Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[CH3:25][NH:26][NH2:27]>N1C=CC=CC=1>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[N:26]([CH3:25])[N:27]=2)[CH:11]=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:9]=1[OH:16])([CH3:18])([CH3:20])[CH3:19]
Reactant: CNN
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: Cn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Yield: 93.3 %

Procedure:
A mixture of 30 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol, 15 g of methylhydrazine and 150 ml of pyridine is reacted and treated in a similar manner as Example 1, and the obtained crude crystals are recrystallized from ethanol to give 27.3 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 152°-154° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.Cl[S:27]([C:30]1[CH:42]=[CH:41][C:33]2[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:32]=2[CH:31]=1)(=[O:29])=[O:28]>C(Cl)Cl>[CH:31]1[C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][C:33]=2[CH:41]=[CH:42][C:30]=1[S:27]([NH:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (II-1) (251 mg, 1.00 mmol) was dissolved in methylene chloride (8 ml) and triethylamine (0.238 ml, 2.00 mmol) was added thereto under a nitrogen atmosphere. To the mixture was added 2-chlorosulfonyldibenzofuran (350 mg, 1.31 mmol) under ice-cooling, and the mixture was stirred for 30 min and allowed to warm up to room temperature. The reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:4)) and recrystallized from n-hexane (10 ml) to yield methyl (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (342 mg, 0.710 mmol). Yield 71%, mp 115-116° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>>[CH3:19][C:18]1[N:1]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=2)[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NCCCc1ccc(C(N)=O)s1
Product: Cc1ccc(C)n1CCCc1ccc(C(N)=O)s1

Procedure:
5-(3-Aminopropyl)-2-thiophenecarboxamide is reacted with acetonylacetone to give 5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide, m.p. 144°-126° C. (see J. Chem. Soc. Chem. Commun. 800 [1982]). This is alkylated with n-butyl bromide to give N-butyl-5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide (see Synthesis 266 [1976]). The latter is cleaved with hydroxylamine hydrochloride to give 5-(3-aminopropyl)-N-butyl-2-thiophenecarboxamide.
Reaction SMILES: CS[C:3]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH:4][N+:5]([O-:7])=[O:6].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1>CCO>[N:8]1([C:3]([NH:21][CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][N+:5]([O-:7])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NCc1cccnc1
Reactant: CSC(=C[N+](=O)[O-])N1CCCCC1
Solvent: CCO
Product: O=[N+]([O-])C=C(NCc1cccnc1)N1CCCCC1
Yield: 28.6 %

Procedure:
In 20 ml of EtOH was dissolved 0.8 g (0.004 mole) of 1-methylthio-1-piperidino-2-nitroethylene followed by addition of 0.4 g (0.004 mole) of 3-pyridylmethylamine. The mixture was refluxed for 2 hours. The ethanol was distilled off and the residue was purified by silica gel column chromatography to give 0.3 g of the title compound as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=3)=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Reactant: CCCCCC(=O)OCc1cc(Cl)ncn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCC(=O)OCc1cc(Oc2ccc3c(C(=O)OCC)csc3c2)ncn1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A suspension of 984 mg (4.05 mMol) hexanoic acid 6-chloro-pyrimidin-4-ylmethyl ester, 751 mg (3.38 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.3) and 1.43 g (6.76 mMol) K3PO4 in 20 ml NMP is stirred for 1.5 h at 60° C. The reaction mixture is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; hexane/EtOAc 4:1→1:1) gives the title compound: MS: [M+1]+=429; TLC(hexane/EtOAc 4:1): Rf=0.14.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:30]([NH:39][CH3:40])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:30]([N:39]([CH3:40])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (0.88 g, 2.76 mmol) in CH2Cl2 (2 ml) was added drop wise to a stirred solution of rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine (0.72 g, 2.70 mmol) and ethyl-diisopropyl-amine (0.64 ml, 3.76 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 1.05 g (74%) of the title product as colorless foam.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)=[O:24].S([O-])([O-])(=O)=[O:43].[Na+].[Na+].CCOCC>N1C=CC=CC=1>[C:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)([OH:43])=[O:24]
Reactant: O=S(=O)([O-])[O-]
Reactant: C[Sn](C)(C)c1cc(C=O)c2c(c1)oc1ccccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[Sn](C)(C)c1cc(C(=O)O)c2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of tetra-n-butylammonium permanganate (5.1 g, 14.0 mmol) in anhydrous pyridine (35 mL) was transferred via cannula needle into a solution of the stannane 305 (5.0 g, 14.0 mmol) in anhydrous pyridine (35 mL) at 0° C. under a nitrogen atmosphere. The reaction was stirred for 30 min., then saturated aqueous sodium sulfate (50 mL) was added to quench the reaction. The mixture was then poured into ether and the layers separated. The organic layer was washed with 2N aqueous HCl (6 times with 100 mL), water (2 times) and then brine (2 times). The solution was dried with magnesium sulfate, then filtered and concentrated under vacuum to provide 4.8 g (92% yield) of the stannane 306 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:6]([CH3:16])[CH:5]=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH:22][CH3:23]>O1CCCC1>[CH3:21][N:22]([CH3:23])[S:17]([C:3]1[CH:4]=[CH:5][C:6]([CH3:16])=[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1NS(=O)(=O)C(F)(F)F
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)C)c(C)c1NS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 69.7 %

