Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[C:14](=[O:23])[N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)=[N:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:13]1[C:14](=[O:23])[N:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][N:9]=2)[CH:12]=1)#[N:31]
Reactant: CC(=O)Oc1ccc(-c2cc(-c3ccccc3C#N)c(=O)n(-c3ccccc3)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(-c2ccc(O)cn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
953 mg of 5-(5-acetoxypyridin-2-yl)-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one and 192 mg of potassium carbonate were added to 50 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. The mixture was further incorporated with 50 ml of methanol, and stirred at 40° C. for 15 minutes. The reaction mixture was diluted with ethyl acetate, and filtered by silica gel. The filtrate was concentrated under a vacuum and washed with a ether/methanol-based solvent, to obtain 786 mg of the subject compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[OH:16][C:17]1[C:18]([SH:23])=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:23][C:18]2[C:17]([OH:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: Oc1cccnc1S
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Product: CCCc1c(CSc2ncccc2O)ccc(C(C)=O)c1O
Yield: 78.6 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.25 g of 3-hydroxy-2-mercaptopyridine, 0.33 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-3-hydroxypyridine was obtained in a manner similar to Example 14.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C@H:5]([OH:25])[CH2:6][NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=2)[NH:11][C:10]([CH3:24])([CH3:23])[CH2:9]1.C(N(C(C)C)C(C)C)C.C(Cl)Cl.N1([C:51](=[O:53])[CH3:52])C=CN=C1>>[CH3:23][C:10]1([CH3:24])[CH2:9][C@H:8]([NH:7][CH2:6][C@@H:5]([OH:25])[C@@H:4]([NH:3][C:51](=[O:53])[CH3:52])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=2)[NH:11]1
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@@H](N)Cc1cccc(F)c1)CC(C)(C)N2
Reactant: CC(=O)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cccc(F)c1)[C@H](O)CN[C@H]1CC(C)(C)Nc2ccc(CC(C)(C)C)cc21

Procedure:
To a solution of (2R,3S)-3-amino-1-((S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-4-(3-fluorophenyl)butan-2-ol dihydrochloride (0.104 g, 0.379 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.27 mmol) in DCM (1.52 ml, 0.379 mmol) was added 1-(1H-imidazol-1-yl)ethanone (0.0396 g, 0.360 mmol) in one portion. The resulting solution was stirred over the weekend. The crude mixture was concentrated and purified with the HPLC. Due to insufficient purity, the title compound was free based and purified with the ISCO MPLC. MS m/z: 470 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[CH3:25]C1C=CC(C=O)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:25])=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Product: Cc1ccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)cc1
Reaction time: 16 h

Procedure:
Compound 21 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 4-methylbenzaldehyde instead of 3-methylbenzaldehyde in Step 1. As a slightly modified procedure, Step 3 was performed at 70° C. for 16 h in a sealed tube.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:44]=[CH:43][C:23]([CH2:24][O:25][C:26]2[CH:27]=[C:28]([NH2:42])[CH:29]=[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH:31]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[NH:42][C:28]2[CH:29]=[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH:31]=[C:26]([O:25][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:44][CH:43]=3)[CH:27]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N#Cc1ccc(COc2cc(N)cc(OCc3ccc(C#N)cc3)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3ccc(C#N)cc3)cc(OCc3ccc(C#N)cc3)c2)CC1
Yield: 64.6 %

