Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][N:12]([CH2:14][C:15]([NH:18][C@@H:19]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21])=[O:17])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 55 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([NH2:34])=[O:33])[CH:30]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32](=[O:33])[NH2:34])[CH:30]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C
Product: NC(=O)Cn1cc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetamide gives the compound “A25”; HPLC/MS: 0.94 min, [M+H]=338;
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].O.[S:9](S([O-])(=O)=O)([O-])(=[O:11])=[O:10].[Na+].[Na+].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+:6].[S:9](=[O:11])=[O:10]
Reactant: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S=O

Procedure:
Accordingly, disclosed herein is a process for hydrometallurgical processing of manganese sulphate and manganese dithionate containing liquors and recovery of water therefrom, comprises the steps of: deriving sodium sulphate and/or sodium dithionate containing liquors from manganese sulphate and manganese dithionate containing liquids; crystallizing sodium sulphate decahydrate and sodium dithionate dehydrate by cooling sodium sulphate/sodium dithionate containing liquor with or without a vacuum; heating the sodium sulphate decahydrate and sodium dithionate dehydrate crystals to a temperature sufficient to decompose the sodium sulphate decahydrate crystals to form anhydrous sodium sulphate crystals, sodium dithionate hydrate crystals and water; removing water from the sodium sulphate and sodium dithionate hydrate crystals; heating the sodium sulphate and sodium dithionate dehydrate crystals to form anhydrous sodium sulphate, sulfur dioxide and water or steam; and separating the anhydrous sodium sulphate from the sulfur dioxide and water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C@@H:18]([OH:19])[CH2:20][N:23]1[CH2:24][CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H](O)CN1CCc2ccccc2C1

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-(2,5-difluoro-phenyl)-ethyl]carbamic acid tert-butylester (0.385 g, 1.3 mmol) and 1,2,3,4,-tetrahydro-isoquinoline (0.200 mL, 1.50 mmol) gives the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)Nc1cccc(OCc2ccccc2)c1

Procedure:
m-hydroxy-3-methoxy-crotonanilide of formula V may be prepared by reacting diketene with m-benzyloxy-aniline to form m-benzyloxy-acetylacetanilide which is then reacted with methyl orthoformate to form m-benzyloxy-3,3-dimethoxybutyranilide which is converted by hydrogenolysis into m-hydroxy 3,3-dimethoxy-butyranilide which is then heated. Other compounds of formula V may be made in an analogous fashion.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(c1ccccc1)c1ccccc1
Yield: 21.3 %

Procedure:
Methyltriphenylphosphonium bromide (4 g, 11.12 mmol) was added over a 15-min period to a mixture of butyllithium (7.3 ml of 1.6 M solution in THF, 11.76 mmol) and dry THF (50 ml) with stirring and under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature and the mixture was then recooled to −78° C. A solution of diphenylacetaldehyde (2.2 g, 11.12 mmol) in dry THF (10 ml) was added to the above mixture over a 15-min period. The reaction mixture was stirred for 24 h at room temperature, followed by addition of ethyl ether (200 ml), and the reaction mixture was then filtered. The ether extracts were washed with water (3×50 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The crude material was purified by flash chromatography on silical gel (Hexane:Ethyl ether=9:1) to give pure 3,3-diphenylpropene 460 mg (46%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][C@H:4]2[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18](=[O:20])[O:19][C@@H:3]12>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:6]1[CH2:7][C@@H:2]([CH3:1])[C@@H:3]2[O:19][C:18](=[O:20])[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:4]2[CH2:5]1
Reactant: C[C@@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H]2[C@H]1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(c2ccncc2N)C[C@@H]2[C@H]1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
To a solution of (3aR,7R,7aS)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in methanol, at a concentration of 0.1M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 14 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7R,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate. LCMS (m/z): 349.1 (MH+); LC Rt=2.06 min.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=CC=1.[OH2:11]>>[CH2:4]([O:11][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O
Reactant: c1ccc2ncccc2c1
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 57.8 g (0.095 mol) α-pivalyl-α-[4-(p-benzyloxyphenylsulfonyl)-phenoxy]-2-chloro-5-amino acetanilide and 13 g quinoline, cooled to 0° C., was added in one portion 45 g (0.095 mol) of the acid chloride B1Cl prepared in Example 4. After stirring 1 h the reaction mixture was poured into 3 L cold water to produce 98 g (after oven drying) crude product. Recrystallization from toluene yielded 84.5 g (0.018 mol) white crystalline dibenzyl ether of the desired coupler. A suspension of 10.4 g (0.01 mol) of this product in 200 mL ethanol and 200 mL tetrahydrofuran was shaken 3 h under 35 psi hydrogen with palladium on charcoal catalyst. Removal of catalyst by filtration, concentration of the filtrate and trituration in hot cyclohexane gave a good yield of coupler Y-2 with the correct elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(COc2ccc(Cl)c([N+](=O)[O-])c2)c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-3-methoxy-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(3-methoxy-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][O:29][CH3:30]>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:27][CH2:28][O:29][CH3:30])[CH2:15][CH2:16]2)[C:6]=1[F:17])[OH:4]
Reactant: OC(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 335 (M+, 1), 291 (15), 290 (bp), 207 (4), 149 (7).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)[CH3:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])[CH2:9]1
Reactant: CN(C)CCCC1CNc2ccccc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CC(CCCN(C)C)c4ccccc43)c2cc1OC
Yield: 52 %

