Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:31][CH3:32])[CH:17]=2)[N:12]=1)(C)(C)C.ClC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=C(OC)C=2)N=1.C(OC(=O)NCCN)(C)(C)C.C(N(C(C)C)CC)(C)C>CCCCO>[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:31][CH3:32])[CH:17]=2)[N:12]=1
Reactant: COc1ccc(N(C)c2nc(NCCNC(=O)OC(C)(C)C)nc3ccc(OC)cc23)cc1
Agent: CC(C)(C)OC(=O)NCCN
Agent: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCN)nc3ccc(OC)cc23)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
(2-{6-Methoxy-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.6 g, 1.81 mmol), (2-amino-ethyl)-carbamic acid tert-butyl ester (0.4 g, 2.54 mmol) and diisopropylethylamine (0.76 mL, 4.4 mmol) in 3 mL of n-BuOH was stirred at 130° C. for 2 days. The solvent was evaporated under reduced pressure. The title compound (0.56 g; 70%) was isolated by preparative TLC (CH2Cl2/MeOH=5/3 as eluent). 1H NMR (DMSO-d6) δ 7.3-7.28 (d, 1H), 7.2 (d, 2H), 7.11-7.08 (d, 1H), 7.02-7.00 (d, 2H), 6.2 (s, 1H), 3.7 (s, 3H), 3.46 (s, 3H), 3.42 (t, 2H), 3.23 (s, 3H), 3.17 (t, 2H), 1.37 (s, 9H); LC-MS (ESI+; 454 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1.Cl.C(N([CH2:28][CH3:29])CC)C.[OH2:30]>C(O)CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:30][C:29]4[CH:28]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:16]=3)[N:4]2[N:3]=1
Reactant: O
Reactant: O=C(NN=c1[nH]nc(Cl)c2ccccc12)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: OCCO
Product: Clc1nn2c(-c3cccc(Oc4ccccc4)c3)nnc2c2ccccc12
Temperature: 130 °C
Reaction time: 3 h

Procedure:
2.5 g benzoic acid (4-chloro-2H-phthalazin-1-ylidene)-hydrazide and 1 g triethylamine hydrochloride are suspended in 60 ml ethylene glycol and stirred at 130° C. for 3 h. The reaction mixture is cooled to ambient temperature and added to 600 ml water. The product is extracted with dichloromethane, the organic layer is dried with sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from N,N-dimethylformamide to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].CS([O:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([O:27][Si](C(C)(C)C)(C)C)[C@H:25]([O:35][Si](C(C)(C)C)(C)C)[C@@H:24]([CH2:43][O:44][CH3:45])[O:23]2)=[C:15]([NH:46][CH2:47][CH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:14]=1)(=O)=O.[CH3:61][N:62]([CH2:64][CH2:65]O)[CH3:63]>CN(C)C=O>[CH3:61][N:62]([CH3:63])[CH2:64][CH2:65][O:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:35])[C@@H:24]([CH2:43][O:44][CH3:45])[O:23]2)=[C:15]([NH:46][CH2:47][CH:48]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:14]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCCN(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 23.5 %

Procedure:
Potassium tert butoxide (112 mg, 1 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (200 mg, 0.25 mmol) (preparation 16) and 2-(N,N-dimethylamino)ethanol (0.16 ml, 1.5 mmol) in N,N-dimethylformamide (3 ml). The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 ml) after 30 min. The aqueous phase was extracted with dichloromethane (60 ml). The organic phase was separated, dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure to give a residue that was azeotroped with toluene to remove traces of N,N-dimethylformamide. This was then purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (94:5:1) increasing in polarity to (84:14:2) to give the title compound (33 mg) as a foam. MS: 563 (MH+).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Ba+2].[OH-]>O>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [Ba+2]
Solvent: O
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 95 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (5 g, 23 mmol) was mixed with barium hydroxide (11.7), and water (10 g), and the mixture was heated to 95° C. and stirred for 2 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 39%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH3:25][CH2:26][CH2:27][CH2:28]CC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (123.2 mg) was dissolved in tetrahydrofuran (3 ml), and the solution was then cooled to −78° C. A 1.56 M n-hexane solution (0.35 ml) of n-butyllithium was added dropwise thereto, and the mixture was stirred at −78° C. for one hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (59.5 mg, yield 41%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[CH3:11][NH2:12].O>C(Cl)Cl.C1COCC1>[CH3:11][NH:12][S:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)(=[O:9])=[O:8]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1-methyl-1H-imidazol-4-yl)sulfonyl chloride (3.14 g, 17.4 mmol) in methylene chloride was added a solution of methylamine (26 mL of a 2M solution in THF, 52 mmol). The resulting mixture was stirred at room temperature for 16 hr. Water (25 mL) was added and the mixture was extracted with methylene chloride (2×100 mL). The combined organic extracts were washed with water (10 mL) and dried (MgSO4). The solvent was evaporated in vacuo to afford the title compound.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)C.[C:18]1([N:24]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]4[C:43]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[NH:37][C:35]4=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cu]=O>[C:18]1([N:24]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]4[C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([C:8]6[CH:7]=[CH:6][C:5]7[NH:4][C:16]8[C:11]([C:10]=7[CH:9]=6)=[CH:12][CH:13]=[CH:14][CH:15]=8)[C:38]=5[NH:37][C:35]4=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(-n2c3ccccc3c3ccc4c5ccccc5[nH]c4c32)cc1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: O=[Cu]
Product: c1ccc(-n2c3ccccc3c3ccc4c5cccc(-c6ccc7[nH]c8ccccc8c7c6)c5[nH]c4c32)cc1
Temperature: 170 °C
Yield: 84 %

