Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.N1CC[O:39][CH2:38]C1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH2:33][O:39][CH2:38][CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1COCCN1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)N1CCOCC1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, morpholine (17 mg, 0.19 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a yellowish foamy powder (37 mg, 91% yield). MS (apci) m/z=429.2 (M+H).
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[CH2:3][CH:4]3[CH2:8][CH2:7][CH2:6][CH:5]3[CH:1]2[CH2:9][OH:10])=[O:34])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: OCC1NCC2CCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the carbamate above in CH2Cl2 was added TFA (1:1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated to afford (octahydrocyclopenta[c]pyrrol-1-yl)methanol as a pale yellow oil. To a solution of (octahydrocyclopenta[c]pyrrol-1-yl)methanol (1 eq) in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 361.1 (M+H)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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.CCOC(C)=O>[CH3:11][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:12]([OH:14])=[O:13])[CH:20]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(C(=O)O)c2)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 96 h
Yield: 36.8 %

Procedure:
To a solution of 2-bromo-5-methylbenzoic acid (5.00 g, 23.3 mmol) in DME (100 mL) were added 3-carboxyphenylboronic acid (3.86 g; 23.3 mmol), a solution of Na2CO3 (9.90 g, 93 mmol) in H2O and tetrakis(triphenylphosphine)palladium. The mixture was stirred at 90° C. for 4 days. The mixture was allowed to cool to rt, diluted with EtOAc (50 mL), and washed with a saturated NaHCO3 solution. The aqueous layer was separated, acidified with 10% HCl, and extracted with EtOAc (3×20 mL). The combined extracts were dried over MgSO4 and concentrated. The crude material was purified by column chromatography (9:1 hexanes/EtOAc 1% acetic acid) to afford 4-methyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid (2.20 g, 37%) as a solid: 1H NMR (DMSO-d6) δ2.40 (s, 3H), 7.30 (m, 1H), 7.42 (m, 1H), 7.52-7.57 (m, 2H), 7.60 (s, 1H), 7.85 (s, 1H), 7.91-7.92 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:30][C:25]2[CH:26]=[CH:27]C=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NC1(C#N)CC1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[NH:30][C:25]2([C:24]#[N:29])[CH2:27][CH2:26]2)[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a suspension of the 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (1.7 g, 8.43 mmol), HATU (3.5 g, 9.3 mmol), and 1-aminocyclopropanecarbonitrile hydrochloride (1.0 g, 8.43 mmol) in THF (34 mL) was added triethylamine (3.5 mL, 25.3 mmol). The yellow suspension was stirred at room temperature for 18 h then most of the THF was removed in-vacuo. The remaining slurry was diluted with 150 mL 10% (w/w) aqueous Na2CO3 and 150 mL EtOAc. The layers were separated and the organic phase was washed with 10% (w/w) aqueous Na2CO3 (2×100 mL). The organic phase was washed with brine (1×75 mL), dried with Na2SO4, filtered, and concentrated to afford a crude light orange solid. This solid was triturated with Et2O and the white solid was filtered off using Et2O to rinse to yield 1.8 g of [1-(1-cyano-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester as an off-white solid, m/z 266.5 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH3:17])=[CH:7][C:6]=1[O:18][CH2:19][CH3:20])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH3:17])=[CH:7][C:6]=1[O:18][CH2:19][CH3:20]
Reactant: CCOc1cc(OCC)c2ccccc2c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOc1cc(OCC)c2ccccc2c1O

Procedure:
A solution of 1-acetyloxy-2,4-diethoxynaphthalene (2.74 g) in 100 ml of methanol and 10 ml of water was stirred with 2.5 g of potassium carbonate for 6 hours. The solvent was then removed under reduced pressure, and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to a solid, which was recrystallized from ethyl acetate/hexane to give 1-hydroxy-2,4-diethoxynaphthalene, m.p. 83°-84° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([O:11][CH2:16][CH3:17])=[O:10])[CH2:4]1
Reactant: CCO
Reactant: CC1CCNC(C(=O)O)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CC(C)CCN1
Yield: 60 %

Procedure:
A solution of 13 g (0.072 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. At the end of this period, the solvent was evaporated under reduced pressure, and the residue was extracted with a solution of chloroform and saturated potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was evaporated. Distillation of the residue gave 7.4 g (60%) of ethyl 4-methyl-2-piperidinecarboxylate, B.P. 76°-77° C/3 mmHg.
Reaction SMILES: C([NH:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=C[CH:11]=1)(OC(C)(C)C)=O.S(Cl)([Cl:23])=O.[CH3:25]O>>[ClH:23].[NH2:8][CH2:9][CH:10]([CH3:11])[CH2:20][CH2:19][CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH3:25])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)/C=C/CCCC(C)CN
Product: Cl
Yield: 86 %