Procedure:
Utilizing a procedure analogous to that described in Example 24 (with conversion to its HCl salt using a procedure analogous to that as described in Example 2), this product was prepared in 52% yield from 3-(N,N-dimethylamino-propyl)indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 230°-232° C.; LC-MS: 393 (MH+); anal. RP18-HPLC RT: 3.23 min.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:12][NH:13][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:24][C:19]1[CH:18]=[C:17]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:33]4[CH:34]=[CH:35][C:30]([C:27]([NH2:28])=[O:29])=[CH:31][CH:32]=4)=[CH:8][CH:9]=3)[CH2:14][NH:13][CH2:12]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=S(=O)(Oc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1)C(F)(F)F
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(-c2ccc3c(c2)CNCC3c2ccc(Cl)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 9 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (225 mg, 0.53 mmol), 4-carbamoylphenylboronic acid (132 mg, 0.8 mmol) and cesium carbonate (521 mg, 1.6 mmol) in water (2 mL) and N,N-dimethylformamide (4 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by semi-preparative HPLC followed by lyophilization to give 4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (19 mg, 7%) as a yellow oil: 1H NMR (CD3OD, 500 MHz) δ 7.96 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 7.62-7.59 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 4.67-4.53 (m, 3H), 3.82 (dd, J=12.6, 6.1 Hz, 1H), 3.51 (dd, J=12.5, 10.9 Hz, 1H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1COCC1>[N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:31](=[O:33])[CH3:32])(=[O:10])=[O:9])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 17.8 %

Procedure:
In the similar fashion using route 15 general procedure 30, 2-amino-N-(quinolin-8-yl)benzenesulfonamide (Example Compound 8) (100 mg, 0.33 mmol), DIPEA (140 μl, 0.83 mmol), acetic anhydride (23 μl, 0.49 mmol), THF (3 ml) gave the title compound (20 mg, 18%) after purification by column chromatography with DCM/MeOH/NH3 (49:1:1) as the eluent.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].Br[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-]>ClCCl.[OH-].[Na+]>[C:1]([C:3](=[C:29]1[CH2:28][CH2:27][CH2:26][O:30]1)[C:4]1[C:5]([CH2:21][CH:22]2[CH2:23][CH2:24]2)=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:15])[F:16])=[N:8][C:9]=1[C:10]([F:13])([F:11])[F:12])#[N:2]
Reactant: O=C(Cl)CCCBr
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CC#N)c1CC1CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC1CC1
Temperature: 0 °C
Yield: 59 %

Procedure:
5(Cyanomethyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example c, (3.0 g, 8.6 mmol) was reacted with 4.0 g (21.6 mmol) 4-bromobutyryl chloride in 160 mL dichloromethane and 82 mL 50% NaOH to which was added 0.3 g benezyltriethylammonium chloride. The solution was poured into 175 mL of ice water and extracted with ethyl ether. The organic layer was washed with water and brine and dried over magnesium sulfate. Purification by HPLC (30% EtOAc/hexane) yielded 2.1 g of the desired product as a light yellow oil, a 59% yield. nD25 1.5028.
Reaction SMILES: CC1(C)OC(=O)[C:5](=[CH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:4](=O)[O:3]1.[F:20][C:21]([F:38])([F:37])[C:22]1[CH:23]=[C:24]([NH:28]/[C:29](/[CH3:36])=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][CH:27]=1>COCCOCCOC.O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:9]2[CH2:5][C:4](=[O:3])[N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:37])([F:38])[F:20])[CH:23]=3)[C:29]([CH3:36])=[C:30]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:11][CH:12]=1)#[N:15]
Reactant: CCOC(=O)/C=C(\C)Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(C#N)cc2)C(=O)O1
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]benzonitrile (Example 18A; 200 mg, 0.77 mmol) and ethyl (2E)-3-{[3-(trifluoromethyl)phenyl]amino}-2-butenoate (212.4 mg, 0.77 mmol) are dissolved in 1-methoxy-2-(2-methoxyethoxy)ethane (3 ml). The solution is stirred at reflux temperature overnight. The reaction mixture is cooled to room temperature and diluted with water (5 ml). After extraction with toluene (2×5 ml), it is dried with anhydrous sodium sulphate, filtered, and the solvent is removed in vacuo. The product is purified via preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(N(C)S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 50 °C
Yield: 90 %

