Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9](OCC)=[O:10])=[CH:4][N:3]=[CH:2]1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][CH:16]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1cccc(-c2cncs2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1cccc(-c2cncs2)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of ethyl 3-(thiazol-5-yl)benzoate (553 mg; 2.37 mmol) in anh. toluene (8 ml) was treated with a solution of 1 M DIBAH in toluene (7.12 ml; 7.12 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 30 min. The mixture was then treated successively with water (35 ml), 1 M aq. NaOH (11 ml), and aq. sat. NaHCO3 (30 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(thiazol-5-yl)phenyl)methanol as an orange oil. LC-MS (conditions A): tR=0.49 min.; [M+H]+: 192.10 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:11][CH3:12])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC)C(=O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A solution of ethylmalonic acid diethyl ester (123.6 g) in 95% ethanol (650 ml) is placed in a 1-l four-necked flask fitted with a mechanical stirrer, a condenser, a thermometer and a dropping funnel, and cooled to about 10° C. A solution of NaOH (26.8 g) in water (33 ml) is added dropwise into the above solution over a period of 15 minutes. The mixture is allowed to go to room temperature and stirring is continued for about 1 hour until a neutral pH is reached. By evaporating the solvent under vacuum and heating to about 30°-35° C., a residue is obtained which is taken up with water (400 ml) and extracted with toluene (two 130-ml portions). The toluene extracts are washed with water and the aqueous phase plus the aqueous wash are brought to pH 2 by the addition of 37% HCl (50 ml) and extracted with methylenechloride (four 125-ml portions). The methylene chloride extracts are combined, dried over Na2SO 4 and concentrated to dryness yielding ethylmalonic acid monoethyl ester (87.7 g) as a thick oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:8][CH2:7]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[C:32]([O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:10][CH2:11]1)(=[O:34])[CH3:33]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc(O)c2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of 207 mg (0.5 mmol) of 3-[1-(3-hydroxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)quinazolinone in 3 mL of pyridine was added 61 mg (0.6 mmol) of acetic anhydride, and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on sodium sulfate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 187 mg (0.41 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[C:18]1[CH:23]=[N:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][N:19]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[N:22]=[CH:23][C:18]([N:10]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:13][O:12][C:11]3=[O:14])=[N:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: O=C1NC(c2cccc(C(F)(F)F)c2)CO1
Reactant: Clc1ccc(Oc2cnc(Br)cn2)cc1
Product: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1

Procedure:
(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one is prepared from 4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and 2-bromo-5-(4-chloro-phenoxy)-pyrazine using the same conditions as example 4. 1H NMR (CDCl3, 400 MHz) δ 8.98 (d, 1H), 7.95 (d, 1H), 7.47˜7.62 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H), 5.82 (dd, 1H), 4.88 (t, 1H), 4.35 (dd, 1H); HPLC-MS calculated for C20H13ClF3N3O3 (M+H+) 436.1, found 436.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH2:10]1.C[Al](C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[S:38][C:39]3[C:45](=[O:46])[O:44][CH2:43][CH2:42][C:40]=3[N:41]=2)=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:25][C:45]([C:39]2[S:38][C:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)=[N:41][C:40]=2[CH2:42][CH2:43][OH:44])=[O:46])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:18])[CH3:17])[CH2:10]1
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Reactant: COc1cc(N)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Agent: C[Al](C)C
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.1 %

Procedure:
Charge an oven-dried round bottom flask with (R)-3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenylamine (750 mg, 2.05 mmol), purge with nitrogen, and dilute with CH2Cl2 (11 mL). Add trimethylaluminum (2M in hexanes, 1.03 mL, 2.05 mmol) dropwise by syringe and stir 20 min at room temperature. Add solid 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (364 mg, 1.37 mmol) to the reaction mixture and stir overnight at ambient temperature. Absorb the reaction mixture on silica gel and purify by silica gel flash chromatography, using a gradient of EtOAc/hexane (0-100%) to give the title compound (1.02 g, 73%). MS (ES+) 630.1 (M+1)+. 1H NMR (CDCl3): δ 9.88 (bs, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.48 (bs, 1H), 7.37 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.69 (bs, 1H), 4.60-4.52 (m, 1H), 4.19-4.11 (m, 2H), 3.81 (s, 3H), 3.69-3.58 (m, 1H), 3.39-3.29 (m, 1H), 3.26 (t, J=5.3 Hz, 2H), 3.20-3.02 (m, 2H), 2.21-2.08 (m, 1H), 1.93-1.83 (m, 1H), 1.59 (bs, 1H), 1.12-0.95 (m, 21H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[C:4]([F:33])[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1.O1CCOCC1>O1CCCC1>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:42])[CH:7]=[CH:6][C:5]=1[N:8]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:31])([C:23]([F:24])([F:25])[F:26])[C:27]([F:30])([F:28])[F:29])=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)[CH3:32]
Reactant: CN(c1ccc(N)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(c1ccc(NC(=O)Nc2ccncc2)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 67 %

