NH:19][C:20]3([C:29]([OH:31])=[O:30])[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:32])[C:15]=2[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)NC2(C(=O)O)Cc3ccccc3C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
5-(2-Carboxy-indan-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (72) (650 mg, 1.49 mmol) is dissolved in 30% solution of TFA in DCM (10 mL) and the resulting solution is stirred at RT for 2 h. The solution is concentrated to give a TFA salt of 2-[(1,2,3,4-tetrahydro-isoquinoline-5-carbonyl)-amino]-indan-2-carboxylic acid (670 mg, 100%). This TFA salt (250 mg, 0.56 mmol) is dissolved in 6N aqueous solution of HCl (20 mL). The resulting suspension is stirred overnight and turned into a clear solution. The solution is concentrated to give a pure product (73) as white solid (130 mg, 62%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH3:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12].CC/C=C/CC>CN1C(=O)CCC1>[CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC/C=C\CC
Agent: CC/C=C/CC
Solvent: CN1CCCC1=O
Solvent: CCC=CCC
Product: C=CCCCC

Procedure:
The 3-hexene feedstock was assumed to have a composition of 33 wt % cis-3-hexene and 67 wt % trans-3-hexene. The normal boiling points for 1-, 2-, and 3-hexene are listed in Example 2. The normal boiling for NMP, the extraction solvent in this example, is 204° C. (400° F.). The isomerization reaction was assumed to occur at the bottom of the column. The column was assumed to have 150 theoretical stages, a kettle reboiler, and a total condenser. The operating conditions for the column consisted of a pressure of 5 atm, condenser temperature of 124° C. (255° F.), and reboiler temperature of 279° C. (533° F.). In addition, 500 lb/hr of NMP was added to the 10th theoretical stage of the column (near the top). This resulted in a column with a diameter of 11.4 ft and a reflux ratio of 455. For this case, the 1000 lb/hr 3-hexene feed resulted in 980 lb/hr of 99 wt % 1-hexene product. The column bottoms contained 98 wt % NMP, which can be recycled back to the column. A detailed material balance is shown in the following table. RXFEED is the distillation column feed stream, SOLVENT is the NMP extractive distillation solvent stream, BOTTOMS is the distillation column bottoms stream, and 1-HEXENE is the product stream, which is obtained from the top of the column.
Reaction SMILES: [CH2:1]([C:5]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH2:2][CH2:3][CH3:4].Br[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: BrC1CCCC1
Reactant: CCCCc1nc(C(F)(F)F)nc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(C(F)(F)F)nc2c1ncn2C1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of 6-(1-butyl)-2-trifluoromethylpurine (35 mg, 0.14 mmol), bromocyclopentane (89 mg, 0.60 mmol), potassium carbonate (83 mg, 0.6 mmol) and N,N-dimethylformamide (3 ml) was heated to 100° C. After 8 hours, the reaction mixture was cooled to 40° C. and concentrated under vacuum. The residue was treated with 15 ml of ethyl acetate and washed with 5% sodium bicarbonate (2×15 mL). The organic layer was concentrated and purified by chromatography (20% ethyl acetate in hexane) to give 6-(1-butyl)-9-cyclopentyl-2-trifluoromethylpurine (26.6 mg, 60% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[C:6]=2[C:26]#[N:27])[CH2:3][CH2:2]1.C1(NC2N3N=CC(C=C4C(=O)NC(=O)N4)=C3N=C(S(C)=O)C=2C#N)CC1.[Cl:54][C:55]1[CH:56]=[C:57]([C@H:61]([NH2:63])[CH3:62])[CH:58]=[CH:59][CH:60]=1>C(O)(C)C>[Cl:54][C:55]1[CH:56]=[C:57]([CH:61]([NH:63][C:7]2[C:6]([C:26]#[N:27])=[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]4)=[C:9]3[N:8]=2)[CH3:62])[CH:58]=[CH:59][CH:60]=1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N
Agent: CS(=O)c1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N
Solvent: CC(C)O
Product: CC(Nc1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N)c1cccc(Cl)c1
Temperature: 90 °C

Procedure:
The mixture of 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile and 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfinyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (20 mg) was mixed with (R)-1-(3-chlorophenyl)ethanamine (33 mg) in i-propanol (0.5 mL). The reaction mixture was heated at 90° C. in the microwave for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The residue was diluted with water, filtered and washed with water followed by 20% ethanol/water mixture. The solid was dried under high vacuum to give 2 mg of the product, 5-(1-(3-chlorophenyl)ethylamino)-7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS (M+1=463)
