Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[C:5]([CH:16]=[N:17][OH:18])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[ClH:1].[NH2:8][C:6]1[C:5]([CH:16]=[N:17][OH:18])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=NO
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(Cl)ccc1C=NO
Reaction time: 0.5 h

Procedure:
15.5 g (57 mmol) of tert-butyl {6-chloro-3-[(hydroxyimino)methyl]pyridin-2-yl}carbamate (Example 26A) were dissolved in 285 ml of 4N hydrogen chloride in dioxane and the mixture was stirred for 30 min. The reaction mixture was concentrated to half of its original volume and the same amount of diethyl ether was added. The reaction mixture was stirred for 20 min and the product was filtered off and washed with diethyl ether. This gave 11 g (94% of theory) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:22]([OH:23])=[CH:21][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([O:18][CH3:19])=[C:13]([F:20])[CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Br:24].[N+]([O-])(O)=[O:26].O>CC(O)=O>[Br:1][C:2]1[C:22](=[O:23])[C:21](=[O:26])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:16]=[C:15]([F:17])[C:14]([O:18][CH3:19])=[C:13]([F:20])[CH:12]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Br:24]
Reactant: COc1c(F)cc(C(=O)c2coc3c(Br)c(Br)c(O)cc23)cc1F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1c(F)cc(C(=O)c2coc3c2C(=O)C(=O)C(Br)=C3Br)cc1F
Temperature: 60 °C
Yield: 90.5 %

Procedure:
To a solution of (6,7-dibromo-5-hydroxybenzofuran-3-yl)(3,5-difluoro-4-methoxyphenyl)methanone (30 mg, 0.065 mmol) in AcOH (1 mL) was added nitric acid—69% (20.03 μl, 0.325 mmol) at room temperature. The mixture was heated to 60° C. for 3 hours, cooled to room temperature, poured onto iced water and the suspension filtered. A red/orange solid was isolated which was dried under vacuum to afford the product (28 mg, 91%).
Reaction SMILES: [CH3:1]OC1C=C(C=O)C=C(I)C=1O.[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.NCCC(O)=O>C(O)C>[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:24](=[CH2:1])[C:25]#[N:26])=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCC(=O)NCCCc1ccccc1
Reactant: COc1cc(C=O)cc(I)c1O
Agent: NCCC(=O)O
Solvent: CCO
Product: C=C(C#N)C(=O)NCCCc1ccccc1
Yield: 71 %

Procedure:
0.69 g, of 5-iodo vaniline, 0.5 g N-3-phenyl-n-propyl cyanoacetamide and 50 mg β-alanine in 30 ml ethanol were refluxed 5 hours. Evaporation gave an oil which was triturated with benzene-hexane and filtered to give 3-(4-hydroxyl-3-iodo-5-methoxyphenyl-2[(3-phenyl-n-propyl)aminocarbonyl acrylnitrile as a bright yellow solid (0.82 g, 71% yield, mp—83° C.). (3-methoxy 4 hydroxy 5-iodo α-cis cinnamone (3′phenyl propane)amide). (Should be kept solid and protected from light. Material in solution, 2 weeks at room light deteriorated partially.), NMR CDCl3 δ 8.12(1H, S), 7.75(1H, d, J=2.0 Hz), 7.68(1H, d, J=2.0 Hz), 7.30–7.10(5H, m), 3.96(3H, S, OCH3), 3.45(2H, q, J=6.0 Hz), 2.70(2H, t, J=6.0 Hz), 1.95(2H, quin, J=6.0. Hz). MS—462(M+, 53), 357(K-CH2)3Ph, 18), 335(M-I, 100), 327(M-NH(CH2)3 Ph, 31), m/e.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>CCO.[Pd]>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(CCCCO)cc3)C1C2
Reaction time: 16 h
Yield: 104.3 %

