Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH2:44]([O:51][NH:52][C@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A solution of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (10.22 g, 34.38 mmol) in dehydrated acetonitrile (113 mL) was cooled to a temperature between −30 and −40° C. under an argon atmosphere, followed by adding 2,6-lutidine (4.4 mL), then adding dropwise trifluoromethanesulfonic anhydride (5.92 mL) over 10 minutes, and further reacting at −30° C. for 15 minutes. To this reaction mixture was added benzyloxyamine (8.46 g) (washed with acetonitrile (5 mL)), followed by raising the temperature to 0° C. within 30 minutes, further adding 2,6-lutidine (4.4 mL), and allowing to react at a temperature between 0 and 5° C. for 3.5 days. This reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with ethyl acetate (200 mL), followed by washing with water (200 mL), 10% citric acid aqueous solution (200 mL× three times), 6.5% sodium bicarbonate aqueous solution (100 mL), and saturated brine (100 mL) sequentially. Each aqueous layer was back-extracted with ethyl acetate (100 mL), the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1) to afford 11.69 g of the title compound as a colorless oil (yield 85%). Enantiomeric excess 99.0% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=9/1, flow rate 1 mL/min., retention time 4.5 min.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]>C(O)(=O)C.C(O)C.ClCCl.[Zn]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of [4-(3-nitro-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (390 mg, 0.96 mmol) in acetic acid (3 mL) and ethanol (15 mL) was added zinc powder portionwise. After being heated at reflux for 2 hours, the mixture was cooled to room temperature, diluted with dichloromethane (30 mL) and filtered through a glass funnel and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (300 mg, 83%) as a semisolid. MS cald. for C17H22N4O4S 378, obsd. (ESI+) [(M+H)+] 379.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][C:12](OC)=[S:13]>>[NH2:1][CH2:2][CH2:3][NH:4][C:12](=[S:13])[CH2:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: NCCN
Reactant: COC(=S)CC1CCCCO1
Product: NCCNC(=S)CC1CCCCO1
Temperature: 75 °C

Procedure:
1,2-Diaminoethane (21 g, 350 mmol) was added to methyl tetrahydropyran-2-ylthioacetate (20 g, 105 mmol) and the mixture heated at 75° C. for 2 h. Volatile components were then removed from the reaction mixture in vacuo to give the N-(2-aminoethyl)-tetrahydropyran-2-ylthioacetamide in essentially quantitative yield. This product was contaminated with a small quantity of 1,2-diaminoethane, but it was sufficiently pure to be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:5][OH:6]
Reactant: COC(=O)c1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
To a solution of methyl 3-chloro-4-methoxybenzoate (1.2 g, 6 mmol) in tetrahydrofuran (10 ml) was added under ice-cooling lithium aluminum hydride (455 mg, 12 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was stirred under ice-cooling and 0.1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.1 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[O:24][C:25]=1[CH3:26].FC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1F
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester (example 8 g]) was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:15])=[C:4]([F:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([N:15]=[C:24]=[S:25])=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1N=C=S

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidinyloxy)-benzenamine (50 g) and triethyl amine (42.2 g) were dissolved in anhydrous ethyl acetate (400 ml) and stirred under ice cooling. Thiophosgene (74.3 g) dissolved in ethyl acetate (400 ml) was slowly added to the stirred solution. The mixture was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded 2-(2-chloro-4-fluoro-5-isothiocyanatophenoxy)-pyrimidine which was used for the next step without purification. 1H NMR, CDCl3, 7.12 (1H, t, J=4.7 Hz), 7.13 (1H, d, J=7.0 Hz), 7.32 (1H, d, J=8.9 Hz), 8.58 (2H, t, J=4.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH:12]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][N:13]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:12]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc(F)ccc21