Procedure:
A mixture of 2.0 g of 9-acetyl-3-bromocarbazole prepared as described above and 2.4 g of N-phenylindolo[2,3-a]carbazole (IC-1) were stirred together in 20 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid (4.5 g) was then taken up for further deprotection using 0.8 g KOH with THF (4 ml), methanol (8 ml) and water (8 ml) at reflux temperature. The reaction mixture was then extracted using ethylacetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene:hexane (1:2) as eluent, yielded 2.9 g of 3-(N-phenyindolo[2,3-a]carbazolyl)carbazole as a light yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])=[O:4].CCN(C(C)C)C(C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([O:1][NH:2][C:3]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])=[O:4])=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)CC(C(=O)O)C(=O)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
Intermediate (3d) (12.7 g, 73.2 mmol, 1.0 eq) was dissolved into 180 mL DCM and cooled to 0° C. DIPEA (13.4 mL, 76.9 mmol, 1.05 eq) was added, followed by pivaloyl chloride (9.5 mL, 76.9 mmol, 1.05 eq). The mixture was warmed to room temperature and stirred for 12 hours. The mixture was concentrated under reduced pressure, dissolved into 300 mL EtOAc, washed 2×200 mL 1M H3PO4, 100 mL saturated aqueous NaCl, dried over MgSO4, and evaporated. The material was triturated with hexanes, filtered and dried the to yield the title compound (10.5 g, 55%). 1H NMR (DMSO) δ (ppm): 0.7 (m, 6H), 1.2-1.4 (m, 1H), 1.4-1.6 (m, 2H), 2.9 (t, 1H), 3.3 (quart, 1H), 8.9 (br s, 1H), 10.5 (br s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.O>O1CCCC1>[CH3:19][O:18][C:16]([CH2:15][S:14][C:2]1[S:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])=[O:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Br)s1
Reactant: COC(=O)CS
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CSc1sc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-bromo-5-methoxycarbonyl-3-nitrothiophene (110.7 g) and methyl mercaptoacetate (37.2 ml) in tetrahydrofuran (1 l) was added triethylamine (63.8 ml). After stirring for 4 hours at room temperature, the reaction mixture was poured into water. The resulting precipitate was collected by filtration and washed with water to give 2-methoxycarbonylmethylthio-5-methoxycarbonyl-3-nitrothiophene (118.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:17]([F:28])[C:16]=3[F:29])=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[C:17]([F:28])[C:16]=3[F:29])=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl)propanoate (101 mg, 0.20 mmol, 1.00 equiv), tetrahydrofuran (2.0 mL), a solution of LiOH (100 mg, 4.18 mmol, 20.91 equiv) in water (2.0 mL). The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by LCMS. The pH value of the solution was adjusted to 1 with aqueous HCl (2 N). The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed by hexane and EtOAc. Then the solid was dried under vacuum. This resulted in 85 mg (89%) of 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl)propanoic acid as a white solid. 1H-NMR (300 MHz, CD3OD) δ 7.69 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H), 5.19 (s, 2H), 2.94 (t, J=7.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H13ClF5NO3S, 478.0 (M+H). found 478.1.
Reaction SMILES: C1C2C(COC([NH:18][NH:19][C:20]([C:22]3[C:23](Cl)=[N:24][C:25]4[C:30]([C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:28]([Cl:38])=[CH:27][CH:26]=4)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)CC)C.O>CN(C=O)C>[Cl:38][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C:22]([C:20]([NH:19][NH2:18])=[O:21])=[C:31]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C1CCNCC1
Reactant: O=C(NNC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 120 °C
Yield: 38.6 %