Procedure:
2,4-Dimethyl-3-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.4 g) was added to tetrahydrofuran (20 ml) containing dimethylamine (0.6 g), and the resultant mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was washed with 5% hydrochloric acid and water in order, dried over anhydrous magnesium sulfate and concentrated to give an oily substance, which was purified by column chromatography with silica gel (150 ml) to give 1.0 g of N,N-dimethyl-2,4-dimethyl-3-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 70.5°-72° C.
Reaction SMILES: C([O-])(O)=O.[Na+].[OH:6][CH2:7][CH2:8][N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)[C:10]1=[O:25].[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41](Cl)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([N:22]3[CH2:23][CH2:24][N:19]([C:13]4[CH:12]=[C:11]5[C:16]([CH:17]=[CH:18][N:9]([CH2:8][CH2:7][OH:6])[C:10]5=[O:25])=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=c1c2cc(N3CCNCC3)ccc2ccn1CCO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN(c2ccc3ccn(CCO)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of sat. aqueous NaHCO3 (80 mL), compound 8 (4.3 g, 15.7 mmol) in tetrahydrofuran was added chloroformic acid 9-fluorenylmethyl ester (1.5 eq.). The mixture was stirred for 2 h at room temperature, then concentrated. The residue was extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo to give 9 (4.6 g, yield 59%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:28][CH:29]=5)[N:24]([CH3:35])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:28][CH:29]=5)[N:24]([CH3:35])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(C(C)(C)C)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(C(C)(C)C)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
To a solution of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (129 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 4 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc to afford 74 mg (73%) of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=485; mp=180-195° C.; 1H NMR (CDCl3, 400 MHz): δ (ppm) 10.08-10.28 (m, 1H), 9.02-9.14 (m, 1H), 8.65 (d, J=7.1 Hz, 1H), 8.46 (d, J=8.6 Hz, 1H), 7.99-8.13 (m, 1H), 7.40-7.49 (m, 1H), 7.36 (s, 1H), 4.86-5.08 (m, 1H), 4.23-4.76 (m, 4H), 4.11 (s, 3H), 3.52-3.59 (m, 1H), 1.55-1.71 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH2:21][CH3:22])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:56][C@H:57]1[CH2:61][NH:60][C@H:59]([C:62]([O:64][CH3:65])=[O:63])[CH2:58]1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH2:21][CH3:22])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:60]1[CH2:61][C@H:57]([OH:56])[CH2:58][C@H:59]1[C:62]([O:64][CH3:65])=[O:63])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCCC(C)C[C@@H](CC)C(NC(=O)OC(C)(C)C)C(=O)O
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: ClCCl
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoic acid (2 g, 6.38 mmole) in dichloromethane (20 mL) was added DIPEA (1.93 mL, 19.19 mmole), HATU (2.42 g, 6.38 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.15 g, 6.38 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was taken to the next step without further purification (1.5 g, 53.4%). MS: MS m/z 441.6 (M++1)
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.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>O1CCCC1.C(O)(=O)C>[CH:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)([CH3:25])[CH3:22]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)C)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (300 mg) in tetrahydrofuran (8 ml) were sequentially added acetone (0.4 ml), acetic acid (0.1 ml) and sodium triacetoxyborohydride (780 mg), and the solution was stirred for 2 days at room temperature. The solution was neutralized with ammonia solution, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (309 mg).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:8]2[C:13](=O)[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36].C1COCC1.B1C2CCCC1CCC2>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[C@H:13]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[O:32][CH3:31])[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CN
Agent: B1C2CCCC1CCC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1CN[C@@H]1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Yield: 23.3 %