Procedure:
A mixture of the product of Step B (0.11 g, 0.3 mmol) and 10% Pd/C (0.06 g) in EtOH (10 ml) was stirred for 16 h under H2. The catalyst was filtered through Celite pad and the filtrate evaporated to dryness to give the title compound (0.11 g, 100%,) as creamy gum. 1H-NMR (CDCl3) 7.74 (d, 2H, J=7.89 Hz); 7.29 (d, 2H, J=8.01 Hz); 4.9 (bs, 1H, NH); 3.71-3.65 (m, 2H); 2.92-2.87 (m, 2H); 2.70 (t, 2H, J=7.74 Hz); 2.45-2.30 (m, 1H); 2.25-2.10 (m, 1H); 1.86-1.58 (m, 9H); 1.3-1.1 (m, 2H); 1.08 (s, 3H); 0.83 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([CH2:16][CH:17]=[CH2:18])(C(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Li+].CN(C=O)C.O>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([CH2:16][CH:17]=[CH2:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CCC(CCOC)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CCOC)C(=O)OCC
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of diester 2 (40 g, 155 mmol), prepared according to Example 1, and lithium chloride (13 g, 300 mmol) in DMSO (100 mL). DMF (20 mL), and water (2 mL) was heated to 170° C. for 6 h and cooled to room temperature. The mixture was poured into water (250 mL), extracted with CH2Cl2 (3×100 mL), and dried over MgSO4. The solvent was removed under reduced pressure to afford the monoester ether 3 (25.2 g, 87%); IR (KBr) υmax 3079, 2974, 2921, 2869, 1732, 1640, 1461, 1443, 1470, 1374, 1177, 1121, 1029, 990, 916, 855 cm−1; 1HNMR (CDCl3) δ1.25 (t, J=7.05 Hz, 3H), 1.65-1.75 (m, 1H), 1.85-1.95 (m, 1H), 2.20-2.40 (m, 2H), 2.50-2.60 (m, 1H), 3.30 (s, 3H), 3.35-3.45 (m, 2H), 4.13 (q, J=7.05, 2H), 5.00-5.07 (dd, J=10.2, 25 Hz, 2H), 5.71-5.74 (m, 1H); 13CNMR (CDCl3) δ14.21, 31.44, 36.45, 42.12, 58.48, 60.12, 70.37, 70.38, 116.79, 135.19, 175.19; mass spectrum (EI), m/Z (rel intensity) 223 (11), 200 (19), 185 (M-1, 4.5), 154 (19), 153 (46), 143 (33), 128 (33), 121 (37), 120 (34), 112 (22), 108 (88), 95 (28), 82 (41), 81 (98), 79 (94), 59 (38), 57 (71), 55 (100), 54 (38), 53 (59),
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][C:5]=1[CH3:13].C(N([CH2:19][CH3:20])CC)C.[OH-].[Na+].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:27]([C:26]2([CH:8]3[C:19]4[C:20](=[CH:9][CH:4]=[CH:5][CH:6]=4)[CH2:11][CH2:10][CH2:7]3)[CH2:24][CH2:25]2)=[O:23])=[CH:6][C:5]=1[CH3:13]
Reactant: COc1ccc(CCN)cc1C
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCNC(=O)C2(C3CCCc4ccccc43)CC2)cc1C
Reaction time: 18 h

Procedure:
A solution of 1,1-carbonyldiimidazole (3.2 g) in tetrahydrofuran (50 ml) was added slowly to a solution of the product from the previous reaction (4.3 g) in tetrahydrofuran (50 ml) and the mixture stirred for 18 hours. 2-(4-Methoxy-3-methylphenyl)ethylamine hydrochloride (4.0 g) then triethylamine (2.8 ml) were added and the mixture stirred for 18 hours. As the reaction had not gone to completion a solution of further starting amine (3.09 g) and triethylamine (2.1 ml) in tetrahydrofuran (20 ml) was added and stirring continued for three days. As the reaction remained incomplete, dilute aqueous sodium hydroxide solution (200 ml) was added and stirring continued for 18 hours. The organic layer was separated and the aqueous layer extracted with ethyl acetate (4×150 ml). The combined organics were washed with brine then dried over magnesium sulphate and the solvent removed in vacuo. The residue was washed well with petroleum ether (bp 60°-80° C.) to give crude N-[2-(4-methoxy-3-methylphenyl)ethyl]-1(1,2,3,4-tetrahydronaphth-1-yl)cyclopropanecarboxamide (7.0 g) as a brown gum which was used without further purification.
Reaction SMILES: C1[O:4][CH2:3]C1.CC1(C)COC1.ClCC1(CCl)COC1.[CH2:19]([C:21]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][O:23][CH2:22]1)[CH3:20].C(C1(CO)COC1)C.[CH2:41]([C:43]1([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH2:56][O:57][CH2:58][C:59]2([CH2:63][CH3:64])[CH2:62][O:61][CH2:60]2)[CH2:46][O:45][CH2:44]1)[CH3:42]>>[CH2:41]([C:43]1([CH2:47][O:48][CH2:49][C:50]2[C:51]([CH2:56][O:57][CH2:58][C:59]3([CH2:63][CH3:64])[CH2:62][O:61][CH2:60]3)=[C:52]([CH2:27][O:26][CH2:25][C:21]3([CH2:19][CH3:20])[CH2:24][O:23][CH2:22]3)[CH:53]=[CH:54][CH:55]=2)[CH2:46][O:45][CH2:44]1)[CH3:42].[CH2:63]([C:59]1([CH2:58][O:57][CH2:56][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[O:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=2[CH2:27][O:26][CH2:25][C:21]2([CH2:19][CH3:20])[CH2:22][O:23][CH2:24]2)[CH2:60][O:61][CH2:62]1)[CH3:64]
Reactant: C1COC1
Reactant: CCC1(COCc2ccccc2COCC2(CC)COC2)COC1
Reactant: CCC1(COc2ccccc2)COC1
Agent: CC1(C)COC1
Agent: CCC1(CO)COC1
Agent: ClCC1(CCl)COC1
Product: CCC1(COCc2cccc(COCC3(CC)COC3)c2COCC2(CC)COC2)COC1
Product: CCC1(COCc2ccccc2Oc2ccccc2COCC2(CC)COC2)COC1