Procedure:
A mixture of N′-(2,6-dichloro-4-phenyl-quinoline-3-carbonyl)-hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester (130 mg, 211 μmol, Eq: 1.00), piperidine (180 mg, 209 μl, 2.11 mmol, Eq: 10) and triethylamine (64.1 mg, 88.2 μl, 633 μmol, Eq: 3) in DMF (2 ml) was heated to 120° C. for 20 min in a microwave. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 9:1-4:1) to afford the title compound as light yellow solid (31 mg). MS (ESI): 381.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([Br:28])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:11][C:12]2[C:17]([Br:18])=[C:16]([Br:19])[C:15]([Br:20])=[C:14]([Br:21])[C:13]=2[Br:22])[CH2:9][O:8][CH2:7]1.O.S(=O)(=O)(O)[OH:31]>O1CCOCC1>[Br:18][C:17]1[C:12]([O:11][CH2:10][C:6]([CH2:5][O:4][C:3]2[C:2]([Br:1])=[CH:26][C:25]([Br:27])=[CH:24][C:23]=2[Br:28])([CH2:7][OH:8])[CH2:9][OH:31])=[C:13]([Br:22])[C:14]([Br:21])=[C:15]([Br:20])[C:16]=1[Br:19]
Reactant: Brc1cc(Br)c(OCC2(COc3c(Br)c(Br)c(Br)c(Br)c3Br)COC2)c(Br)c1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: OCC(CO)(COc1c(Br)cc(Br)cc1Br)COc1c(Br)c(Br)c(Br)c(Br)c1Br

Procedure:
A mixture of the oxetane derivative of Example 2 (47.5 g., 0.053 moles), dioxane (290 ml.), water (10 ml.) and 1 g. of conc. sulfuric acid was stirred and refluxed 22 hours. The cooled reaction mixture was poured into 1.5 liters of water. A gummy solid formed which became crystalline when heated with dioxane. This product was recrystallized twice from dioxane, yielding 19.4 g. of the desired product which had a melting point of 184°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].CC#N.[OH2:19]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[C:6]1=[O:19])=[O:4]
Reactant: COC(=O)N1CCc2nc(Cl)ccc2C1
Reactant: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)N1CCc2nc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Chloro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester (226.7 mg, 1 mmol) was dissolved in CCl4 (3.57 mL) and MeCN (0.357 mL) at room temperature before adding NaIO4 (0.643 g) in 1 mL of H2O, followed by RuCl3.hydrate (62.2 mg). The reaction mixture was stirred vigorously at room temperature for 2 hours. After dilution with DCM, it was filtered through Celite and the filter cake was washed three times with DCM. The combined organic solution was concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 12 g, 20% EtOAc in hexane) then afforded the tile compound (143 mg, 60%) as a white solid. MS: 241.1 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].[CH3:16]N.[C:18]([BH3-])#[N:19].[Na+]>CO>[ClH:15].[CH3:18][NH:19][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH2:10][C:11]([O:13][CH3:16])=[O:12]
Reactant: CN
Reactant: [BH3-]C#N
Reactant: O=C(O)CCC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(CCC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5 -phenyllevulinic acid (4.0 g, 206 mmoles), methylamine hydrochloride (6.75 g), sodium cyanoborohydride (1.0 g) and methanol (100 ml) was stirred at room temperature for 4 days, then acidified to pH 1.0 and evaporated to dryness. The residue was partitioned between water and ether, and the water phase was evaporated to dryness. The residue was extracted with dichloromethane (2 × 250 ml) which was then dried and evaporated. The residue was re-dissolved in dichloromethane, the solution filtered from some insolubles and evaporated. The residue was crystallized by a slow addition of ether to its solution in ethanol to give methyl 4-methylamino-5-phenylpentanoate hydrochloride. m.p. 117°-20°.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]3[CH:23]=2)=[CH:8][C:7]=1O)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCCC1.O>[CH3:22][C:20]1[CH:19]=[CH:18][N:17]2[CH:23]=[C:14]([CH2:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]4[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[O:25][C:7]=4[CH:8]=3)[N:15]=[C:16]2[CH:21]=1
Reactant: CCNC(=O)Nc1ccc(CCc2cn3ccc(C)cc3n2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Reaction time: 1 h
Yield: 8.5 %