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH2:3]1.[C:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[C:16]([C:19]1[CH:20]=[C:21]([S:25]([N:7]2[CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=3)[CH2:3][C@H:2]2[CH3:1])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN(c2ccc(C#N)nc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(S(=O)(=O)N2CCN(c3ccc(C#N)nc3)C[C@H]2C)c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a stirred solution of 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile (250 mg, 1.24 mmol) and 3-acetylbenzenesulfonyl chloride (270.3 mg, 1.24 mmol) in anhydrous dichloromethane (4 mL) was added diisopropylethylamine (0.43 mL, 2.48 mmol). The mixture was stirred at room temperature for over night. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to yield 5-{(3R)-4-[(3-acetylphenyl)sulfonyl]-3-methylpiperazin-1-yl}pyridine-2-carbonitrile in 80.3% yield (383 mg) as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[C:25]2[O:26][CH2:27][CH:28]=[N:29][C:24]=2[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[C:25]2[O:26][CH2:27][CH2:28][N:29]([C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Clc1cccc2c1OCC=N2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCOc2c(Cl)cccc21
Yield: 42.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 220 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 157 mg of 8-chloro-2H-benzo[b][1,4]oxazine (which can be prepared according to WO 2008100463) and 214 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 135 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 140 mg of 2-[2-(8-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)CCC.[Cl-].[Li+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ncccn2)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A microwave vial was charged with 5-bromo-2-fluoropyridine (commercially available from Acros, Pittsburgh, Pa.)(0.200 mL, 1.738 mmol), 2-(tributylstannyl)pyrimidine (commercially available from Frontier Scientific, Inc., Logan Utah) (0.718 mL, 2.173 mmol), lithium chloride (0.147 g, 3.48 mmol), copper (I) iodide (0.033 g, 0.174 mmol), and DMF (5.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.201 g, 0.174 mmol) was added, the system was purged with argon, and the tube was sealed. The resulting mixture was stirred at 120° C. in a microwave for 1 hour. The reaction mixture was then concentrated to afford a brown oil. The resulting oil was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-25% EtOAc-heptane) to afford 2-(6-fluoropyridin-3-yl)pyrimidine (0.150 g, 0.856 mmol, 49% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.35 (dddd, J=8.51, 7.65, 2.91, 0.59 Hz, 1H), 7.54 (t, J=4.89 Hz, 1H), 8.28-8.43 (m, 1H), 8.78-8.89 (m, 1H), 8.96 (d, J=4.89 Hz, 2H). m/z (ESI) 176(M+H)+.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].Br[CH2:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35]3[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH:30]=[C:31]([CH3:33])[CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:33][C:31]1[CH:32]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])=[N:26][CH:25]=2)[CH:28]=[C:29]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=2)[CH:30]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CBr)nc2)c1
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CN3CCCC3=O)nc2)c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.6 M, 303 μL, 0.484 mmol) was added to diisopropylamine (67.3 μL, 0.473 mmol) in THF (394 μL) at −78° C. The reaction was warmed to −40° C. and was stirred for 1 hour. The reaction mixture was cooled back to −78° C. and a solution of pyrrolidin-2-one (15.1 mg, 0.177 mmol) in THF (100 μL) was added dropwise. The reaction mixture was warmed to −40° C. and stirred for 1 hour. The reaction mixture was cooled back to −78° C. and a solution of N-{3-[6-(bromomethyl)pyridin-3-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (50.0 mg, 0.118 mmol) in THF (300 μL) was added. The reaction mixture was slowly warmed to room temperature and quenched with saturated aqueous ammonium chloride (1.00 mL) and THF was removed under reduced pressure. The reaction mixture was extracted with dichloromethane and the organic was dried over sodium sulfate and concentration under reduced pressure. The residue was purified by reverse phase prep HPLC (10-80% MeCN in water with 0.5% TFA) to yield 1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}pyrrolidin-2-on. MS APCI calc'd for C22H21F3N5O [M+H]+ 428. found 428. