Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=[C:9]([C:42]2[CH:50]=[CH:49][C:45]3[O:46][CH2:47][O:48][C:44]=3[CH:43]=2)[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[O:46]1[C:45]2[CH:49]=[CH:50][C:42]([C:9]3[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=4[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=3)[C:6]([OH:51])=[O:5])=[CH:43][C:44]=2[O:48][CH2:47]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester (6.9 g) was dissolved in a mixture of TFA and dichloromethane (1:1, 50 mL) and stirred at room temperature overnight. The solvents were removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (6.3 g, 99% yield).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH3:25][CH:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:25][CH:26]([CH3:27])[C:29]([F:32])([F:31])[F:30])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: CC(C=O)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CC(CN1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1)C(F)(F)F

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with rac-2-methyl-trifluoropropionaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3,3,3-trifluoro-2-methyl-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 464.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](I)[CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Reactant: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1

Procedure:
In a manner analogous to that described in Example 1, 4-chloro-2-iodobenzoic acid is reacted with 3-trifluoromethyl-phenol, and there is obtained 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid having a melting point of 146° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[Cl:23][P:24]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH:32]=[CH:31]2)(Cl)=[O:25]>C(Cl)Cl>[Cl:23][P:24]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH:32]=[CH:31]2)([NH:12][C@@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])=[O:25]
Reactant: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)Cl)ccc2c1
Reactant: C[C@H](N)C(=O)OCC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)N[C@@H](C)C(=O)OCC(C)(C)C)ccc2c1
Yield: 85.9 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates and tosylate salt of (S)-neopentyl 2-aminopropanoate (1.0 g, 2.8 mmol), (S)-methyl 2-(6-(dichlorophosphoryloxy)naphthalen-2-yl)propanoate (990 mg, 2.8 mmol), TEA (0.8 mL, 5.6 mmol) and DCM (20 mL) were combined to give 1.13 g of desired (2S)-methyl 2-(6-(chloro((S)-1-(neopentyloxy)-1-oxopropan-2-ylamino)phosphoryloxy)naphthalen-2-yl)propanoate in 83% yield as a gummy syrup.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1.[NH4+].[Cl-]>[CH3:29][S:30]([O:20][CH2:19][C@@H:11]1[C@@H:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12]1)(=[O:32])=[O:31]
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)C[C@@H]2O1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (1.86 g, 4.86 mmol) in pyridine (11 mL) at −20° C. was added MeSO2Cl (0.723 g, 6.31 mmol). The mixture was slowly warmed to room temperature and stirred for 4 h. The reaction was diluted with aqueous saturated NH4Cl (100 mL) and extracted with EtOAc (2×60 mL). The extracts were washed with 0.5 N HCl (3×60 mL), dried with MgSO4. The solvent was evaporated to give ((3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-2-oxooctahydrobenzo[d]oxazol-6-yl)methyl methanesulfonate as a white solid (2.25 g, 100%) which was pure enough for next reaction. MS m/z 484.1 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.30-7.44 (m, 10H), 4.92 (d, J=11.9 Hz, 1H), 4.87 (d, J=11.1 Hz, 1H), 4.66-4.70 (m, 2H), 4.65 (d, J=11.0 Hz, 1H), 4.57 (d, J=11.9 Hz, 1H), 4.43 (dd, J=9.7 Hz, 4.2 Hz, 1H), 4.21 (dd, J=9.7 Hz, 3.0 Hz, 1H), 3.59 (t, J=6.8 Hz, 1H), 3.51 (t, J=7.6 Hz, 1H), 3.41 (t, J=8.9 Hz, 1H), 2.12-2.26 (m, 2H), 1.79-1.87 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture containing 35.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 300 ml of methanol and 30 ml of dimethylformamide dimethyl acetal was heated with stirring on a steam bath for 4 and 1/2 hours and then allowed to cool to room temperature. The precipitated yellow solid was collected, washed with methanol and dried in an oven under reduced pressure at 95° C. to yield 16.4 g of 5-acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, m.p. 267°-270° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[OH:29][CH:30]([CH3:51])[CH2:31][N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[C:33]1=[O:50]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:50])[N:32]([CH2:31][CH:30]([OH:29])[CH3:51])[CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC(O)CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CC(C)O)C5=O)c3cn2)c1F