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1cc(F)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 8-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and benzoyl chloride; 1H-NMR (CDCl3): δ 10.57 (1H, br s), 8.05 (1H, s), 7.55 (3H, m), 7.45 (3H, m), 7.05 (1H, dd), 6.87 (1H, m), 4.22 (4H, m), 3.24 (2H, t), 1.2 (3H, t); MS (ES): 379 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.0 g, ˜0.0070 mol) in DMF (10 mL), phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.74 g, 0.0067 mol) was added. The reaction mixture was stirred at 60° C., overnight. The solvent was evaporated under vacuum and the residue was sonicated in the presence of ethyl ether (60 mL). The solid was filtered and washed with ethyl ether to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (2.75 g, 87.5% yield). 1HNMR (DMSO-d6): δ 10.53 (s, 1H), 9.57 (s, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 7.52 (d, 2H), 7.37 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.18 (s, 1H), 4.00 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: NCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[NH:6][CH:5]=1.OC1C=C2C(=CC=1)NC=C2.C([O-])([O-])=O.[K+].[K+].BrC(CCC)CC1C=CC=CC=1>CC(=O)CC.C(Cl)Cl>[C:19]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCc1c[nH]c2ccc(OCCCCCc3ccccc3)cc12
Agent: CCCC(Br)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: Oc1ccc2[nH]ccc2c1
Solvent: CCC(C)=O
Solvent: ClCCl
Product: c1ccc(CCCCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C

Procedure:
Synthesis of 3-(2-aminoethyl)-5-(5-phenylpentyloxy)indole was based on the protocols of example 1. A stirred mixture of 5-hydroxyindole (0.5 g, 3.8 mmol), anhydrous K2CO3, (2-bromopentyl)benzene, and a catalytic amount of KI in 2-butanone (40 ml) was heated at reflux overnight under nitrogen. After allowing to cool to room temperature, the reaction mixture was filtered, the flitrate was then concentrated under reduced pressure to give an oil. The oil was taken up in CH2Cl2 (50 ml) and washed successively with 2N-NaOH (1×20 ml) and water (1×20 ml). The organic portion was dried (MgSO4) and the solvent was removed under reduced pressure to give an oil. The oil was purified by column chromatography using a solvent system of CH2Cl2 /Hexane (40:60) to give 5-(5-phenylpentyloxy)indole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.[Br:23]Br>C(O)(=O)C.ClCCl>[Br:23][C:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[C:6]([F:18])=[CH:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[CH:3][C:2]=2[F:1])[NH:15][CH:16]=1
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1.05 g (3.45 mmol) of N-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide are dissolved in 35 ml of glacial acetic acid and, using an ice bath, cooled to about 10° C. 4.8 ml (4.8 mmol) of a 1M solution of bromine in dichloromethane are added, and the mixture is stirred at 20° C. for about 30 min, resulting in the precipitation of a solid. The solid is filtered off with suction and washed with ethyl acetate. The mother liquor is neutralized using conc. aqueous sodium hydroxide solution and extracted with ethyl acetate. The crystals that were filtered off with suction are dissolved in 3 ml of DMF. The mixture is diluted with ethyl acetate and extracted three times with 1N sodium hydroxide solution. The combined organic phases are dried over magnesium sulfate. The solvent is removed under reduced pressure. The product is reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4](=[O:21])[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCN(CC)CC>CN(C1C=CN=CC=1)C>[C:22]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4]=1[OH:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C=C(O)C2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a 