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.78 (d, J=2.0, 1H), 8.04 (dd, J=2.3 Hz, 8.1 Hz, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.38 (d, J=8.1, 1H), 7.27 (d, J=4.9 Hz, 1H), 7.20 (s, 1H), 4.52 (s, 3H), 4.38 (br s, 2H), 3.37 (t, J=7.0 Hz, 2H), 2.31 (t, J=8.1 Hz, 2H), 1.96 (q, J=7.6 Hz, 15.1 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22])[C:16]([CH:26]3[CH2:28][CH2:27]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6](O)=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH4+:30]>>[NH2:30][C:6](=[O:7])[CH2:5][C:4]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][C@@H:20]([CH3:25])[C:21]([F:23])([F:24])[F:22])[C:16]([CH:26]2[CH2:27][CH2:28]2)=[CH:15][N:14]=1)=[O:12])([CH:1]1[CH2:2][CH2:3]1)[CH3:9]
Reactant: C[C@H](Oc1cc(C(=O)NC(C)(CC(=O)O)C2CC2)ncc1C1CC1)C(F)(F)F
Reactant: [NH4+]
Agent: [Cl-]
Product: C[C@H](Oc1cc(C(=O)NC(C)(CC(N)=O)C2CC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]butanoic acid (example 247b) and ammonium chloride as starting materials and isolated (150 mg, 72%); MS (ESI, m/z): 400.2 (M+H+).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(C(C)C)CC)(C)C.[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]([N:3]4[CH2:4][CH2:5][CH2:6][O:2]4)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:38])([CH3:39])[CH2:36][CH3:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C1CNOC1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(C(=O)N3CCCO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
Following the same procedure in Example 3, Step A, using isoxazolidine hydrochoride (29.5 mg, 0.26 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (82.1 mg, 0.25 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (114.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature, and quenched by adding H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 94.8 mg (76%) of a white solid. 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.42 Hz, 3 H), 1.27 (m, 5 H), 1.66 (m, 3 H), 1.69 (s, 6 H), 1.79 (m, 2 H), 2.04 (q, J=7.49 Hz, 2 H), 2.13 (m, 1 H), 2.43 (m, 2 H), 3.94 (m, 2 H), 4.07 (t, J=6.74 Hz, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 8.00 (m, 2 H), 8.19 (s, 1 H). MS (ESI) (M+H)+=384.2. Anal. Calcd for C23H33N3O2+1.40 TFA+1.30 H2O (566.59): C, 54.69; H, 6.58; N, 7.42. Found: C, 54.66; H, 6.50; N, 7.68.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[NH:1][C:2]([CH3:7])([CH2:3][CH2:4][OH:5])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a 150-mL round-bottomed flask was added 3-amino-3-methyl-butan-1-ol (2.18 mL, 19.39 mmol, Tyger Sci. Inc) and Na2CO3 (3.08 g, 29.1 mmol) (1 M in water) and the solution was cooled to 0° C. Benzyl chloroformate (3.03 mL, 21.33 mmol, Sigma-Aldrich) was added dropwise and the mixture was stirred at 0° C. for 2 h. The mixture was extracted with EtOAc (100 mL×3) and the combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 10-50% EtOAc in Hex) to give benzyl(4-hydroxy-2-methylbutan-2-yl)carbamate (3.33 g, 14.03 mmol, 72% yield) as a clear oil. MS (ESI, pos. ion) m/z: 238.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([OH:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)OCCC2O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
7-Cyano-4-chromanone (Step A) (7.7 g, 44 mmol) was dissolved in THF (75 mL) and MeOH (150 mL), and cooled to 10° C. NaBH4 (1.9 g, 49 mmol) was added and the reaction was warmed to RT and stirred overnight (14 h). The reaction was quenched with acetone (5 mL) and 2 N HCl (100 mL) was added. The reaction was concentrated in vacuo to approximately 75 mL in volume and the reaction was partitioned between 2N HCl (200 mL) and EtOAc (400 mL). The layers were separated and the aqueous layer was back extracted with EtOAc (200 mL). The organic layers were combined, washed successively with H2O (200 mL) and brine (200 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:8]=1)=[O:5].