Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: COC(=O)Cc1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
n-BuLi (1.60M in hexanes, 40.7 mL, 65.1 mmol) was added to a 0° C. solution of diisopropylamine (9.4 mL, 67.0) in 280 mL THF. The mixture was allowed to stir at 0° C. for 30 minutes, then cooled to −78° C. A solution of p-tolyl-acetic acid methyl ester (10.48 g, 63.8 mmol; prepared from p-tolyl-acetic acid) in 10 mL of THF was added to the −78° C. LDA solution by syringe, which was then stirred for 45 minutes. Neat tert-butyl bromoacetate (28 mL) was added by syringe, and the reaction was stirred 15 minutes at −78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH4Cl solution, and the organics were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by on silica gel (25:1 hexanes:EtOAc) to afford the 2-p-tolyl-succinic acid 4-tert-butyl ester 1-methyl ester as a pale yellow oil (15.3 g, 86%). 1H NMR (CDCl3, 400 MHz) δ 7.16 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 3.99 (dd, J=10.4, 5.6 Hz, 1H), 3.66 (s, 3H), 3.09 (dd, J=16.8, 10.4 Hz, 1H), 2.57 (dd, J=16.8, 5.6 Hz, 1H), 2.32 (s, 3H), 1.41 (m, 1H). HPLC Rt=3.71 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:41])[NH:15][N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:41])[NH:15][N:14]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)n[nH]c(=O)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
1-(2-Methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (40 mg, 0.066 mmol) was dissolved in DCM (664 μl) and then TFA (25.6 μl, 0.332 mmol) was added at RT. After stirring for 30 min, the reaction was quenched with saturated aqueous NaHCO3 (1 mL). A white solid precipitated out of the solution and was filtered off with the aid of water. The solid was washed with 3 mL of water and dried to afford the product 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (16 mg, 50% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 6.83 (d, J=4.38 Hz, 1H), 7.24 (d, J=4.49 Hz, 1H), 7.41-7.53 (m, 3H), 7.60 (d, J=7.80 Hz, 1H), 8.15 (dd, J=8.49, 1.87 Hz, 1H), 8.63 (d, J=1.82 Hz, 1H), 13.10 (s, 1H). m/z (ESI) 483.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:8]([O:12][C:13](ON1C(=O)C2=CC=CC=C2C1=O)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: CC(C)(C)OC(=O)ON1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1

Procedure:
A solution of (2S)-2-methylpiperazine (3.8 g, 38 mmol) and N-(tert-butyloxycarbonyloxy)phthalimide (10 g, 38 mmol) in dichloromethane (100 mL) was stirred at room temperature for 3 hours. The mixture was washed with 2N sodium hydroxide solution, the organic solution dried over magnesium sulphate, and concentrated in vacuo to afford the title compound as a clear oil, 4.31 g.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].S(Cl)(Cl)=O.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Nc1ccccc1-c1ccco1
Reactant: Cc1cc(C(=O)O)ccc1C#N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Nc2ccccc2-c2ccco2)ccc1C#N
Reaction time: 18 h

Procedure:
To a solution of 4-cyano-3-methylbenzoic acid from Example C (187 mg, 1.16 mmol) in toluene (10 ml) was added thionyl chloride (425 μl, 5.8 mmol). The mixture was heated at reflux for 2 h, cooled, evaporated in vacuo and azeotroped with toluene. The residue was taken up in CH2Cl2 (5.0 ml) and added to a solution of 2-furan-2-yl-phenylamine from Example 21A (185 mg, 1.16 mmol) and triethylamine (324 μl, 2.32 mmol) in CH2Cl2 (5.0 ml). The mixture was stirred for 18 h, partitioned between water and chloroform and separated. The organic layers were dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant pet. ether:EtOAc 80:20) to give a yellow solid; yellow solid 233 mg, 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[F:31][C:32]([F:52])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[CH:37][C:36]=1[S:47](Cl)(=[O:49])=[O:48]>>[F:52][C:32]([F:31])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:44])([F:45])[F:46])=[CH:37][C:36]=1[S:47]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([N:20]2[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:21]2[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:6]1=[O:11])(=[O:49])=[O:48]
Reactant: O=S(=O)(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c2ccc(Cl)cc21
Yield: 66.8 %