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(2-hydroxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=481.1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:36])=[CH:29][CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:36])=[CH:31][CH:32]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2(C#Cc3ccc(OCC(=O)N4CCCCC4)cc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(C#Cc3ccc(OCC(=O)N4CCCCC4)cc3)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
A stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-[4-(1-piperidinocarbonylmethoxy)phenyl]ethynyl)cyclohexane (0.232 g, 0.40 mmol) in tetrahydrofuran (9 mL) was treated with 3N hydrochloric acid (0.90 mL) as described in Example 12 above. The crude product was purified by chromatography (silica, 50% ethyl acetate/hexanes) and the solvent removed in vacuo to afford the titled compound as a resin (0.127 g, 59%). Anal. (C28H30O5.1/10 H2O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. 1H-NMR (400 MHz, CDCl3) δ 7.41 (d, J=9.1 Hz, 2H), 7.22 (d, J=2.3 Hz, 1H), 7.11 (d-d, J=8.4 Hz, J=2.3 Hz, 1H), 6.92 (d, J=8.6, 1H), 6.86 (d, J=8.5, 1H),4.80 (p, 1H), 4.70 (s, 2H), 4.00 (s, 4H), 3.85 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.03 (d-t, J=6.1 Hz, J=14.3, 2H), 2.47 (d,br, J=14.9, 2H), 2.4-2.2 (m, 4H), 2.0 to 1.5 (m, 25H with H2O).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[C:6]([CH3:21])[NH:5][N:4]=1.[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:16][C@H:14]([C:13]2[N:12]=[C:11]3[CH:17]=[CH:18][N:19]([CH3:20])[C:10]3=[CH:9][C:8]=2[C:7]2[C:6]([CH3:21])=[N:5][NH:4][C:3]=2[CH3:2])[CH3:15])[N:24]=1
Reactant: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Reactant: N#Cc1c(N)nc(N)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(N)nc(N)c1C#N
Temperature: 120 °C
Yield: 54.9 %

Procedure:
(1S)-1-(6-(3,5-Dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (123 mg, 0.403 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (82 mg, 0.484 mmol), and N-ethyl-N-isopropylpropan-2-amine (211 μL, 1.21 mmol) were combined in acetonitrile (4030 μL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated in vacuo. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30% ACN in water. The fractions containing the desired product were combined, concentrated, and lyophilized to give the title compound as an off-white solid (89 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (d, J=6.35 Hz, 3 H), 1.92 (br s, 3 H), 2.06 (br s, 3 H), 3.82 (s, 3H), 5.20 (br s, 1 H), 6.43 (br s, 2 H), 6.53-6.60 (m, 3 H), 6.96 (br s, 1 H), 7.62-7.69 (m, 2H), 12.36 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C26H22N10, 403; found 403.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1.[CH3:27][Mg+].[Br-]>C1COCC1>[OH:1][C:2]1([CH3:27])[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1
Reactant: C[Mg+]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(=O)C3C4)nc2n(CCC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C)(O)C3C4)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
8-(4-Oxo-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (51 mg) was taken in THF (3 ml) at 0° C. CH3MgBr (1 ml, 3.0 M) was added and stirred for 2 hrs. The reaction was quenched with sat. NH4Cl, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over Na2SO4. Concentration followed by purification on silica column gave the desired product. Mass (ES+ 375).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>[Fe].C(O)C.O>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]([CH3:1])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1C

Procedure:
A mixture of ethyl 4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.40 g, 7.60 mmol), iron powder (4.20 g, 76.00 mmol), 2 N aqueous hydrochloric acid (3.80 mL, 7.60 mmol), and 85/15 ethanol/water (100 mL) was stirred at reflux for 2.5 h. The reaction mixture was filtered through a pad of Celite®, and concentrated to give ethyl 4-(4′-amino-3-methyl-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate as a light, brown solid (2.94 g, 93% yield). LC-MS ret. time 3.23 min, m/z 416.1 (MH+); 1H NMR (CDCl3) δ 1.32 (t, 3H), 1.82–2.17 (m, 2H), 2.58 (s, 3H), 2.68–2.77 (m, 2H), 2.98–3.09 (m, 2H), 3.49 (dd, 1H), 3.74 (br s, 2H), 4.10 (q, 2H), 6.79 (d, 2H), 7.12–7.37 (m, 5H), 7.38–7.54 (m, 4H), 7.78 (d, 1H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-:11]>>[CH2:16]([O:15][C:13]([C:12]1[NH:10][N:11]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]=1[NH2:9])=[O:14])[CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: N#CCc1ccccc1
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1N

Procedure:
4-Amino-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester is prepared from benzyl cyanide and ethyl diazoacetate, using the condition described in Rochais, C.; Lisowski, V.; Dellemagne, P.; Rault, S. Tetrahedron Lett. 2004, 45, 6353. HPLC-MS calculated for C12H13N3O2 (M+H+) 232.1. Found: 232.2.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1.FC(F)(F)C(O)=O>ClCCl>[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)=[O:34]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and biphenyl-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile) to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14]=[C:13]([CH3:18])[C:11]3=2)[NH:6][CH:5]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14]=[C:13]([CH3:18])[C:11]3=2)[N:6]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1=NCCOc2ccc3[nH]cc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Yield: 21.1 %