[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.C(O)(=O)C>C(O)C>[Cl:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][C:19]([O:21][CH3:22])=[CH:18][CH:17]=3)[NH:1][CH:23]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Nc2ccc(OCCCl)cc2)c(N)c1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C2Nc3cc(OC)ccc3C(=O)N2c2ccc(OCCCl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 14.9 g (0.0465 mol) of 2-amino-N-[4-(2-chloro-ethoxy)-phenyl]-4-methoxy-benzamide in 300 mL of ethanol was added 5.6 mL (0.0465 mol) of p-anisaldehyde and 30 mL of acetic acid. The reaction mixture was stirred and heated under a mild reflux overnight. After cooling to room temperature, the solvent was evaporated in a rotary evaporator. After the addition of diethyl ether and petroleum ether, the oily residue was chilled on ice. The precipitate that formed was collected by vacuum filtration. An analytical sample (mp 157-158° C. was obtained by recrystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH:13]1[N:17]=[C:16]([NH2:18])[S:15][CH:14]=1.[BH4-].[Na+].CO>ClC(Cl)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:18][C:16]1[S:15][CH:14]=[CH:13][N:17]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CC(Cl)Cl
Solvent: CO
Product: COc1ccc(CNc2nccs2)c(OC)c1
Yield: 64 %

Procedure:
2,4 Dimethoxybenzaldehyde (25 g, 150 mmol, 1 eq), 2 aminothiazole (15.1 g, 150 mmol, 1 eq) and piperidine (150 mg, 1.76 mmol, 0.012 eq) were combined in dichloroethane (500 ml) and the reaction mixture heated to reflux over sieves for 18 hours. The sieves were removed by filtration and the reaction mixture diluted with MeOH (300 ml). Sodium borohydride (25 g, 662 mmol, 4.4 eq) was added portionwise and the reaction mixture heated to reflux for 2 hours. The mixture was cooled, quenched with water and the organic solvent evaporated in vacuo. The reaction mixture was extracted into ethyl acetate and the combined organic solutions extracted with 2M HCl. The acidic solution was basified with potassium carbonate, re-extracted into ethyl acetate, dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography eluting with 9:1 DCM: MeOH to yield the title compound (24 g, 96 mmol, 64%).
Reaction SMILES: [N:1]([CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N+:11]([O-:13])=[O:12])=[O:2]>O1CCOCC1>[N+:11]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:3]1=[N:1][OH:2])([O-:13])=[O:12]
Reactant: O=NC1CCCCCCC1[N+](=O)[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])C1CCCCCCC1=NO

Procedure:
1-Nitroso-2-nitrocyclooctane, in a three-fold amount of dioxane, is heated for 2 hours under nitrogen at 100° C, whilst stirring. After removing the solvent on a rotary evaporator, 2-nitro-cyclooctan-1-one-oxime is obtained, in quantitative yield, as a brown oil.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>>[NH2:14][C:13]1[C:8]2[N:9]([C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[N:6][C:7]=2[C:15]2[CH2:16][CH2:17][N:18]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:19][CH:20]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-cyclobutyl-1-(1,2,3,6-tetrahydropyridin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0742 mmol), benzoic acid (9.97 mg, 0.0817 mmol), TBTU (47.7 mg, 0.148 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was directly given for Gilson HPLC purification. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.96-2.06 (m, 1H) 2.09-2.23 (m, 1H) 2.40-2.63 (m, 4H) 2.72-2.93 (m, 2H) 3.57-3.88 (m, 3H) 3.98-4.34 (m, 1H) 4.47 (br. s., 1H) 5.13-5.45 (m, 2H) 5.72-6.14 (m, 1H) 7.04-7.08 (m, 2H) 7.42-7.51 (m, 5H). MS (ES+): m/z 374.07 (100) [MH+]. HPLC: tR=2.13 min (polar—5 min).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([CH3:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([CH3:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(C)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C)c(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
2.95 g of ethyl 1-ethyl-6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate are suspended in 50 ml of ethanol, and 50 ml of an aqueous 2% sodium hydroxide solution are added thereto. The suspension is stirred at room temperature for 2 hours. Then, the reaction mixture is evaporated to remove solvent, and the residue is adjusted to about pH 1 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water and then dried. 2.41 g of 1-ethyl-6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid are thereby obtained as crystalline powder. Yield: 90%