Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+].CC1C=C[C:19]([CH3:22])=CC=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:8]([N:9]([CH2:19][CH3:22])[CH2:10][CH2:6][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH3:7]
Reactant: Cc1ccc(C)cc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
A slurry of 5-nitroindole (2.0 g, 12.3 mmol) and NaOH pellets (0.49 g, 1 eq) in H2O (2.0 mL) was stirred at RT. After 10 min, p-xylene (15.0 mL, 1.4 M), K2CO3 (2.55 g, 1.5 equ) and N-diethylaminoethyl chloride hydrochloride (2.12 g, 12.3 mmol, 1 eq) was added, and the reaction mixture was heated to 100° C. After 4 h the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1N NaOH (2×) and H2O (1×). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to afford the nitro compound (1.79 g, 56%). TLC (5% MeOH/EtOAc), Rf=0.25; LC MS m/z 262.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@H:12]([NH:22][C:23](=[O:38])CN2C3CCCCC=3C(C(F)(F)F)=N2)[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])CC2C=C(F)C=C(F)C=2)=NC(SC)=NC=1.C(OC(C)(C)C)=O>>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:38])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: CSc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)n1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br

Procedure:
The title compound (23B) was prepared according to the method presented for the synthesis of compound 11H of Example 11 utilizing 23A. MS (m/z) 394.03 [M+H-Boc]+.
Reaction SMILES: Br.[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.C(O[CH:23]=[C:24]([C:30](=[O:43])[C:31]1[CH:36]=[C:35]([F:37])[C:34]([N+:38]([O-:40])=[O:39])=[C:33]([CH3:41])[C:32]=1F)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:4]=1[N:5]1[C:32]2[C:31](=[CH:36][C:35]([F:37])=[C:34]([N+:38]([O-:40])=[O:39])[C:33]=2[CH3:41])[C:30](=[O:43])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23]1
Reactant: COc1cc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2F)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
2,4-Difluoro-5-methoxyaniline monohydrobromide (780 mg) and a solution of triethylamine (328 mg) in chloroform (10 ml) were added dropwise to a solution of ethyl 3-ethoxy-2-(2',5'-difluoro-3'-methyl-4'-nitrobenzoyl)acrylate (2.0 g) in chloroform (10 ml) at 0° C. After the mixture was stirred for 10 minutes, the solvent and the like were distilled off. Anhydrous potassium carbonate (510 mg) was added to a solution of the whole amount of the residue in N,N-dimethylformamide (10 ml), and the mixture was stirred at 70° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture to collect an organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Ethanol was added to the residue to disperse it therein, and filtration was conducted to obtain the title compound (660 mg) as a pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Product: CN(C)CCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.35) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 34%). MS (ISP) 582.2 (M+H)+]; mp 146–147° C.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:30][CH2:31][O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(O)(=O)C>[CH3:33][O:32][CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:8])[CH2:14][CH2:13]3)=[CH:17][CH:18]=2)[CH2:24][CH2:25]1
Reactant: COCCCl
Reactant: O=C(c1ccccc1)N1CCN(Cc2ccc(OC3CCNCC3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: COCCN1CCC(Oc2ccc(CN3CCN(C(=O)c4ccccc4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
1-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone (E32) (150 mg, 0.40 mmol) was dissolved in 2-butanone and treated with 1-chloro-2-methoxy-ethane (0.08 ml, 0.80 mmol), potassium carbonate (132 mg, 0.96 mmol) and potassium iodide (159 mg, 0.96 mmol). The reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool to room temperature, acidified by the addition of glacial acetic acid and passed down an SCX ion exchange column (2 g) eluting with methanol followed by ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (76 mg). MS(ES+) m/e 438 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4](Br)[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][CH3:16])[CH:6]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)([O-:21])=[O:20]>>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][CH3:16])[CH:6]=1)[S:28][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][C:24]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=[N+]([O-])c1ccc(S)c(C(F)(F)F)c1
Reactant: COC(=O)C(Br)c1cc(SC)cc(C(F)(F)F)c1
Product: COC(=O)C(Sc1ccc([N+](=O)[O-])cc1C(F)(F)F)c1cc(SC)cc(C(F)(F)F)c1