Procedure:
Compound 7 (357 mg, 0.904 mmol), 2-methoxybenzylamine (189 mg, 1.38 mmol) and camphorsulfonic acid (2.0 mg) were dissolved in toluene (30 ml), and the resultant mixture was heated at reflux for 3 days under a dehydrating condition with MS 4A. After replacement of the solvent with THF a solution of 9-BBN (0.5M in THF, 5.4 ml) was added, and the resultant mixture was stirred for 4 days at room temperature. After evaporation of the solvent the residue was basified at pH=13, extracted with CH2Cl2, dried over Na2SO4, and concentrated down. The crude material was purified by combination of column chromatography (silica-gel, MeOH/CH2Cl2), preparative TLC (silica-gel, 10% MeOH/CH2 Cl2) and crystallization from MeOH to provide pure compound 8 (109 mg, 23%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:30])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[CH2:8][NH:30][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(NCC2OCCO2)ccc1OCCN1CCCC1

Procedure:
A suspension of K2CO3 (235 mg, 1.70 mmol), 2-(bromomethyl)-1,3-dioxolane (400 mg, 1.70 mmol), and 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (3.0 g, 14.5 mmol), preparation described in Patent: WO2002/101146, in DMSO (17 mL) was heated at 80° C. for 24 hr. After removal of any precipitate by filtration, the filtrate was partitioned between EtOAc/H2O (100/20 mL). The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 0%-20% gradient EtOAc/Hexanes to elute the title compound as a yellow brownish oil (150 mg, 27%) MS (ESI) 323 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][N:3]=1.C[O:8][C:9]([C:11]1[N:15]=[CH:14][NH:13][N:12]=1)=[O:10]>>[O:4]1[CH2:5][CH2:6][C:2]([N:13]2[CH:14]=[N:15][C:11]([C:9]([OH:10])=[O:8])=[N:12]2)=[N:3]1
Reactant: COC(=O)c1nc[nH]n1
Reactant: Brc1ccon1
Product: O=C(O)c1ncn(C2=NOCC2)n1

Procedure:
1-(4,5-dihydroisoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylic acid I-171a and I-171b were prepared using the analogous procedure to Example 35 except that racemic compound I-75 was used as the starting bromo-isoxazole and 1H-1,2,4-triazole-3-carboxylic acid methyl ester as the nucleophile Additionally, at some point during the course of the reaction or workup, the ester hydrolyzed to the corresponding acid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M−H]−=356.6 m/z. Activity: C
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(O)C>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Solvent: CCO
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CCN2CCNCC2)c1
Yield: 5.2 %

Procedure:
A solution of 58 mg (0.1 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 74) and 100 mg of piperazine in 2 ml of ethanol was heated at 50° C. for 3 hours. The reaction mixture was evaporated and the crude material purified by flash chromatography on silica gel, eluting with dichloromethane/methanol/acetic acid/water (90:18:3:2). Product containing fractions were combined and evaporated. The residue was dissolved in 10 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated to give 3 mg (5%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-[2-(1-piperazinyl)-ethyl]phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 126° C. [Mass spectrum (ESI) MH+ =574].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[N:12].[K].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(S)C=CC=CC=1.[OH-].[K+]>CO.CN(C)C=O>[C:14]1([S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]#[N:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-3-cyanonitrobenzene (12.5 g, 6.84 mmol) was added portionwise to a stirred N,N-dimethylformamide (50 mL) solution of thiophenol potassium salt [prepared by adding thiophenol (7.1 mL, 6.9 mmol) to a solution of potassium hydroxide (3.84 g, 6.84 mmol) in methanol followed by removal of the methanol in vacuo]. After stirring at 105° C. for 2.5 hours the mixture was poured into ice-water, filtered, the collected solid washed with water, dissolved in 300 mL of refluxing ethanol (charcoal), filtered, treated with 35 mL of water and refrigerated. The resulting pale yellow solid weighed 13.3 g (76%), mp 82°-84° C. 1H-NMR (250 MHz, CDCl3): 6.93 (d, 1H, J=9.0 Hz, aromatic), 7.51-7.62 (m, 5H, aromatic), 8.12(dd, 1H, J=9.2, 2.5 Hz, aromatic), 8.46 (d, 1H, J=2.5 Hz, aromatic). MS (CI, CH4): 257(M+1).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:27])=[O:26])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(N)c2c(-c3ccccc3)c(C)sc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3ccccc3)c(C)sc2n1
Yield: 19.1 %

Procedure:
Following the general method as outlined in Example 28, starting from 2,6-dimethyl-3-phenylthieno[2,3-b]pyridin-4-amine (97 mg, 0.381 mmol) (Description 10) and benzenesulfonyl chloride (135 mg, 0.763 mmol), the title compound (28.7 mg) was isolated. LCMS (A) m/z: 395 [M+1]+, Rt 0.96 min (basic), Rt 1.39 min (acidic).