200 mL recovery flask was added 3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30F, 4.9 g, 16.3 mmol, 1.0 eq.), CH2CT2 (100 mL), acetic anhydride (2.15 g, 21.1 mmol, 1.3 eq.), Et3N (6.8 mL, 48.8 mmol, 3.0 eq.), and DMAP (catalytic). The reaction mixture was stirred overnight at room temperature whereupon LC/MS showed two signals corresponding to M+H=344. Additional acetic anhydride (0.5 mL, 5.3 mmol, 0.32 eq.) was added and the reaction mixture was heated for 6 h at 40° C. LC/MS analysis showed the reaction to be complete whereupon the mixture was concentrated to a solid and purified via flash chromatography (70% CH2Cl2/Hex to 100% CH2Cl2) to yield a dark orange solid 30G (1.72 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.57 (m, 3H) 2.83 (m, 2H) 3.09 (m, 2H) 3.78 (s, 3H) 4.68 (m, 1H) 6.74 (d, J=8.34 Hz, 1H) 7.32 (d, J=7.33 Hz, 1H) 7.41-7.47 (m, 1H) 7.51 (d, J=5.31 Hz, 1H) 7.76 (t, J=7.96 Hz, 1H). ESI-MS: m/z 344.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:21]=[C:20]2[C:11]([N:12]3[C:17]([CH2:18][O:19]2)=[N:16][NH:15][C:14](=[O:22])[CH:13]3[CH3:23])=[CH:10][C:9]=1[NH:24][C:25]1([CH3:29])[CH2:28][NH:27][CH2:26]1.C=O.[BH3-][C:33]#N.[Na+].O>CO.C(O)(=O)C>[CH3:33][N:27]1[CH2:26][C:25]([NH:24][C:9]2[CH:10]=[C:11]3[C:20](=[CH:21][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:19][CH2:18][C:17]2[N:12]3[CH:13]([CH3:23])[C:14](=[O:22])[NH:15][N:16]=2)([CH3:29])[CH2:28]1
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(NC4(C)CNC4)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(NC4(C)CN(C)C4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 7-(2-fluoro-phenyl)-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.216 g, 0.545 mmol) in MeOH (10 mL) and acetic acid (1 mL) was added paraformaldehyde (0.05 g, 1.635 mmol) followed by NaBH3CN (0.068 g, 1.090 mmol). The mixture was stirred at ambient temperature for 30 min. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the residue, which was purified by chromatography on silica gel (eluting with 50% EtOAc in petroleum ether to 10% methanol in EtOAc) to give 6-(1,3-dimethyl-azetidin-3-ylamino)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.150 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 7.37 (m, 2H), 7.24 (m, 2H), 6.78 (s, 1H), 6.02 (s, 1H), 4.78 (m, 1H), 4.55 (m, 2H), 3.90 (m, 2H), 3.80 (m, 2H), 2.75 (s, 3H), 1.59 (s, 3H), 1.48 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.715 min.; MS m/z: 410 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1([O:13][CH3:14])[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].P(=O)(O)(O)O.O>C1(C)C(C)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:4][C:3]1([CH3:5])[C:10]2[C:11](=[CH:12][C:6]([O:13][CH3:14])=[C:7]([OH:8])[CH:9]=2)[CH2:1][CH2:2]1
Reactant: COc1ccccc1O
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc2c(cc1O)C(C)(C)CC2
Reaction time: 8 h
Yield: 38.4 %

Procedure:
449 g of isoprene, stabilized with 1.4 g of phenothiazine, were added dropwise over the course of 6 hours to a solution of 744 g of guaiacol, 76 g of 85% strength phosphoric acid and 6 ml of water in 1.4 liters of xylene at 110° C. To complete the reaction, stirring of the mixture was continued overnight at 110° C. The acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 443 g of 3,3-dimethyl-5-hydroxy-6-methoxy-indane, boiling point: 145- 46° C/12 mm Hg, melting point 43.5° - 44.5° C. ##STR35##
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:15])[S:5][C:6]=1[C:7]#[C:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:16](N1C=CN=C1)([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)=[O:17].C(N(CC)CC)C.CC(OC)(C)C>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:15][C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:17])[S:5][C:6]=1[C:7]#[C:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(N)sc1C#Cc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)n2ccnc2)sc1C#Cc1cccnc1