Procedure:
A mixture of 2-[2-{4-(3-ethylureido)-3-hydroxyphenyl}ethyl]-7-methylimidazo[1,2-a]pyridine (17.5 g) and polyphosphate ester (170 g) was stirred at 110° to 120° C. for one hour. The reaction mixture was dissolved in a mixture of ethyl acetate, tetrahydrofuran and water and the resultant solution was adjusted to pH 8.0 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was purified by alumina column chromatography eluting with chloroform. The eluted fraction containing the desired product was evaporated to give 6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-ethylaminobenzoxazole (1.41 g).
Reaction SMILES: CS(C)=O.[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-:11].[Na+].[I-].C[S+](C)(C)=O.[CH:19](O)([CH3:21])[CH3:20]>O>[CH3:20][CH:19]([C:5]12[CH2:10][CH:9]1[C:8](=[O:11])[CH2:7][CH2:6]2)[CH3:21]
Reactant: c1ccccc1
Reactant: [OH-]
Reactant: CC(C)O
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C12CCC(=O)C1C2
Reaction time: 5 h
Yield: 42 %

Procedure:
25 ml of DMSO, 35 ml of benzene, 25 ml of isopropyl alcohol, 3.1 g (25 mM) of CP, 2.4 g (30 mM) of 50% aqueous sodium hydroxide and 5 ml of water were added to 6.9 g (31.25 mM) of trimethylsulfoxonium iodide and the reaction was carried out at room temperature for 5 hours. Then, the treatments were carried out as described in Example 8. 2.6 g (76% yield) of crude product were produced, from which1.45 g (42 % yield) of sabina ketone were obtained by distillation.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1Br)=[O:11].[C:18](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:18][C:15]1[S:14][C:13]2[O:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2Br)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)Oc1sc(C)cc1C(=O)N2
Temperature: 820 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of N-(2-hydroxy-4-methylphenyl)-2-bromo-3-thiophenecarboxamide (3.4 g) in dimethyl sulfoxide (30 ml) was added potassium carbonate (2.9 g) and the mixture was stirred at 140-1500° C. for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into water. The precipitated crystals were collected by filtration, washed with water and purified by silica gel column chromatography (chloroform) to give 2,8-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH3:24])[C:10]([O:12]CC)=[O:11].[OH-].[Li+].O>C(Cl)Cl.C1COCC1>[CH3:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:17]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N2CCCCC2C)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
Methanesulfonyl chloride (1.68 mL; 21.72 mmol; 1.10 eq.) was added dropwise (addition took 5 min) to a cold (0° C.) solution of Py (10 mL) and ethyl 3-amino-4-(2-methylpiperidin-1-yl)benzoate (5.18 g; 19.74 mmol; 1 eq.) in DCM (40 mL) and the reaction mixture was allowed to return to RT over one hour. The reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated and the residue was taken up in water. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with 1M HCl then brine, dried over MgSO4 and concentrated giving a yellow oil. This oil was taken up in THF (30 mL) and lithium hydroxide (2.36 g; 98.72 mmol; 5 eq.) was added, followed by water (30 mL). The resulting mixture was stirred at RT for 2 days. THF was removed under vacuum and the solution diluted with water. This solution was washed with Et2O and acidified to pH 2 with conc HCl. The aqueous phase was extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid (5.48 g, 88%). 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (br s, 1H), 8.53 (br s, 1H), 8.07-8.06 (d, J=1.91 Hz, 1H), 7.77-7.73 (dd, J=8.34 Hz, 1.97 Hz, 1H), 7.47-7.45 (d, J=8.34 Hz, 1H), 3.43-2.58 (m, 6H), 1.84-1.46 (m, 6H), 0.83-0.81 (d, J=6.09 Hz, 3H). HPLC (Method A) Rt 2.29 min (Purity: 99.0%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)(=[O:22])=[O:21]
Reactant: CCc1ccc(CCO)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1ccc(CCOS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
66.0 g (436 mmol) of 2-(5-ethylpyridin-2-yl)ethanol was dissolved in 500 mL of toluene. 72.5 mL (523 mmol) of triethylamine was added to this solution, at room temperature. The resulting solution was cooled between 0 and 10° C., after which 34.0 mL (438 mmol) of methanesulphonyl chloride was added dropwise during 75 minutes. When addition was completed, it was stirred for 1 hour at room temperature. Next, the organic phase was washed with a saturated solution of sodium bicarbonate (400 mL) and with water (400 mL), and was dried over sodium sulphate, obtaining a toluene solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulphonate, a compound of formula (III) in which Z=OMs.