Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:35]=[CH:34][C:33]=1[NH2:45].C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[CH:35]=[CH:34][C:33]=1[NH:45][C:18]1[N:17]=[CH:16][C:15]2=[CH:14][CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]2[N:19]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1cc(CN2CCOCC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(CN2CCOCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C
Yield: 45.1 %

Procedure:
Into an 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), 2-Methoxy-4-morpholin-4-ylmethyl-phenylamine (0.174 g, 0.782 mmol), N,N-Diisopropylethylamine (0.136 mL, 0.782 mmol), and 1-Methoxy-2-propanol (0.880 mL, 9.00 mmol) were added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were concentrated under vacuum to give a glassy solid. The solid was triturated with Et2O to give N-{2-[2-(2-Methoxy-4-morpholin-4-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a yellow solid (46 mg, 37%). LCMS (E/I+) 523.15 (M+H). NMR 1H (DMSO-d6)-9.61 (s, 1H), 8.13 (d, 1H, J=8.58 Hz), 7.95-8.00 (m, 1H), 7.86 (s, 1H), 7.66-7.70 (m, 1H), 7.53-7.58 (m, 1H), 7.16 (d, 1H, J=1.72 Hz), 7.04 (d, 1H, J=4.66 Hz), 7.01 (d, 1H, J=4.66 Hz), 6.96 (d, 1H, J=8.58 Hz), 4.29 (d, 2H, J=3.50 Hz), 3.86-4.04 (m, 5H), 3.61 (t, 2H, J=11.67 Hz), 3.20 (d, 2H, J=12.84 Hz), 3.00-3.15 (m, 5H), 2.88 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])=[O:4].CN(C)C=O.[H-].[Na+].Cl[C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:21]=1>C(Cl)(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:22]2[N:21]=[C:20]([O:1][CH2:2][C:3]([N:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])=[O:4])[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[N:23]=2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(-c2nc(Cl)c3c(n2)CCCC3)cc1
Reactant: CCCN(CCC)C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)COc1nc(-c2ccc(F)cc2)nc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a mixture of 2-hydroxy-N,N-dipropylacetamide (1.8 g) and dimethylformamide (20 ml) is added sodium hydride (about 60% oily, 0.5 g) at 0 to 5° C., and the mixture is stirred at 0° C. for one hour. To the reaction mixture is added 4-chloro-2-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (2.0 g) at the same temperature, and the mixture is stirred at room temperature for four hours. To the mixture are added chloroform and ice-water, and the chloroform layer is collected, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from a mixture of diethyl ether and n-hexane to give the desired compound (2.2 g), m.p. 95-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc(C)cc2C)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc(C)cc2C)sc2ncccc12
Yield: 52.4 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2,4-dimethylbenzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.17 g, 0.31 mmoles), CH2Cl2 (5 ml), triethylsilane (0.5 ml, 3.1 mmoles) and boron trifluoride etherate (0.2 ml, 1.5 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 87 mg (53%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.9 %

Procedure:
2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) and 6-chlorooxindole (3.6 g, 22 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.85 g, 26 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([C:37]#[N:38])[C:28]=1[O:39][CH3:40].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:10][O:11][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[C:29]([C:37]#[N:38])[C:28]=2[O:39][CH3:40])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2ccc(F)c(Cl)c2)CC1
Reactant: COc1c(C#N)cc2ccccc2c1CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C#N)cc2ccccc2c1COCC(c1ccc(F)c(Cl)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
The requisite tert-butyl 4-{1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1-naphthyl)methoxy]ethyl}piperazine-1-carboxylate was synthesized using the following method. tert-Butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate (65 mg, 0.18 mmol) was dissolved in THF (1.8 mL). 4-(Iodomethyl)-3-methoxy-2-naphthonitrile (70 mg, 0.22 mmol) was added followed by NaH (9 mg, 0.36 mmol). After reacting at RT overnight, water (60 mL) was added. The mixture was extracted with EtOAc (40 mL). The organic phase was dried over Na2SO4, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on SiO2 (0-30% EtOAc:hexane) afforded the title compound (99 mg). MS m/z 554.6 (M+H)+. The requisite tert-butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate was synthesized using the following method.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1.[N:33]1([CH2:38][CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH:37]=[CH:36][N:35]=[CH:34]1.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:42](=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: O=C(O)CCCCn1ccnc1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCn1ccnc1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g; 2.0 equiv; 1.50 mmoles) to a solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.20 m; 1.0 equiv; 0.75 mmoles), 5-imidazol-1-ylpentanoic acid (0.152 g; 1.2 equiv; 0.90 mmoles), and 1-hydroxybenzotriazole (0.203 g; 2.0 equiv; 1.50 mmoles) in dichloromethane (20 mL) and triethylamine (0.52 mL). Stir the mixture for 18 hours, then concentrate, add water (10 mL), and extract with ethyl acetate (3×20 mL). Dry the combined organic extracts over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-(1H-imidazol-1-yl)pentan-1-one (0.14 g; 45%) as a colorless oil: MS (m/z): 417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C-]#N.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]([CH:4]([C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[OH:5])=[O:5]
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1Cl)C(O)c1ccc(Cl)cc1Cl
Temperature: 105 °C