Procedure:
Using the procedures of Example 1, bromo-(3-methylsulfanyl-5-trifluoromethyl-phenyl)-acetic acid methyl ester 106 and 4-nitro-2-trifluoromethyl-benzenethiol 107, prepared as described in Preparation 7 were combined to form (3-methylsulfanyl-5-trifluoromethyl-phenyl)-(4-nitro-2-trifluoromethyl-phenylsulfanyl)-acetic acid methyl ester, 108, which was then hydrolyzed under basic conditions to afford the title compound 109.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[C:27]1(B(O)O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:35]1[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.447 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 1-naphthylboronic acid (0.344 g) in ethanol (1 ml). The mixture was heated under reflux for 3 hours, then left at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) were added and the mixture heated under reflux for 3 hours. The cooled reaction mixture was then poured into ether (25 ml) and water (25 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (25 ml). The combined organic layers were washed with water (2×25 ml), brine (25 ml) and then dried (MgSO4) and evaporated. The residue was purified by colurn chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as an off-white crystalline solid, m.p. 208° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)(=[O:29])=[O:28])[CH2:3][NH:4][C:5](=[O:24])[O:6][C@H:7]([CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:8]([CH3:11])([CH3:10])[CH3:9].O[C@@H](CNS(C1C=CC=CN=1)(=O)=O)CNC(=O)O[C@H](CN1C2C=C(Cl)C(Cl)=CC=2N=C1)C(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:1]=[C:2]([CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)(=[O:29])=[O:28])[CH2:3][NH:4][C:5](=[O:24])[O:6][C@H:7]([CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:8]([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)NC[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)NC[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)NCC(=O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 9.3 %

Procedure:
To a solution of 43 mg (0.079 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 2 mL of chloroform was added 42 mg (0.1 mmol) of Dess-Martin periodinane, and the mixture was stirred at room temperature for 1.25 h. An additional portion of 21 mg (0.05 mmol) of Dess-Martin periodinane was added, and the reaction mixture was stirred for another 0.5 h. The mixture was diluted with ethyl acetate and a saturated aqueous sodium thiosulfate solution. The combined layers were mixed vigorously and then a saturated aqueous sodium bicarbonate solution was added. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with a methanol:chloroform solution (1:9). The sample was further purified by HPLC using a Waters Symmetry C18 19 mm×150 mm column with 7 μm packing eluted with a five minute gradient of 30%–70% acetonitrile in water. The mobile phase contained a 0.1% trifluoroacetic acid modifier. This purification yielded 4 mg (9%) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl 2oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. ES-LCMS m/z 542 (M+H) retention time=3.59 min. HRMS C22H25Cl2N5O5S m/z 542.1032 (M+H)Cal; 542.1026 (M+H)Obs.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:32])([F:31])[CH2:28][N:27]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:31])([F:32])[CH2:28][N:27]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
A solution of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidin-1-yl]-3-oxopropanenitrile (120 mg, 0.24 mmol, 1.00 equiv), cyclopropanecarbaldehyde (80 mg, 1.14 mmol, 5.00 equiv), piperidine (41 mg, 0.48 mmol, 2.00 equiv) in ethanol (10 mL) was stirred at 70° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm, to give 24 mg (18%) of the title compound as a white solid.
Reaction SMILES: [Br-].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:33]([O:37][C:38]([NH:40][C@@:41]([CH2:53][CH3:54])([CH2:44][O:45][C:46](=[O:52])[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:42]=O)=[O:39])([CH3:36])([CH3:35])[CH3:34].[Cl-].[NH4+]>O1CCCC1>[C:33]([O:37][C:38]([NH:40][C@:41]([CH2:53][CH3:54])([CH:42]=[CH:7][C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)[CH2:44][O:45][C:46](=[O:52])[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:39])([CH3:35])([CH3:36])[CH3:34]
Reactant: CCCCCC(=O)OC[C@](C=O)(CC)NC(=O)OC(C)(C)C
Reactant: c1ccc([P+](Cc2ccco2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCC(=O)OC[C@](C=Cc1ccco1)(CC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a suspension of (furan-2-yl)methyl triphenylphosphonium bromide (4.04 g, 9.54 mmol) obtained in Reference example 1 in tetrahydrofuran (32.4 ml) was added potassium t-butoxide (1.06 g, 9.45 mmol) with stirring under ice-cooling, and the resulting mixture was furthermore stirred under ice-cooling for 15 minutes. After stirring, to the reaction mixture was added a solution of (2S)-2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal (2.01 g, 6.37 mmol) obtained in Reference example (14b) in tetrahydrofuran (10 ml) with stirring under ice-cooling over a 5-minute interval, and the resulting mixture was furthermore stirred under ice-cooling for 30 minutes. After stirring, saturated aqueous ammonium chloride solution was added to the reaction mixture to quench the reaction, and the reaction temperature was raised to room temperature. After evaporation of the reaction mixture in vacuo, ethyl acetate and water were added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1) as the eluent to afford the title compound (2.385 g, yield: 99%).
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2.ICl>CO>[Cl:3][C:4]1[CH:13]=[C:12]([I:1])[C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2
Reactant: II
Reactant: Cc1ccc2c(Cl)ccc(O)c2n1
Agent: ClI
Solvent: CO
Product: Cc1ccc2c(Cl)cc(I)c(O)c2n1
Reaction time: 3 h