Procedure:
2-(4-((4-((4-Amino-2-fluorophenyl)(methyl)amino)piperidin-1-yl)methyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.209 mmol, 100 mg) and phenyl pyridin-4-ylcarbamate (0.313 mmol, 67.0 mg) were combined in tetrahydrofuran (1 mL) and dioxane (1 mL) and heated to 80° C. overnight. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to afford title compound (83.9 mg). MS (ESI) m/z 600.2 [M+H]+
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH2:15][N:16]1[C:22](=[O:23])[C@@H:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][O:19][C:18]3[C:32]([C:36]([O:38]C)=[O:37])=[CH:33][CH:34]=[CH:35][C:17]1=3)=[C:10]([O:40][CH3:41])[CH:9]=[CH:8]2>CO>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH2:15][N:16]1[C:22](=[O:23])[C@@H:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][O:19][C:18]3[C:32]([C:36]([OH:38])=[O:37])=[CH:33][CH:34]=[CH:35][C:17]1=3)=[C:10]([O:40][CH3:41])[CH:9]=[CH:8]2
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2cc(Br)ccc12
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 47.5 °C
Reaction time: 7 h
Yield: 90.7 %

Procedure:
A 0.1 M aqueous solution of LiOH.H2O (5.98 mL, 598 μmol, Eq: 1.00) was added to a solution of (S)-methyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-(tert-butoxycarbonylamino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (0.35 g, 598 μmol, Eq: 1.00) in MeOH (20 mL) and the mixture was warmed to 45-50° C. After 7 h, the MeOH was removed in vacuo and the mixture diluted with sat. NaHCO3 then extracted with EtOAc. The aqueous mixture was cooled to 0° C., acidifed to pH 3.0 with 3 N HCl and extracted with EtOAc. The combined organic extracts were washed with brine and concentrated a to give a material that was purified by silica gel chromatography to afford (S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-(tert-butoxycarbonylamino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (310 mg, 90%) as a white foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[NH:24][C:33]2=[O:35])=[CH:15][CH:16]=1
Reactant: Nc1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cccnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a mixture of N2-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.080 g) and triethylamine (0.0638 g) in THF (1.5 mL) at 0° C., was added dropwise a solution of triphosgene (0.030 g) in THF (0.6 mL). The reaction mixture was stirred at 0° C. for 0.5 h. The cold bath was removed and the stirring continued at ambient temperature for another 0.5 h. After this time, a saturated aqueous solution of sodium bicarbonate was added. The organic layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 0.3:5:95 ammonium hydroxide/methanol/methylene chloride) to afford 3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.038 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:21]1[CH2:31][CH2:30][C:24]2[N:25]=[CH:26][N:27]=[C:28](Cl)[C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:28]2[C:23]3[CH2:22][N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:31][CH2:30][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 85.4 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.94 g, 5.01 mmol) in THF (20 mL) was added under argon NaH (0.23 g, 5.78 mmol). The mixture was stirred at rt for 25 min., then 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (1 g, 3.85 mmol) was added and stirring continued at rt for 4 h. The mixture was quenched with H2O, extracted with CH2Cl2. The organic layer was filtered and evaporated to dryness. Purification by flash chromatography on silica gel (heptanes/ethyl acetate, 1/1) gave the (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.35 g, 85% yield) as a yellow gum. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.39 (s, 9 H) 2.00-2.20 (m, 2 H) 2.35-2.81 (m, 4 H) 3.36-3.63 (m, 6 H) 3.70 (br.s, 2 H) 5.50-5.59 (m, 1 H) 7.25-7.37 (m, 5 H) 8.56 (s, 1 H). LCMS: [M+H]+=411.6, Rt(7)=1.00 min
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][C:49]([C:51](Cl)=[O:52])=[O:50].C(N(CC)CC)C>O1CCCC1>[CH3:47][O:48][C:49]([C:51](=[O:52])[NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:50]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added methyl(chlorocarbonyl)formate (0.068 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 689 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.C(O)(C(F)(F)F)=O>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30])[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate (67 mg, 0.12 mmol) and TFA (0.6 mL) in dichloromethane (0.6 mL) was stirred at room temperature for 60 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was diluted with saturated NaHCO3 and then extracted with dichloromethane. The combined organic layers were dried by Na2SO4, filtered, concentrated to give (1R,2S)—N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)cyclohexane-1,2-diamine which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][CH2:26][CH2:27][OH:28].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(O)(=O)C>[CH2:1]([N:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:25]([CH3:24])[CH2:26][CH2:27][OH:28])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(CCO)Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of 39 (600 mg, 2.0 mmol) in THF (25 mL) was added 2-(methyl amino) ethanol (224 mg, 3.0 mmol) and a catalytic amount of acetic acid (0.1 mL) and cooled to 0° C. Na(OAc)3BH (1 g, 5.0 mmol) was added portion wise and the reaction mixture allowed to warm and stired at rt for 3 h. The reaction mixture was neutralized by using NaHCO3 (aq), diluted with water (25 mL, 1:3 dilution), extracted with EtOAc (2×100 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by column chromatography (neutral alumina, eluted with 5% MeOH/CHCl3) to obtain compound 40 (400 mg, 55%) as a brown solid. Rf: 0.3 (10% MeOH/CHCl3); (m/z): 362 [MH]+; 1H NMR (400 MHz, DMSO-d6) δ 7.91 (1H, d, J=2.8 Hz), 7.35-7.22 (10H, m), 7.12 (1H, d, J=8.8 Hz), 7.02 (1H, dd, J=2.8, 8.8 Hz), 4.72 (4H, s), 4.37 (1H, br s), 3.46-3.44 (4H, m), 2.40 (2H, t, J=6.4 Hz), 2.13 (3H, S).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: CCOc1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOc1cnc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
2,4-dichloro-5-ethoxy-pyrimidin (2.83 g, 1.0 eq) was stirred in toluene (20 ml) and a solution of morpholine (1.93 ml, 1.5 eq) in toluene (20 ml) was added dropwise at −10˜0° C. After stirring the resulting solution overnight at r.t., NH4Cl(aq) was added to the solution and the solution was extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo. A product was obtained as a white solid (2.7 g, 73.5%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:38][CH2:39]C)(=[O:37])[CH3:36]>C(#N)C>[CH3:39][O:38][C:35](=[O:37])[CH2:36][N:23]1[C:24]2[C:20](=[CH:19][C:18]([S:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)(=[O:17])=[O:16])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: CCOC(C)=O
Reactant: O=S(=O)(c1ccc2[nH]ccc2c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Yield: 99 %