Procedure:
With 100 mg of (4R)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-L-prolinamide (levorotatory isomer), which is the compound described in Preparation 3.2 (Isomer B) of the brochure Publication No. WO01/55130, and 89 mg of 2,5-bis (2,2,2-trifluoroethoxy)benzene sulfonyl chloride as starting materials, 119 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH2:18]([S:20]Cl)[CH3:19].C(SSCC)C.ClCl>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:20][CH2:18][CH3:19])=[C:7]([OH:11])[CH:6]=1
Reactant: N#Cc1ccc(Oc2cccc(O)c2)c(Cl)c1
Reactant: CCSCl
Agent: ClCl
Solvent: CCSSCC
Solvent: ClCCl
Product: CCSc1ccc(Oc2ccc(C#N)cc2Cl)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-chloro-4-cyanophenoxy)phenol (0.01 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of ethyl sulfenyl chloride freshly prepared by reacting diethyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml), with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2-chloro-4-cyanophenoxy)-2-(ethylthio)phenol as the residue.
Reaction SMILES: C=C1OC(=O)C1.C1C2=[C:18]3[C:13](=CC=C2)[CH:12]=[CH:11][CH:10]=[C:9]3[CH2:8]1.C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.COC1C=CC2C(=CC=C(OC)C=2)C=1.[Cl-].[Al+3].[Cl-].[Cl-].CC(=O)C(=O)C.[C:59](F)(=[O:64])[CH2:60][C:61]([CH3:63])=[O:62].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.ClCCCl>[C:9]1([CH3:8])[CH:18]=[CH:13][CH:12]=[CH:11][C:10]=1[C:59](=[O:64])[CH2:60][C:61](=[O:62])[CH3:63]
Reactant: CC(=O)CC(=O)F
Reactant: c1cc2c3c(cccc3c1)CC2
Agent: C=C1CC(=O)O1
Agent: CC(=O)C(C)=O
Agent: COc1ccc2cc(OC)ccc2c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)CC(=O)c1ccccc1C
Yield: 6.5 %

Procedure:
In the reaction of diketene with aromatic compounds that are solid at room temperature, for example acenaphthene, pyrene, or 2,6-dimethoxynaphthalene, solvents have to be added which do not react with diketene. The aforesaid literature references do not contain any description of corresponding experiments. In proper experiments with 1,2-dichloroethane it has been found that with acenaphthene the yield is drastically reduced and resinifications do occur and that the aluminum chloride-butanedione complexes with pyrene have a high stability. If, however, the diketene is transformed into acetoacetyl fluoride which is then reacted with toluene in the presence of aluminum chloride in chloroform, a yield of 6.5 % only of 1-tolyl-butane-1,3-dione is obtained, calculated on the diketene (cf. G. A. Olah and S. J. Kuhn, J.Org. Chem. 26, page 225 (1961)).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](Cl)=O.N>>[Br:11][C:12]1[CH:20]=[C:16]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:15]=[N:14][CH:13]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Brc1cncc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 5-bromonicotinoyl chloride (Alfa). 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.69 (m, 1 H), 8.45-8.49 (m, 1 H), 8.79 (t, J=1.7 Hz, 1 H), 8.84 (dd, J=1.7, 2.0 Hz, 1 H), 9.07 (d, J=2 Hz, 1 H), 9.28-9.29 (m, 1 H), 9.34 (d, J=1.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH2:27]([NH:34][C:24]([C:10]1[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)=[N:12][C:7]([N:3]2[CH2:4][CH:5]3[CH:1]([CH2:6]3)[CH2:2]2)=[N:8][CH:9]=1)=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In THF (50 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (16 g, 42.8 mmol), benzylamine (5.0 g, 47 mmol), HATU (17.9 g, 47 mmol) and DIEA (11 g, 85.6 mmol). The reaction mixture was stirred at ambient temperature overnight and concentrated, followed by addition of DCM (500 mL). After the completion of the reaction, water (500 mL×4) was added to the reaction mixture for extraction. The organic phase was concentrated. The crude product was purified by silica gel column chromatography to give N-benzyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-formamide as the product (50 mg, 24% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH2:14])[S:11][N:10]=2)=[CH:5][CH:4]=1.C[Al](C)C.[CH3:19][C@@H:20]1[CH2:22][C@H:21]1[C:23](OCC1C=CC=CC=1)=[O:24].N#N>ClCCl.CC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([NH:14][C:23]([C@@H:21]3[CH2:22][C@H:20]3[CH3:19])=[O:24])[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(N)sn2)cc1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: N#N
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[CH2:9][C@H:4]2[O:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]2[O:7][C@H:8]([C:10](=[O:14])[CH2:11][O:12][CH3:13])[CH2:9][C@H:4]2[O:3]1
Reactant: COC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCC(=O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Yield: 87.5 %