Procedure:
Iodine monchloride (19.0 g) is added to a solution of 5-chloro-8-hydroxy-2-methylquinoline (21.5 g) in 250 mL of MeOH, and the resulting mixture is stirred for 3 h. Additional iodine monochloride (4.5 g) is then added, and the mixture is stirred for another 18 h. The reaction mixture is quenched with sat'd Na2SO3 (aq), then neutralized with sat'd NaHCO3 (aq). The solid precipitate is collected by filtration and dried under vacuum to give 31.22 g of the title compound as a pale green solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[ClH:11].CN.[C:14]([BH3-])#[N:15].[Na+].Cl>>[ClH:11].[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:15][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(C=O)cc1
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CNCc1ccc(C#N)cc1
Yield: 52 %

Procedure:
Prepared analogously to Example 61a) from 4-cyanobenzaldehyde, methylamine-hydrochloride and sodium cyanoborohydride. The resulting base was converted into the corresponding hydrochloride by treating the methanolic solution with ethereal hydrogen chloride. Yield: 52% of theory. Colourless crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[N:4]=1.[Na].C1C2NC3C(=CC=CC=3)C=2C=CN=1.[Cl:34][C:35]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:36]=1[CH2:37]Cl>CN(C=O)C.O>[Cl:34][C:35]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:36]=1[CH2:37][N:14]1[C:15]2[CH:3]=[N:4][C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:6][C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a suspension of sodium hydride (1.60 g of 60% dispersion in oil, 0.04 mol) in dry DMF (60 mL) was added methyl 9H-β-carboline-3-carboxylate (8.7 g, 0.0385 mol) at −20° C. with stirring. The mixture was allowed to warm to room temperature with stirring under nitrogen. After stirring for 10 minutes at room temperature, formation of the sodium salt of the β-carboline appeared to be complete, resulting in a clear brown solution. The reaction mixture was cooled in an ice bath, 2,5-dichlorobenzyl chloride (7.82 g, 0.040 mol) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (200 mL), filtered, and the cake washed with water, ethyl acetate, ether, and dried, affording 13.05 g (88%) of the title product. 1H NMR (CDCl3) δ8.88 (s, 1H), 8.78 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.45-7.35 (m, 3H) 7.18 (dd, J=8.2, 1.7 Hz,1H), 6.52 (s, 1H), 5.56 (s, 2H), 4.06 (s, 3H); MS (APCI; (M+H)+) m/z 385.
Reaction SMILES: [CH2:1]([C:3]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:4]=1[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].[CH:21]([O-])([O-])[O:22][CH2:23][CH3:24]>>[CH2:1]([C:3]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:4]=1[C:5]([C:7](=[CH:21][O:22][CH2:23][CH3:24])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1CC
Reactant: CCOC([O-])[O-]
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1CC