Procedure:
Following the procedure of Example 107(e) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.255 g (1.04 mmol) and [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-amine (0.37 g, 1.04 mmol) were used to afford 0.39 g of the required product. Percentage purity (LCMS): 94.8%, (M−1)=580.0-1.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[ClH:18].N([O-])=O.[Na+]>[Cl-].[Na+].O.O>[Cl:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A mixture of 7-ADCA (25 g, 0.117 mol), ethanol (700 ml), water (163 ml) and concentrated hydrochloric acid (163 ml) was cooled to 5° C. Sodium nitrite (11.5 g, 0.167 mol) was added in small portions over 25 minutes and the mixture was stirred for 3.5 hours at 0°-5° C.; 300 ml of brine was added and the reaction mixture was extracted with methylene chloride. The organic extract was washed with water, brine, dried over sodium sulfate and concentrated (16.1 g, 58.9%). This crude acid was directly used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:40])[CH:32]=2)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of acryloyl chloride (24 μL, 0.30 mmol) in CH2Cl2 (1 mL) was added dropwise to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 146, 140 mg, 0.30 mmol) and DIPEA (57 μL, 0.33 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1 h and was then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (43 mg, 28%) as a beige solid after trituration with CH3CN; 1H NMR: 1.63-1.76 (2H, m), 2.00-2.10 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.64 (2H, d), 3.86 (3H, s), 3.89 (3H, s), 3.93 (2H, d), 5.70 (1H, dd), 6.21 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.13 (1H, d), 7.16-7.29 (2H, m), 7.51 (1H, d), 7.73 (1H, s), 7.93 (1H, s), 8.26 (1H, d), 8.31-8.39 (2H, m), 9.24 (1H, s); m/z: ES+ MH+ 524.7.
Reaction SMILES: [H-].[Na+:2].[OH-].[OH-].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:8][CH:7]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)Oc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an aqueous solution (40 ml) of sodium hydride (3.8 g), sodium 4-hydroxybenzenesulfonate dihydroxide (20 g) and tetrahydrofuran (28 ml) was added. To the mixture, benzyl chloroformate (12.3 ml) was added at 0° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature. The reaction mixture was concentrated. The precipitated crystals was washed with water and dried to give the title compound (18.1 g) having the following physical data.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccccc1
Yield: 97.7 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-phenoxypropionate (4.00 g), which is the product of Reference example 4(f), and sodium azide (1.93 g) and the reaction mixture was treated to afford the desired compound (3.40 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:18]([C:12]2[CH:11]=[C:10]3[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:8](=[O:21])[NH:9]3)=[CH:14][CH:13]=2)=[O:20])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Product: O=C(NCCCN1CCOCC1)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
30 mg (25%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 3-morpholine-4-yl-propylamine (87 mL, 0.598 mmol).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([O:24]C)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Br:33][CH2:34][Br:35]>O1CCCC1>[CH2:26]([C@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:22](=[O:24])[CH:34]([Br:35])[Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: BrCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Br)Br
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
Under nitrogen gas, a solution of diisopropylamine (2.4 g, 21.6 mmol) in tetrahydrofuran (10 mL) was added to n-butyllithium (in 1.6 M hexane, 13.5 mL, 21.6 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (2.0 g, 7.2 mmol), dibromomethane (2.5 g, 14.4 mmol) and tetrahydrofuran (10 mL) and cooled to −70° C. (liquor B). To this liquor B was added said liquor A over 30 minutes at −70° C., and the mixture was stirred for 30 minutes at the same temperature and then warmed to 20° C. This reaction mixture was poured in 25 mL of2N-HCl for hydrolysis and, then, extracted with 10 mL of ethyl acetate. The organic layer was washed with 20 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 2.670 g of black solid. This solid was recrystallized from ethyl acetate/hexane to provide brown crystals of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (630 mg, 92.2 area %, yield 19%).
Reaction SMILES: [CH3:1][C:2]([Cl:15])([CH3:14])[CH2:3][CH2:4][CH:5]1[N:9]([CH3:10])[S:8](=[O:12])(=[O:11])[NH:7][C:6]1=[O:13].[C:16]1([S:22][CH2:23]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:16]1([S:22][CH2:23][N:7]2[C:6](=[O:13])[CH:5]([CH2:4][CH2:3][C:2]([CH3:1])([Cl:15])[CH3:14])[N:9]([CH3:10])[S:8]2(=[O:12])=[O:11])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCSc1ccccc1
Reactant: CN1C(CCC(C)(C)Cl)C(=O)NS1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CN1C(CCC(C)(C)Cl)C(=O)N(CSc2ccccc2)S1(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
A mixture of 4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2.5 g, 9.81 mmol), phenylthiomethyl chloride (2.18 g, 13.74 mmol) and tetrabutylammonium bromide (0.369 g, 1.145 mmol) suspended in 150 ml of DMF was heated at 100° C. for 18 hours. After adding additional TBAB (0.369 g), the mixture was stirred at 95° C. for 4 hours, cooled, and poured into ice/water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (15% ethyl acetate in hexane) to afford 1.396 g (39%) of 2-phenylthiomethyl-4- (3-methyl-3-chlorobutyl) -5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =(CH2)2C(Cl) (CH3)2 ; R3 =CH3) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][S:13]([CH3:12])(=[O:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
3,5-Dimethoxyaniline (1 g mg, 6.53 mmol) was dissolved in pyridine (48 ml) and was treated with methanesulfonyl chloride (0.56 ml, 7.18 mmol). The reaction mixture was stirred at room temperature overnight. Methanesulfonyl chloride (0.28 ml, 3.59 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed to give 1.7 mg (100% yield) of the title compound as a dark oil. Purity 89%.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][OH:8])[CH3:4].Br[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][O:20][C:21]2[CH:42]=[CH:41][C:24]([C:25]([NH:27][C:28]3[CH:29]=[C:30]([CH:37]=[CH:38][C:39]=3[CH3:40])[C:31]([NH:33][CH:34]3[CH2:36][CH2:35]3)=[O:32])=[O:26])=[CH:23][CH:22]=2)[CH:16]=[CH:15][CH:14]=1>CC(N(C)C)=O>[CH:34]1([NH:33][C:31](=[O:32])[C:30]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:28]([NH:27][C:25](=[O:26])[C:24]3[CH:41]=[CH:42][C:21]([O:20][CH2:19][C:17]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:12][O:8][CH2:7][CH2:6][N:5]([CH2:9][CH3:10])[CH2:3][CH3:4])[N:18]=4)=[CH:22][CH:23]=3)[CH:29]=2)[CH2:35][CH2:36]1
Reactant: CCN(CC)CCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CBr)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCOCc1cccc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
To a 60% dispersion of NaH in mineral oil (25 mg, 0.625 mmol) in DMA (4 mL) was added N,N-diethylethanolamine (24 mg, 0.205 mmol). The reaction was stirred at room temperature for 20 minutes. A solution of 3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide (77 mg, 0.155 mmol) in DMA (2 mL) was added dropwise to the reaction which was then stirred for 1 h at room temperature. The reaction was quenched by the addition of water (1 mL) and was purified by preparative HPLC to give the title compound as a white solid (29 mg, 35%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 0.96 (t, 6H), 2.26 (s, 3H), 2.50 (m, 4H), 2.64 (t, 2H), 2.86 (m, 1H), 3.59 (t, 2H), 4.59 (s, 2H), 5.75 (s, 2H), 7.18 (d, 2H), 7.33 (d, 1H), 7.42 (m, 2H), 7.64 (dd, 1H), 7.80 (s, 1H), 7.87 (t, 1H), 7.96 (d, 2H), 8.36 (d, 1H), 9.83 (s, 1H); Mass Spectrum: M+H+ 531.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:14](OC)=[O:15])=O.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[C:20]([CH2:19][CH2:18][C:13]1[C:4]2[C:3](=[CH:8][C:7]([O:9][CH3:10])=[C:6]([O:11][CH3:12])[CH:5]=2)[CH:1]=[N:28][C:14]=1[OH:15])([O:22][CH3:23])=[O:21]
Reactant: [NH4+]
Reactant: COC(=O)CCC(C(=O)OC)c1cc(OC)c(OC)cc1C=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)CCc1c(O)ncc2cc(OC)c(OC)cc12
Temperature: 75 °C
Yield: 77.1 %