Procedure:
To a mixture of 2,4-dichlorobenzaldehyde (5.0 gm, 29 mmol) in ethanol (10 mL) was added a solution of sodium cyanide (500 mg, 10 mmol) in water (5 mL). The reaction was heated to reflux (100-110° C.) for 1 hr and was then cooled, diluted with water, and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (10% methylene chloride, 10% ethyl acetate in hexanes) to afford the title compound as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)=[CH:3]1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([Cl:27])=[O:23])=[CH:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-oxoandrost-4-ene-17β-carboxylic acid (30 g) in methylene chloride (300 mL) and dimethylformamide (1.82 mL) a solution of oxalyl chloride (9.28 mL) in methylene chloride (30 mL) was added dropwise at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 1 hour the reaction was completed. The volatile compounds were removed under vacuum, the solid was taken up with cyclohexane (200 mL) and evaporated to dryness (twice). The 3-oxo-androst-4-ene-17β-carbonyl chloride (30.33 g) so obtained was dissolved in chloroform (1.5 L), cooled to 0° C. and treated with 1,1,1,3,3,3-hexafluorophenylpropyl amine (46.078 g) and pyridine (38.3 mL). The reaction mixture was heated at reflux for 7 hours. After staying overnight at room temperature the reaction mixture was washed with 1N HCl (2×100 mL), with brine, with water until neutral and dried over sodium sulfate. The solvent was evaporated under vacuum and the brownish solid purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 70/30) to yield 9.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH2:11])=[N:7][CH:6]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH:11][C:23](=[O:24])[CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:26][CH3:27])=[N:7][CH:6]=1
Reactant: Cn1c(Cc2ccccc2Cl)cnc1N
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)n1C)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-1-methyl-1H-imidazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (13 mg, 0.035 mmol, 18%). ESI-MS m/z calc. 367.2. found 368.1 (M+1)+ Retention time 2.42 minutes.
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][N:7]=1>O1CCCC1.O>[CH3:1][CH:2]([CH3:37])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:8][N:7]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(Oc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoate (0.40 g, 0.77 mmol) in tetrahydrofuran (5 mL) was added a solution of LiOH monohydrate (326 mg, 7.77 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. Tetrahydrofuran was removed under reduced pressure and the aqueous residue was acidified to pH=3 by addition of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Phenomenex Gemini 200×21.2 mm, 10 μm; modifier: ammonium hydroxide (to pH 10); gradient: 28 to 50% acetonitrile in water) gave (+/−)-3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoic acid (30 mg) as a white solid.
Reaction SMILES: [Mg].II.[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.C(Cl)C1C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH:27]([CH3:33])[CH2:26]2>CCOCC>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1)[C:27]([CH3:33])=[CH:26]2
Reactant: CSc1ccc(CCl)cc1
Reactant: CC1Cc2cc(F)ccc2C1=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCc1ccccc1
Product: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Reaction time: 0.07 h

Procedure:
13.44 G. (0.56 mole) of magnesium turnings were placed in a dried flask under N2 with 125 ml. of ether and a crystal of iodine. 6 Ml. of 65 ml. solution of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether was added. After 3 to 5 minutes of stirring, the iodine color disappeared and the reaction began. After aging for 5 minutes, the rest of the benzyl chloride was added dropwise over 45 minutes. It was rinsed in with 10 ml. of ether and the reaction aged for 2 hours with stirring. 21 G. (0.128 mole) of 5-fluoro-2-methyl-1-indanone dissolved in 50 ml. of ether was added dropwise over 30 minutes. After aging for 1 hour, the milky supernatent mixture was decanted from the magnesium into 100 ml. of acetic acid. The flask and residual magnesium were rinsed into the acid solution with 4 × 50 ml. of benzene. 200 Ml. of water were added, the layers were separated and the organic layer was washed with 5 × 200 ml. water. It was stripped to dryness after drying over Na2SO4. The crude reaction product is crystallized from hexane to give pure 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene, melting point 58°-59°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([C:23]4[N:27]=[N:28][NH:29][N:24]=4)=[CH:25][CH:26]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)ccc1-c1nn[nH]n1
Temperature: 120 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile (11 mg, 0.031 mmol), sodium azide (5.5 mg, 0.085 mmol) and triethylamine hydrochloride (6.0 mg, 0.043 mmol) in 2 mL of DMF was stirred at 120° C. for 6 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine. Yield 12 mg, 97% yield; HPLC: Rt=2.09 min; MS 394 [M−H].
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 91.5 %