Procedure:
Employing ethyl 2-ethyl-3,4,5,6-tetrafluorobenzoylacetate (8 g) and ethyl orthoformate (6.1 g), the procedure of Reference Example 20 is repeated to give ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH3:15]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH2:15])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-hydroxy-2-nitrobenzoate (48 g) in 340 ml methanol was heated 30 hours at 107° in a pressure vessel with 140 ml NH3. The mixture was cooled and concentrated to dryness on the rotovap. Water was added (200 ml) and the solid filtered and dried to give 12 g product, m.135-8°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.C(OC(=O)[NH:17][C@H:18]([C:20](=[O:36])[N:21]([CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][CH2:23]O)[CH3:19])(C)(C)C.C(N(CC)CC)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([O:28][CH2:27][CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][NH:17][C@@H:18]([CH3:19])[C:20]1=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)CCCOCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H]1NCCN(CCCOCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Dimethyl sulfoxide (7.60 g, 97.2 mmol) was added dropwise at −78° C. to a solution of oxalyl chloride (6.17 g, 48.6 mmol) in dichloromethane (300 ml) then after 10 min a solution of {(S)-1-[(3-benzyloxy-propyl)-(2-hydroxy-ethyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester (16.8 g, 44.2 mmol) in dichloromethane (300 ml) was added at a temperature below −70° C. After 1 h, triethylamine (16.1 g, 159 mmol) was added, then after 15 min the ice bath was removed. The reaction mixture was allowed to reach room temperature, then washed with sat. aq. sodium hydrogencarbonate solution and brine, dried (MgSO4), filtered, and evaporated. The residue was taken up in dichloromethane (300 ml), then triethylsilane (10.3 g, 88.4 mmol) and trifluoroacetic acid (75.6 g, 663 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h, then evaporated. The residue was dissolved in dichloromethane (100 ml), then triethylamine (60 ml) was added at 0° C. over 30 min, then after 45 min the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and water, then 2 M aq. sodium carbonate solution was added under ice cooling. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (9.07 g, 78%). Colorless oil, MS (ISP)=263.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl-].[Ca+2].[Cl-].CO.[OH-].[K+].Cl>CO>[OH:1][C:2]1[C:9]([CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCCCCCCC=O
Agent: Cl
Agent: O=Cc1ccc(O)cc1O
Agent: [Ca+2]
Solvent: CO
Product: CCCCCCCCCCCC(O)c1c(O)ccc(C=O)c1O
Reaction time: 24 h
Yield: 51 %

Procedure:
2,4-Dihydroxybenzaldehyde (1.39 g, 10.0 mmol), dodecanal (2.21 g, 12.0 mmol) and calcium chloride dehydrate (1.03 g, 7.0 mmol) were dissolved in methanol (21 ml), added with a potassium hydroxide methanol solution (1.0 M, 14 ml) at 0(C and stirred for 24 hours. The reaction mixture was made acidic with 1 M hydrochloric acid and extracted with ethyl acetate, and after post-treatment, the crude product (2.84 g) was purified by silica gel column chromatograophy (hexane:ethyl acetate=5:1) to obtain 2,4-dihydroxy-3-(1-hydroxy-dodecyl)benzaldehyde (colorless solid 1.65 g, yield 51%) and 2,4-dihydroxybenzaldehyde (552 mg, recovery 40%).