Procedure:
To a solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-methoxy-ethanol (compound 21b, 1.62 g, 7.4 mmol) in DCM (50 mL) was added Dess-Martine periodinane (4.7 g, 11 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:2 EtOAc in petroleum ether) to afford 1.4 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-methoxy-ethanone (compound 21c) as a colorless oil. MS obsd. (ESI+) [(M+NH4)+]: 234.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:24]1[C:20]([C:10]2[CH:11]=[C:12]([O:15][C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:21][CH:22]=[N:23]1
Reactant: Cn1nccc1-c1cc(OC(F)(F)F)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1nccc1-c1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 5-[2-(benzyloxy)-5-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrazole (Preparation 534, 2.3 g, 6.6 mmol) in methanol (25 mL) was degassed with argon before the addition of palladium on carbon (10%, 230 mg). Reaction mixture was stirred at room temperature under hydrogen atmosphere (using a balloon) for 16 hours. After filtration through Celite™, filtrate was concentrated in vacuo to afford the title compound as a white solid, 1.6 g, 94% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Nc1ccc(Cl)cc1
Product: Clc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and 4-chloroaniline in a similar manner as described in Example 13 to give 25-mg (16% yield) of a tan solid. 1H-NMR (CDCl3): δ 8.01 (m, 1H), 7.46 (d, 1H), 7.21-7.14 (m, 3H), 7.11 (dd, 1H), 6.65 (d, 2H), 4.76 (m, 1H), 2.70 (m, 2H), 2.22 (m, 1H), 2.01 (m, 1H), 1.94-1.75 (m, 2H); MS m/z 329 (M−1).
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][CH2:3][CH2:2]1.[C:16](OC(=O)C)(=[O:18])C.C(O)=O>O>[CH:16]([N:4]1[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:1][CH2:2][CH2:3]1)=[O:18]
Reactant: CCOC(=O)C(=NOC)C1=CSCCN1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOC)C1=CSCCN1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Ethyl 2-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.8 g.) was added to a mixture of acetic anhydride (7.7 g.) and formic acid (3.48 g.), which was warmed at 50° C. for 2 hours previously, under ice-cooling, and stirred at room temperature overnight. After adding chilled water (100 ml.) to the resultant solution, the solution was extracted with ethyl acetate three times. The extract was washed with a saturated aqueous solution of sodium chloride once, an aqueous solution of sodium bicarbonate four times and a saturated aqueous solution of sodium chloride once in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diisopropyl ether (15 ml.). The crystals were collected by filtration and washed with diisopropyl ether to give ethyl 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.0 g.), mp. ν maxNujol :1735, 1725, 1675 cm-1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([Br:24])=[C:20]([CH:23]=1)[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:24][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:23][C:20]=1[CH2:21][O:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(O)cccc2c1
Reactant: COc1ccc(Br)c(CO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(COc2cccc3cc(OC)ccc23)c1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 6-methoxynaphthol (12.9 g, 74.1 mmol), 5-methoxy-2-bromobenzyl alcohol (17.7 g, 81.6 mmol), and triphenylphosphine (31.1 g, 119 mmol) in THF (400 mL) was slowly added a solution of DEAD (20.6 g, 119 mmol) in THF (50 mL). The solution was stirred overnight, concentrated onto silica, and purified by silica column (10% ethyl acetate—hexanes) to yield 16.38 g (59%) of the title compound as a white solid: mp 83-84° C.; 1H NMR (CDCl3): δ 3.78 (3H, s), 3.92 (3H, s), 5.25 (2H, s), 6.75-6.77 (2H, m), 7.12 (1H, d, J=2.44 Hz), 7.15 (1H, dd, J=2.44 Hz, J=9.28 Hz), 7.24 (1H, d, J=2.93 Hz), 7.32-7.36 (2H, m), 7.48 (1H, d, J=8.79 Hz), 8.27 (1H, d, J=9.23 Hz); MS (ESI) m/z373/375 ([M+H]+);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][CH2:44][N:45]1[CH2:51][CH:50]([OH:52])[C:47]2([CH2:49][CH2:48]2)[CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:52][CH:50]1[C:47]2([CH2:49][CH2:48]2)[CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:22]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:23]([C:25]5([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]5)=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:51]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (260 mg, 0.534 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (266 mg, 1.068 mmol) and Cs2CO3 (520 mg, 1.602 mmol). The reaction was then stirred at rt for 2 days. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (264 mg, 77%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15].[Cl-].[NH4+]>CCO.O.[Fe]>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15]
Reactant: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1C(=O)CSc2cc(N)ccc21
Temperature: 80 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzothiazin-3-one (4.50 g, 20.07 mmol) in EtOH (100 mL) and water (50 mL) is added ammonium chloride (10.76 g, 200.7 mmol). To this mixture is added iron (3.37 g, 60.21 mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for 2 h at which time the reaction is cooled to room temperature. This mixture is filtered and the filtrate is concentrated under reduced pressure and extracted with EtOAc (3×50 mL). The organic phase is washed with water and saline, dried over MgSO4, and concentrated under reduced pressure to give the title compound (for reference see DE 19802239) as a dark brown oil (3.60 g, 93%), MS m/z 195.5 (M+H)+.