Procedure:
1.03 g (5 mmol) of 1,1-dimethylethyl 1,4-diazepane-1-carboxylate, 1.19 g (5 mmol) of 2,5-dibromopyridine and 0.7 g (5 mmol) of potassium carbonate suspended in 0.90 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is heated at 150° C. for 22 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate, and the organic solution is washed with water and then brine, and dried over sodium sulfate. The filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 99.5/0.5 mixture of dichloromethane and methanol. 1.63 g of product are obtained in the form of an oil, and are used without further purification in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccccc1Br
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccccc1Br
Reaction time: 0.75 h

Procedure:
To a solution of o-bromo-benzaldehyde (4 g, 21.6 mmol) and nitromethane (1.32 g, 21.6 mmol) in methanol (5 mL) was added NaOH (0.908 g, 22.7 nmol) in 1 mL of H2O. After 45 minutes, the precipitate was dissolved in 10 mL of H2O. The product precipitated out after the addition of 6N HCl. The product was recrystallized from ethanol; 0.312 g (6%).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCC)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 17 h
Yield: 75 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:8) to furnish IV as a colourless oil (12 mg, 75%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>CN(C=O)C.CCOC(C)=O>[NH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:11]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1n[nH]c2ccc(I)cc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 5-iodo-1H-indazole-3-carboxaldehyde (544 mg, 2 mmol) and 1,2-diaminobenzene (216 mg, 2 mmol) in DMF (5 mL) was add 4 Å molecular sieves. The mixture was kept at 60° C. for 2 hr, then the mixture was heated up to 80° C. overnight under air atmosphere (air balloon). The mixture was diluted with EtOAc, washed with water, dried and concentrated. The crude product was purified by flash chromatography to afford 3-(1H-benzimidazol-2-yl)-5-iodo-1H-indazole (500 mg, 69%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Cl[CH2:21][N:22]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=2[CH:34]([CH3:36])[CH3:35])[S:23]1(=[O:25])=[O:24]>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:21][N:22]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=3[CH:34]([CH3:36])[CH3:35])[S:23]2(=[O:24])=[O:25])=[O:7])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1ccsc1)C2=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 3-thiophene carboxylic acid (0.26 g, 2.0 mmol), K2CO3 (0.28 g, 2.0 mmol) and DMF (4 ml) was stirred for 1 hour. 2-Chloromethyl-4-isopropyl-6-methoxy-saccharin (0.61 g, 2.0 mmol) was then added and the mixture was stirred for 24 hours. Water (20 ml) was added to the reaction mixture and the solution was extracted with ether (2×40 ml). The organic layer was separated, washed with water, then brine and was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the solid residue was recrystallized from toluene/hexane to afford 0.5 g (65%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl thiophene-3-carboxylate as a white powder, m.p. 125°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[CH3:11][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:13]([C:15]1[CH:16]=C(O)[CH:18]=[C:19]([CH:21]=1)[OH:20])[CH3:14].Cl>C(O)C>[OH:20][C:19]1[C:18]2[C:9]3[CH2:8][S:7][CH2:6][C:5]=3[C:3](=[O:4])[O:2][C:1]=2[CH:16]=[C:15]([CH:13]([CH:12]([CH3:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:14])[CH:21]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1CSCC1=O
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSC3
Reaction time: 72 h

Procedure:
A solution of 20 g. (0.125 mole) of methyl-4-oxo-2,3,4,5-tetrahydrothiophene-3-carboxylate and 32 g. (0.135 mole) of 5-(3-methyl-2-octyl)resorcinol in 200 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. The reaction mixture was allowed to stand at room temperature for 72 hours and the solid which formed was removed by filtration. Recrystallization from ethanol gave 16 g. (37%) m.p. 165°-166°. The structure was confirmed by the IR and nmr spectra.