Yield: 91.7 %

Procedure:
As shown in step 2-iii of Scheme 2, compound 1004 (91 mg, 0.423 mmol), 1,1′-carbonyldiimidazole (103 mg, 0.634 mmol), and triethylamine (85.6 mg, 0.845 mmol) were stirred in 2.1 mL of DMF at 60° C. for 2 hours. After this time, MTBE was added and the resulting precipitate collected by filtration to produce N-(4-methyl-5-(pyridin-3-ylethynyl)thiazol-2-yl)-1H-imidazole-1-carboxamide (compound 1005, 120 mg), which was immediately used in subsequent reactions as is.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(COC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCC(COC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
2-{2-[4-(1,1-Diphenyl-methoxymethyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione (0.95 g, 2.1 mmol) was dissolved in ethanol (5 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was stirred at room temperature overnight. The white solid was precipitated. The white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×20 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product 2-[4-(1,1-diphenyl-methoxymethyl)-piperidin-1-yl]-ethylamine was obtained (0.335 g, 49.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13](O)=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH2:55][CH2:54]1>CC(N(C)C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:53]3[CH2:54][CH2:55][CH:56]([N:59]4[CH2:63][CH2:62][CH2:61][C:60]4=[O:64])[CH2:57][CH2:58]3)=[O:14])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Reactant: O=C1CCCN1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: O=C(Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1)N1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (164 mg, 0.53 mmol) in DMA (3 mL) at room temperature was added HOBt (78 mg, 0.58 mmol), EDCI (111 mg, 0.58 mmol), NMM (0.20 mL, 1.84 mmol) and 1-piperidin-4-ylpyrrolidin-2-one hydrochloride (150 mg, 0.73 mmol) and the mixture sonicated to a fine suspension and stirred for 64 hours at room temperature. The volatiles were removed under high vacuum and the residue partitioned between EtOAc (70 mL) and water (25 mL). The aqueous layer was removed and the organics washed with NaHCO3 (30 mL), brine (30 mL), dried over MgSO4, filtered and stripped to yield the title compound as an off-white solid, 123 mg, 51%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.51-8.54 (2 H, m), 7.64-7.69 (2 H, m), 7.25-7.35 (2 H, m), 7.11-7.21 (2 H, m), 6.53 (1 H, s), 5.11-5.28 (2 H, m), 4.37 (1 H, d, J=13.14 Hz), 3.90-4.05 (4 H, m), 3.23-3.31 (2 H, m), 3.08-3.20 (1 H, m), 2.57-2.70 (1 H, m), 2.22 (2 H, t, J=8.08 Hz), 1.84-1.95 (2 H, m), 1.40-1.73 (4 H, m); m/z (APCI+) for C26H28N5O2F 462.2 (M+H)+.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Br:9][C:10]1[N:11]=[C:12]([C@@:15]2([NH:24][C:25]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[S:26])[C@H:20]([CH2:21]O)[CH2:19][C@H:18]([CH3:23])[O:17][CH2:16]2)[S:13][CH:14]=1>ClCCl>[Br:9][C:10]1[N:11]=[C:12]([C@:15]23[CH2:16][O:17][C@@H:18]([CH3:23])[CH2:19][C@H:20]2[CH2:21][S:26][C:25]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24]3)[S:13][CH:14]=1
Reactant: C[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2nc(Br)cs2)CO1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2nc(Br)cs2)CO1
Reaction time: 1 h

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (Ghosez's reagent, 7.85 mL, 59.3 mmol) was added drop-wise to a solution of C5 (9.30 g, 19.8 mmol) in dichloromethane (200 mL). After 1 hour at room temperature, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a solid. Yield: 6.90 g, 15.2 mmol, 77%. LCMS m/z 452.1, 454.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.69 (br s, 1H), 8.38-8.43 (m, 2H), 7.64-7.70 (m, 1H), 7.54-7.60 (m, 2H), 7.34 (s, 1H), 4.45 (d, J=12.5 Hz, 1H), 3.93 (d, J=12.5 Hz, 1H), 3.74-3.83 (m, 1H), 3.28-3.36 (m, 1H), 3.23 (dd, J=13.5, 4.0 Hz, 1H), 2.77 (dd, J=13.5, 2.8 Hz, 1H), 1.66-1.82 (m, 2H), 1.32 (d, J=6.2 Hz, 3H).