Procedure:
Sodium hydride (60% in mineral oil, 38 mg, 0.95 mmol) was added to 10-chloro-1-methyl-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (Intermediate 40, 45 mg, 0.19 mmol) and benzensulfonyl chloride (74 μl, 0.58 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature for 10 minutes before water was added dropwise. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (15 mg) as a red solid. MS m/z 375 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[N:6]=[C:7]2[S:22][CH:21]=[C:20]([CH3:23])[N:8]2[C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH3:4].Cl[C:25]1[N:30]=[CH:29][NH:28][C:27]2=[N:31][CH:32]=[CH:33][C:26]=12.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9](=[O:19])[N:8]3[C:20]([CH3:23])=[CH:21][S:22][C:7]3=[N:6][C:5]=2[CH:3]([NH:2][C:25]2[C:26]3[CH:33]=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH3:4])[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]ccc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 100 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one hydrochloride (0.030 g, 0.084 mmol), 4-chloropyrrolo[2,3-d]pyrimidine (0.013 g, 0.084 mmol), and N, N-diisopropylethylamine (0.044 mL, 0.25 mmol) in isopropyl alcohol (0.2 mL) was heated at 100° C., in a sealed tube, for three days. The resultant mixture was applied on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C21H17F2N6OS (M+H)+: m/z=439.1. Found: 439.1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl.[C:15](Cl)(Cl)=[S:16].C(=O)([O-])O.[Na+]>O1CCCC1>[N:9]([C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])=[CH:6][CH:7]=1)=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COc1ccc(N=C=S)cc1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
4-(2,2,2-Trifluoroethoxy)aniline (10 g) was dissolved in tetrahydrofuran (100 ml), 6M hydrochloric acid (9 ml) was added thereto, and the mixture was cooled to −5° C. A solution of thiophosgene (4.01 ml) in tetrahydrofuran (20 ml) was added dropwise thereto over 5 min, and the mixture was stirred at −5° C. for 10 min. Saturated aqueous sodium hydrogen carbonate solution (125 ml) was poured into the mixture, and the mixture was extracted twice with ethyl acetate (200 ml). The extracted layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the obtained brown crude product was purified by silica gel column chromatography, and the obtained pale-yellow solid was washed with hexane to give the title compound (10.7 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH2:8][CH:9]1[CH2:14][N:13]2[CH2:15][CH2:16][NH:17][CH2:18][CH:12]2[CH2:11][NH:10]1)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:17]1[CH2:16][CH2:15][N:13]2[CH2:14][CH:9]([CH2:8][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:6])[CH3:7])[NH:10][CH2:11][CH:12]2[CH2:18]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)CC1CN2CCNCC2CN1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN2CC(C[Si](C)(C)C(C)(C)C)NCC2C1

Procedure:
To a solution of the (3R,9aS or 9aR)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]methyl}octahydro-2H-pyrazino[1,2-a]pyrazine (D86, 217 mg) in 9 mL of dichloromethane was added triethylamine (212 μL) and it was brought to −10° C. A solution of acetyl chloride (54 μL) in 2 mL of dichloromethane was added dropwise. After 15 min the reaction was quenched by addition of MeOH. The crude was purified by flash chromatography (silica, CH2Cl2 to CH2Cl2: (0.5 M NH3 in MeOH) 95:5). The sample thus obtained was dissolved in CH2Cl2 and extracted with sat. NaHCO3. The organics were dried and the solvent removed, leading to the title compound (128 mg).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([C:26]1[CH:27]=[C:28]([C:34]2[S:38][C:37]([CH2:39][OH:40])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([C:26]1[CH:27]=[C:28]([C:34]2[S:38][C:37]([CH:39]=[O:40])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc(-c2ccc(CO)s2)cc1C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C=O)s2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.15 g (19 mmol) of pyridinium dichromate and 350 ml of dichloromethane are introduced into a round-bottomed flask. A solution of 3.9 g (14 mmol) of 5-(3-tert-butyl-4-methoxyphenyl)-2-thiophenemethanol in 50 ml of dichloromethane is added dropwise, at 0° C., and the mixture is stirred at room temperature for two hours. The reaction medium is filtered through silica and, after evaporation, 3.26 g (84%) of the expected aldehyde are recovered, in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[N:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1.C(O)(=[O:19])C>[Cl-].[Zn+2].[Cl-]>[OH:19][C:2]1[N:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc2[nH]c(=O)c3cnc(O)cc3n2n1
Temperature: 25 °C

Procedure:
2.3 g. of 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one of Example 1b are refluxed with 1 g. of zinc chloride in 20 ml. of acetic acid for 100 hours. The mixture is cooled to room temperature, diluted with 10 ml. of water and the precipitated 8-hydroxy-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin5(4H)-one is filtered off, yield: 1.7 g. (81%); m.p. > 300° (DMF).