Procedure:
Specific examples of the compound (d) include trimethylene oxide, 3,3-dimethyloxetane, 3,3-bis(chloromethyl)oxetane, 3-ethyl-3-phenoxymethyloxetane, 3-ethyl-3-hydroxymethyloxetane (EOXA, trade name, produced by Toa Gosei), bis[(3-ethyl-3-oxetanylmethoxy)methyl]benzene (also called xylylene dioxetane; XDO, trade name, produced by Toa Gosei), tri[(3-ethyl-3-oxetanylmethoxy)methyl]benzene, bis[(3-ethyl-3-oxetanylmethoxy)methylphenyl]ether, (3-ethyl-3-oxetanylmethoxy)oligodimethylsiloxane, and compounds containing a plurality of oxetane rings having a high molecular mass, specifically, oxetane oligomer (Oligo-OXT, trade name, produced by Toa Gosei), 2-oxaspiro[3.5]nonane, 7-methyl-2-oxaspiro[3.5]nonane, spiro[adamantane-2,3′-oxetane], spiro[bicyclo[2.2.1]heptane-2,3′-oxetane], spiro[bicyclo[2.2.2]octane-2,3,-oxetane], spiro[7-oxabicyclo[2.2.1]heptane-2,3′-oxetane], 2-oxaspiro[3.5]non-6-ene, 5-methyl-2-oxaspiro[3.5]non-6-ene, spiro[bicyclo[2.2.1]hept-5-ene-2,3′-oxetane], spiro[3-methylbicyclo[2.2.1]hept-5-ene-2,3′-oxetane], 5-methyl-2-oxaspiro[3.5]nonane and spiro[3-methylbicyclo[2.2.1]heptane-2,3′-oxetane.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O:23]C)=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.O.O.[OH-].[Li+:28]>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O-:23])=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2ccn(CCN[C@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2ccn(CCN[C@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.6 g, 5.0 mmol) from Step C above in THF (20 ml) and H2O (20 ml) was added lithium hydroxide monohydrate (632 mg, 15.1 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (R)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate which was used in the next step without further purification: MS (ESI+) m/z 314 (M+H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].CI.[C:31](=O)([O-])[O-].[K+].[K+].CN([CH:40]=[O:41])C>[Cu]>[CH3:31][O:28][C:16]1[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][C:15]=1[C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[O:41][CH3:40]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)CCc1ccc(OC)c(-c2cc(CCC(=O)OCC)ccc2OC)c1
Yield: 85 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.05181 mmol) of 2,2'-dihydroxy-5,5'-bis(2-ethoxycarbonylethyl) biphenyl and 2.316 ml (20.72 mmol) of methyl iodide, there was added 572 mg (2.072 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 4 days at room temperature and for a further 2 days at 60° C. The reaction mixture was filtered by suction through Celite to remove the solid matter, which was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and saline solution in this sequence and was dried over anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 182 mg (0.4936 mmol, 85%) of 2,2'-dimethoxy-5,5'-bis(2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:34])[N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:36]([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])=[O:37]>ClCCl.CN(C)C1C=CN=CC=1.CO>[C:36](=[O:37])([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])[O:27][C@@H:24]1[CH2:25][CH2:26][N:22]([CH:21]([C:18]2[S:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[N:20][CH:19]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH2:23]1
Reactant: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)O[C@@H]1CCN(C(c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccccc2Cl)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)-cyclopropanecarboxamide (3.00 g, 6.02 mmol) was suspended in 200 mL of anhydrous dichloromethane containing N,N-dimethylpyridin-4-amine (2.20 g, 18.0 mmol), (1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl chloroformate (1.91 mL, 9.00 mmol) was slowly added to the suspension and the resulting mixture was heated to reflux for 16 hours. The resulting pale yellow solution was allowed to cool to room temperature, diluted with 20 mL of methanol, and then evaporated to dryness. The crude reaction mixture was separated on 330 g of silica gel utilizing a gradient of 0-5% methanol in dicholoromethane to yield the pure product as a pale yellow solid (2.008 g, 2.9529 mmol, 49.1%). ESI-MS m/z calc. 679.3, found; 680.5 (M+1)+; Retention time 3.88 minutes.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(Cl)Cl.CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])c4ccccc34)ccn2)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)c4ccccc34)ccn2)CC1