Procedure:
To a mixture of 4-(N-Boc-aminomethyl) cinnamic acid (5 g, 0.018 mol) in methanol (200 mL) was added thionylchloride (11 g) at 0° C. and slowly heated to reflux for 3 h. The reaction mixture was concentrated to give solid product. The solid hydrochloride salt was washed with EtOAc and filtered off to give the title compound (3.5 g, 86%).
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[CH2:11][CH3:12])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:32]>>[CH:3]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[CH2:11][CH3:12])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CCC(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
0.48 g (0.0016 mol) of 2-aminomethyl-4-(1-methylpropyl)-6-methylsulfonylphenol hydrochloride is reacted with 0.22 g of hexamethylenetetramine in 3 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 68°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([OH:22])=O)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH2:68])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:68][C:65]2([C:62]3[CH:63]=[CH:64][C:59]([C:58]([F:57])([F:69])[F:70])=[CH:60][CH:61]=3)[CH2:67][CH2:66]2)=[O:22])[N:10]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NC1(c2ccc(C(F)(F)F)cc2)CC1
Yield: 16.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (10 mL), di-isopropyl ethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.066 g, 0.320 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 4H), 3.94 (s, 3H), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 3H), 7.30-7.48 (m, 4H), 7.99 (d, J=9.3 Hz, 1H), 8.05 (s, 1H), 8.96 (s, 1H), 12.51 (br s, 1H); MS (m/z): 547.15 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[Na+]>OS(O)(=O)=O.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([OH:16])([C:14]([NH2:15])=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
1-Benyl-4-hydroxy-piperidine-4-carbonitrile (5 g, 23.12 mmol) is dissolved in a mixture of H2SO4 (18 mL) and H2O (2 mL) at 0° C. The mixture is warmed to room temperature for 14 h, transferred into cold 2 N NaOH and adjusted to pH>8. The solid is filtered and washed with H2O, and dried over sodium sulfate to give the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH2:12][N:11]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[NH2:15])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH:9]=2)[CH:7]=1.C(NCC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH2:12][N:11]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[NH2:15])[C@H:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH:9]=2)[CH:7]=1
Reactant: CC(C)(N)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O)c1
Solvent: CCO
Solvent: CCNCC
Product: CC(C)(N)C(=O)N1CC(c2cc(Cl)ccc2F)=C[C@H]1c1cccc(O)c1

Procedure:
Resolution of enantiomers of racemic 4-(5-chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-1-(2-methylalanyl)-2,5-dihydro-1H-pyrrole (174) by chiral normal-phase HPLC (Chiralcel OD column: 0.1% diethylamine in 10% ethanol in hexanes initially, grading to 30% ethanol in hexanes) provided (2S)-4-(5-chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-1-(2-methylalanyl)-2,5-dihydro-1H-pyrrole (17-5) as the first eluting, minus (−) enantiomer.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[CH:7]=[C:6]([S:17](Cl)(=[O:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.[NH:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][NH2:24].C(N(CC)CC)C>ClCCl>[NH:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][NH2:24].[C:31]([O:30][C:28]([NH:21][CH:22]([CH2:23][NH:24][S:17]([C:6]1[CH:5]=[CH:4][C:3]2[N:2]([CH3:1])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[C:8]=2[CH:7]=1)(=[O:19])=[O:18])[C:25]([OH:27])=[O:26])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cn1c2ccccc2c(=O)c2cc(S(=O)(=O)Cl)ccc21
Agent: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c2ccccc2c(=O)c2cc(S(=O)(=O)NCC(NC(=O)OC(C)(C)C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg of the material (2) shown in Table 2 was dissolved in 12 ml of dichloromethane (DCM) (Wako Pure Chemical). 80 mg of Boc-Dap-OH (Bachem) was added to the solution, and then 6 ml of triethylamine (TEA) (Wako Pure Chemical) was added little by little, followed by stirring at room temperature overnight. After the reaction was over, the reaction solution was subjected to evaporation by an evaporator to remove the solvent, supplied with 5% NaHCO3(aq), and further supplied with 0.3 N HCl until the solution got acidic to form a precipitate, which was then filtered by suction and dried in a desiccator. Boc-Dap-OH and the compound (3) thus obtained, 2-tert-butoxycarbonylamino-3-(10-methyl-9-oxo-9,10-dihydro-acridine-2-sulfonylamino)-propionic acid were analyzed to get their respective 1H-NMR data. The results are shown in FIG. 6 and FIG. 7. The product was further purified by silica gel column chromatography to give a substance, which was then analyzed to give the 1H-NMR data. The result was shown in FIG. 8.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[N:17]1[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH3:11]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 10 starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (S)-tert-butyl 3-methylpiperazine-1-carboxylate gave (S)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as an orange gum (134 mg, 73% over two steps). LCMS (ES+) m/z 296 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([CH2:10][CH3:11])=[C:4]([NH2:12])[C:3]=1[CH2:13][CH3:14].CC(C)([O-])C.[K+].[H][H]>[Ru].C(O)(C)(C)C>[NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][CH:5]([CH2:10][CH3:11])[CH:4]([NH2:12])[CH:3]1[CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCc1cc(CC)c(N)c(CC)c1N
Agent: [Ru]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC1CC(CC)C(N)C(CC)C1N
Yield: 65.9 %