Procedure:
A mixture of 8.34 grams of dimethyl 2-(2-formyl-4,5-dimethoxyphenyl)glutarate (25.74 mmol) (which is the product of Example 8e(1)), 17.86 grams anhydrous ammonium acetate (232 mmol) and 15 ml glacial acetic acid was heated to 75° C. and was maintained at that temperature for 30 minutes. After cooling, the yellow precipitate was isolated by filtration, washed with water and dried to provide 5.78 grams of Compound Q (77% yield). Recrystallization from methanol and trituration with ether (to remove any trace amounts of methanol) provided 4.57 grams of pure Compound Q having a melting point of 178° to 180° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[C:4](=O)[NH:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[CH2:1][CH2:2][N:3]=1
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)C(Cl)=NCC2

Procedure:
Tricyclic heterocycles can be prepared by the process outlined in Scheme 28. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 123 is heated in POCl3 at a temperature above RT, preferably at a temperature sufficient for reflux, to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 124. The 1-chloro-7-nitro-3,4-dihydroisoquinoline 124 is dissolved in a solvent, such as THF, and H2NNH2 is added. The reaction is evaporated to a residue, then heated with HC(OEt)3 at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 115° C. to give the nitro-substituted tricyclic. Hydrogenation, such as with an H2 atmosphere in the presence of a catalyst, such as Pd/C, gives 2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 125.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:24]=O)[C:18]=2[CH:17]=[CH:16]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>C1COCC1.ClCCl.C([O-])(O)=O.[Na+]>[N:26]1([CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][NH:15]3)[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1cc(CN2CCC2)c2cc[nH]c2c1
Reaction time: 1 h

Procedure:
Sodium triacetoxy borohydride (1.46 g, 6.9 mmol) was added to a solution of 1H-indole-4-carbaldehyde (0.5 g, 3.4 mmol) and azetidine (0.39 g, 6.87 mmol) in THF (15 ml). The mixture was stirred for 1 h and diluted with dichloromethane and NaHCO3 (aq). The organic phase was washed with brine (1×), dried (MgSO4) and evaporated. The crude product was dissolved in dichloromethane and hexane was added (1:1). The off white powder was filtered and washed with a mixture of dichloromethane hexane (1:1). Yield: 400 mg (52%). Off white solid. MS (ESI+) for C12H14N2 m/z 187 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C=CC([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=3)=CC=2C(=O)CC1>>[OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[CH:6][C:5]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=3)=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 1.00 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow solid) using 1.00 g (15.30 mmol) of zinc, 0.639 ml (5.76 mmol) of ethyl bromoacetate and 70 ml of dry benzene.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1)(=O)=O>O>[CH2:1]([NH:3][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Solvent: O
Product: CCNCCc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A 70% aqueous ethylamine solution (2.14 g, 33.23 mmol) was added to ethyl 4-(2(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.70 g, 1.66 mmol). The mixture was stirred at 100° C. for 2 hours in a sealed tube and cooled to room temperature. Then water (40 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (=8/2) to give the desired ethyl 4-(2-(4-(2-ethylaminoethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.40 g, 65%).