Procedure:
A solution of the urea product, obtained above, (130 mg, 0.32 mmol) in DCM/MeOH (1:1 v/v, 40 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm, 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (10 mL) and sat. aq NaHCO3 and the organic layer was separated and washed with brine (10 mL), dried and evaporated in vacuo to afford the title compound, Intermediate D6, as a red solid (87 mg, 69%); Rt 1.05 min (Method 2); m/z 378 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:5][C:3]=1[NH2:4].[CH3:14][C:15]1=[C:16]([CH3:22])[C:17]([O:19][C:20]1=O)=[O:18]>C(O)(=O)C>[Cl:9][C:7]1[C:6]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:5][C:3]([N:4]2[C:17](=[O:18])[C:16]([CH3:22])=[C:15]([CH3:14])[C:20]2=[O:19])=[C:2]([F:1])[CH:8]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)N(c2cc(OC(C)C)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
A mixture of 20.4 g (0.1 mol) of 2-fluoro-4-chloro-5-isopropoxyaniline and 12.6 g (0.1 mol) of dimethylmaleic anhydride in 100 ml of glacial acetic acid is stirred for 6 hours at a temperature of 130°-140°. It is then allowed to cool to room temperature and the almost black reaction solution is concentrated in a rotary evaporator. The residue is taken up in ethyl acetate and the solution is washed in succession with water, 1M soda solution, water and concentrated salt brine. It is then dried over sodium sulphate, filtered and concentrated in vacuo. The dark oil remaining is crystallised from ethanol with the aid of activated carbon. 17.6 g of title product (56.5% of the theoretical yield) which melts at 93°-95° is thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.CS[C:13](=[NH:15])[NH2:14]>>[O:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:13]([NH2:15])=[NH:14])=[N:7]1
Reactant: NCCSCc1ccon1
Reactant: CSC(=N)N
Product: N=C(N)NCCSCc1ccon1

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole with S-methyl-isothiourea by the procedure of Example 1 gives [2-(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:21])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:14]2)[CH3:11])=[O:21])=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, the trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 390 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[CH:15][C:16]4[O:17][CH2:18][CH2:19][O:20][C:21]=4[C:12]=3[O:11][CH2:10]2)[C:2]1=[O:22].Cl.CO.Cl.[F:27][C:28](F)([F:37])[C:29]1[C:30]([CH2:35]O)=[N:31][CH:32]=[CH:33][CH:34]=1>>[F:27][CH:28]([F:37])[C:29]1[C:30]([CH2:35][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:13]4[C:12](=[CH:21][C:16]5[O:17][CH2:18][CH2:19][O:20][C:15]=5[CH:14]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: OCc1ncccc1C(F)(F)F
Reactant: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Agent: Cl
Solvent: CO
Product: O=C1N(Cc2ncccc2C(F)F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 11.78 and making non-critical variations using (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one, and 3-(difluoromethyl)pyridin-2-yl]methanol hydrochloride to replace (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride, (8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (50%) as a colorless solid: mp 181-182° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=4.9 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.52-7.50 (m, 1H), 7.52-7.42 (m, 1H), 7.25-7.15 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.42 (s, 1H), 5.18 (ABq, 2H), 4.72 (ABq, 2H), 4.19-4.12 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 152.9 (t, JC-F=4.3 Hz), 151.4, 144.6, 143.2, 138.2, 135.0 (t, JC-F=7.0 Hz), 132.5, 129.1, 128.0 (t, JC-F=22.6 Hz), 123.9, 123.5, 123.3, 122.0, 113.8 (t, JC-F=236.6 Hz), 112.3, 109.7, 99.1, 79.7, 64.7, 64.1, 57.8, 42.3; MS (ES+) m/z 436.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:32][C@H:33]([CH3:37])[C:34](O)=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:34](=[O:35])[C@H:33]([OH:32])[CH3:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](O)C(=O)O
Product: C[C@H](NC(=O)[C@@H](C)O)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and (R)-2-hydroxypropanoic acid (12 mg, 150 μmol). Yield 14 mg (60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10]([Br:13])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[N:7]([C:8]1[S:9][C:10]([Br:13])=[CH:11][N:12]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ncc(Br)s2)cc1
Reaction time: 8 h

Procedure:
To a single necked round bottom flask (5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (1.4 g, 5.01 mmol) was dissolved in 25 ml dry DCM. To it 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU) (2.24 ml, 15.03 mmol) was added followed by 1-Chloromethyl-4-methoxy-benzene (1.02 ml, 7.52 mmol) addition was done and reaction mixture was stirred for overnight. Reaction was quenched by addition of water (20 ml), extracted with DCM (25 ml), Organic layer was separated and washed with brine (30 ml) and dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with DCM (20 ml) and solvent was evaporated on rotavapour to get required product. The crude material was purified by silica-gel column chromatography, eluting with 4% acetone in hexane. (1.4 g).