Procedure:
5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (60 mg, 0.15 mmol), methyl bromo acetate (16 μL, 0.18 mmol) and cesium carbonate (95 mg, 0.29 mmol) were stirred in acetonitrile (10 ml) overnight at 70° C. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated to provide {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (99%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, 1H) 7.60 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 1H), 7.24 (d, 1H), 6.83 (d, 2H), 6.90 (d, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.32-3.30 (m, 4H), 3.15-3.13 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Na+].[Cl-]>C1COCC1.O.CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH2:15]
Reactant: COc1ccc(CNc2ccc(C#N)cc2[N+](=O)[O-])c(OC)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(C#N)cc2N)c(OC)c1
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
A solution of 4-(2,4-dimethoxybenzylamino)-3-nitrobenzonitrile (4.54 g) in THF (400 mL) was treated with a solution of sodium hydrosulfite (20 g) and sodium bicarbonate (10 g) in distilled water (350 mL). Enough methanol was immediately added (50 mL) to maintain a homogeneous solution. After 15 minutes, EtOAc (500 mL) and saturated aqueous NaCl (500 mL) were added and the organic layer was separated. The aqueous layer was extracted again with 400 mL EtOAc. The combined organic layers were washed with saturated aqueous NaCl (500 mL) and separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide 4.33 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:32][O:33][CH2:34][CH:35](O)[CH2:36][O:37][CH3:38].CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>C1COCC1.C(OCC)(=O)C.O>[CH3:32][O:33][CH2:34][CH:35]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH2:36][O:37][CH3:38]
Reactant: COCC(O)COC
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCC(COC)Oc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.1 %

Procedure:
To a solution of 2-methylquinolin-8-ol (4.10 g, 25.76 mmol), PPh3 (16.89 g, 64.39 mmol) and 1,3-dimethoxypropan-2-ol (4.02 g, 33.48 mmol) in THF (20 mL) was added DIAD (8.40 mL, 41.21 mmol) dropwise at ambient temperature. The reaction mixture was stirred at room temperature for two days. 4 N HCl (7.73 mL, 30.91 mmol in water), water (20 mL), and ethyl acetate (50 mL) were added. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was neutralized with ammonium hydroxide to about pH 9 and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate) to give 8-(1,3-dimethoxypropan-2-yloxy)-2-methylquinoline (6.00 g, 89.15%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[H][H]>O1CCCC1.[Pt]>[CH:9](=[C:6]1[O:5][C@H:4]2[N:8]([C:2](=[O:1])[CH2:3]2)[CH2:7]1)[CH3:10]
Reactant: [H][H]
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Agent: [Pt]
Solvent: C1CCOC1
Product: CC=C1CN2C(=O)C[C@H]2O1
Yield: 12 %

Procedure:
(5R)-7-oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (2.4 mmole) in tetrahydrofuran (20 ml) was shaken with 5% platinum on charcoal (150 mg) under 1 atmosphere of hydrogen at room temperature for 1.5 hours. The catalyst was removed by filtration and was washed with tetrahydrofuran. The solvent was evaporated from the filtrate and the residue was chromatographed on silica gel using 1:7 ethyl acetate/petroleum ether (b.p. 60-80°). A mixture of E- and Z- isomers of the title compound was thus obtained as a colourless oil(40 mg).