Procedure:
A suitable autoclave was charged with 1 g (0.052 mol) of purified 1,3-diamino-2,4,6-triethylbenzene, 0.15 g (1.2 mmol) of potassium t-butoxide, 1.0 g of 5% Ru on alumina, and 50 mL of t-butanol and heated to 190° C. at 25.5 MPa hydrogen for 17 hours. The autoclave was then cooled and its contents filtered. The solvent was removed from the filtrate in vacuo and the resulting liquid distilled through a 20.3 cm. Vigreaux column at about 1 mm Hg/187°-191° C. to give 6.8 g (66%) of 1,3-diamino-2,4,6-triethylcyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][C:22](=[O:24])[CH3:23])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)=O)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.0 g) in pyridine (5 ml) was added acetic anhydride (5 ml), and the solution was stirred for 10 minutes at room temperature. An ice water was added thereto, the solution was stirred, was neutralized with a saturated aqueous solution of sodium bicarbonate, and the resulting solid was filtered and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (1.1 g). To a suspension of lithium aluminum hydride (400 mg) in tetrahydrofuran (20 ml) was added aluminum chloride (1.4 g) on an ice bath under a nitrogen atmosphere, the solution was stirred for 15 minutes at room temperature, then N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (1.1 g) was added thereto followed by stirring for 1 hour at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto, the resulting suspension was filtered through celite pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (604 mg).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH:5]1([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1>C(O)C>[CH:5]1([C:8]2[N:13]=[C:12]([C:14](=[NH:15])[O:1][CH2:2][CH3:3])[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1cncc(C2CC2)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cncc(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.9 %

Procedure:
Sodium ethoxide (140 mg, 2.06 mmol) was added to a solution of 6-cyclopropylpyrazine-2-carbonitrile (150 mg, 1.03 mmol) in ethanol (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (250 mg). MS (ES+) (M+H) 192.1012
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:16].[Na+]>CO>[OH:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CO
Product: O=C(CO)c1ccc(C(F)(F)F)cc1
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-4′-trifluoromethyl acetophenone (40.0 g), sodium formate (40.0 g) and methanol (200 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was concentrated and poured into water (500 ml). The precipitated crystals were filtered, washed with water, and air-dried to give crystals of 2-hydroxy-4′-trifluoromethyl acetophenone (24.5 g, 80%). Melting point 112-114° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1>>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([CH2:12][CH:10]4[CH2:11][N:8]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C1C=COCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C4CCOCC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 2H-pyran-4(3H)-one underwent reductive amination with 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine to give 503. 517.3 (MH+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.CCN(CC)CC.Cl.[CH:21]12[O:28][CH:25]([O:26][CH2:27]1)[CH2:24][NH:23][CH2:22]2>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]2=[C:2]([N:23]2[CH2:24][CH:25]3[O:28][CH:21]([CH2:27][O:26]3)[CH2:22]2)[N:7]=1
Reactant: C1NCC2OCC1O2
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc2c(N3CC4COC(C3)O4)nc(Cl)nc21
Yield: 46.2 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.46 mmol), Et3N (1.05 mL, 7.5 mmol) and 6,8-dioxa-3-azabicyclo[3.2.1]octane hydrochloride (373 mg) in CH2Cl2 (5 mL) is stirred for 18 h. Concentration in vacuo followed by silica gel chromatography (hexane/ethyl acetate) gives 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6,8-dioxa-3-azabicyclo[3.2.1]octane as a white powder (320 mg). This material (0.16 g, 0.57 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.186 g, 0.85 mmol), aq. Na2CO3 (0.425 mL, 2M), and tetrakis triphenylphosphine palladium (20 mg) in 1:1 toluene:ethanol. The reaction mixture was heated in a microwave at 120 C for 20 min to give 4-(4-(6,8-dioxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. To this material (190 mg, 0.56 mmol) in CH2Cl2 is added Et3N (0.42 mL) and a solution of triphosgene (83 mg, 0.28 mmol) in CH2Cl2. After 30 min half of the solution is added to 3-aminopyridine (105 mg, 1.12 mmol). After 2 h aq. workup and silica gel chromatography (EtOAc/MeOH) gives the title compound as an off-white solid (104 mg). HRMS m/z=459.1894 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:5]2=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: COC(=O)c1c(N)ccc2c1OCc1cnsc1-2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cnsc1-2
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a stirred solution of methyl 7-amino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (Intermediate 74, 0.300 g) in DCM (15 mL) was added pyridine (2.5 mL), followed by 2-bromo-4-fluorobenzenesulfonyl chloride (0.468 g). The resultant mixture was stirred at room temperature overnight. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.300 g) was added and stirring was continued overnight. The mixture was diluted with DCM and washed with 0.5M hydrochloric acid and aqueous sodium bicarbonate. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 15-45% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-chromeno[3,4-d]isothiazole-6-carboxylate (0.460 g) as a cream solid.