Procedure:
A solution of 13A (1 g, 3.67 mmol) in DMF (15 mL) was added with an. K2CO3 (1.5 mol eq, 0.76 g) and, after few minutes, 2-iodomethane (1.2 mol eq, 0.81 ml) was added and the mixture was heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (60 mL) and the aqueous phase was extracted with EtOAc (3×30 mL). The recombined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 14A as a pale yellow oil (950 mg, 90% yield). 1HNMR (DMSO, 200 MHz) δ 2.43 (bs, 4H), 2.88 (s, 3H), 2.90 (s, 3H), 7.42 (t, 2H, J=8.2), 7.87 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][O:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16](=[O:19])[C:17]([CH:18]=1)=[C:5]23.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([F:25])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][O:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16](=[O:19])[C:17]([C:18]=1[N+:26]([O-:28])=[O:27])=[C:5]23
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCOC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of ethyl 9′,10′-difluoro-7′-oxospiro[oxolane-3,3′(2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (2.90 g, 8.26 mmol) in concentrated H2SO4 (40 mL) was treated portion wise at 0° C. with solid KNO3 (1.17 g, 11.6 mmol). After stirring at 0° C. for 2 h, the reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration, washed with water and dried to yield ethyl 9′,10′-difluoro-8′-nitro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido-[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (3.20 g, 98%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ1.26 (3H, t, J=7.3 Hz), 2.41-2.46 (2H, m), 3.78 (1H, d, J=10.4 Hz), 3.92-3.98 (1H, m), 4.09-4.14 (1H, m), 4.21-4.29 (3H, m), 4.62 (1H, d, J=11.6 Hz), 4.72 (1H, d, J=11.6 Hz), 8.53 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:10][NH2:11].[CH2:20]1[C:22]2([CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]2)[CH2:21]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:18][CH3:19])[CH2:10][NH:11][CH2:28][CH:25]1[CH2:26][CH2:27][C:22]2([CH2:20][CH2:21]2)[CH2:23][CH2:24]1
Reactant: O=CC1CCC2(CC1)CC2
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1CCC2(CC1)CC2)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (248 mg, 0.774 mmol) in DCM (2581 μl) was added spiro[2.5]octane-6-carbaldehyde (107 mg, 0.774 mmol), AcOH (35.5 μl, 0.619 mmol) and NaBH(OAc)3 (246 mg, 1.161 mmol). The slurry mixture was stirred at room temperature for overnight. The mixture was quenched with 0.5 M NaOH and mixture was stirred at rt for 30 min. Evolution of gas was observed. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane to give 2-(2,6-dichlorophenyl)-N-(spiro[2.5]octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11].C([Li])CCC.[CH3:17][S:18]SC.Cl>C(OCC)C.CCCCCC>[Br:11][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[S:6][C:2]=1[S:18][CH3:17]
Reactant: Brc1sc2ccccc2c1Br
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.76 g of 2,3-dibromobenzo[b]thiophene in 75 ml of diethyl ether was cooled to 0° C. and 19 ml of a 1.6M solution of n-butyl lithium in hexane and 10 ml of diethyl ether were added. A pink slurry formed which was stirred for one hour. A solution of 2.7 ml of methyl disulfide in 10 ml of diethyl ether was added and the reaction mixture was stirred for 4 hours at 0° C. Approximately 100 ml of 1N hydrochloric acid were added and the reaction was allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was vacuum distilled at 1.5 torr providing 1 g of the desired subtitled intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[O:23][N:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COCc1ncc(C(=O)OC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ncc(C(=O)OC)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg 2-Methoxymethyl-3H-imidazole-4-carboxylic acid methyl ester in 1 ml DMF, 95 mg caesium carbonate and 82 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 72 mg.