Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.[N-:47]=[C:48]=[O:49].[K+]>O.C(O)(=O)C>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH2:47])=[O:49])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(NC(N)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a suspension of (S)-2-(1-((5-(4-amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in water (0.40 mL) and acetic acid (0.20 mL) was added potassium isocyanate (19 mg, 0.23 mmol) according to the method described in Preparation 181 but stirring at 60° C. overnight. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 34 mg (61% yield) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:28]=[C:27]([NH2:29])[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=3)[N:20]=2)[CH2:15][CH2:14]1)#N.[O:34]1CCCC1>CCCCCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:28]=[C:27]([NH2:29])[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=3)[N:20]=2)[CH2:15][CH2:14]1)=[O:34]
Reactant: c1ccoc1
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Temperature: -20 °C
Reaction time: 8 h

Procedure:
In a 100 ml. flask equipped with thermometer and drying tube was charged 10 ml. of dry tetrahydrofuran and 0.5 ml. (6.2 mmoles) of furan. The solution was cooled to -20° C. and 2.8 ml. (6.2 l mmoles) of n-butyl lithium in hexane was added. To the resulting light amber mixture was added 400 mg. (1.24 mmoles) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline dissolved in 30 ml. of dry tetrahydrofuran. After the addition was complete, the reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction was quenched into 88 ml. of 2N hydrochloric acid, washed with 100 ml. of chloroform, adjusted to pH 10 with aqueous sodium hydroxide solution and extracted twice with 100 ml. portions of chloroform. The aqueous phase was concentrated in vacuo to about 2 ml. and filtered to afford 15 mg of the title compound, M.P. 263°-264° C. The infrared spectrum and thin-layer chromatography behavior were identical to that of an authentic specimen.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:28]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(Br)c(C(=O)Nc2ccc3ncn(C(CC(=O)O)c4ccccc4)c3c2)c1

Procedure:
Using the procedure of Preparation 21, the title compound (56 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 2-bromo-5-methoxybenzoic acid, and purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.35 min, MH+ 496].
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-:3].[C:4]1([CH:10]2[CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[Cl:1][C:10]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]1[Cl:3].[Mn+2:2]
Reactant: [Cl-]
Reactant: c1ccc(C2CNCCNCCNCCNCCN2)cc1
Agent: [Mn+2]
Product: ClN1CCNCCNCCNCCNCC1(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a methanolic solution (50 ml) at low reflux containing anhydrous manganese(II) chloride (150 mg, 1.19 mmol) was added a methanolic solution of 2-phenyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 31E (0.35 g, 1.2 mmol). The reaction was refluxed for 3 h under a dry nitrogen atmosphere and was then allowed to stir at room temperature overnight. The yellow solution was then filtered through celite and taken to dryness. The solid glassy oil was washed with hot ethyl ether (30 ml) and then dissolved in hot EtOH. The EtOH solution was filtered and then evaporated. The solid was recrystallized from acetone/CH3CN to give 255 mg (52% yield) of a white microcrystalline solid: FAB mass spectrum (NBA) m/z (relative intensity); 416 (M+, 2), 381/383 [(M-Cl)+, 100/32] Anal calcd for C16H29N5MnCl2 : C, 46.05; H, 7.01; N, 16.78. Found: C, 46.23; H, 7.04; N, 16.62.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:34])([CH3:33])[C@@H:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([OH:24])=[O:23])(=[O:17])=[O:16].[C:35](Cl)(=O)[C:36](Cl)=O.C(O)C.N1C=CC=CC=1>ClCCl>[O:11]=[C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:34])([CH3:33])[C@@H:21]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:22]([O:24][CH2:35][CH3:36])=[O:23])(=[O:16])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O)[C@@H](OCc1ccccc1)C(=O)O
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Yield: 84.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-{[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (20) (0.8 g, 1.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane (DCM) and reacted with 0.96 mL (1.92 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2.0 mL (1.58 g, 34.3 mmol) of ethanol (EtOH) and 0.14 mL (0.127 g, 1.6 mmol) of pyridine in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.7 g (83% yield) of the title compound (22a) as a colorless oil. Rf=0.64 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.04 (s, 3H), 1.05 (s, 3H), 1.31 (t, J=6.8 Hz, 3H), 2.18-2.25 (m, 2H), 3.12-3.17 (m, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.83 (s, 1H), 3.96 (d, J=8.8 Hz, 1H), 4.18-4.24 (m, 3H), 4.36 (d, J=11.2 Hz, 1H), 4.60 (d, J=11.6 Hz, 1H), 7.32-7.33 (m, 5H), 7.72-7.75 (m, 2H), 7.84-7.86 (m, 2H) ppm. MS (ESI) m/z 518.16 (M+H)+, 540.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(/C=C/c2nc(C)cc(O)n2)c1
Product: COc1cccc(/C=C/c2nc(C)cc(Cl)n2)c1
Yield: 82 %

Procedure:
In analogy to example 12c),by heating (E)-2-[2-(3-methoxy-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.6 g, 2.48 mmol) in POCl3 (4.6 ml, 29.5 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3-methoxy-phenyl)-vinyl]-6-methyl-pyrimidine (0.53 g, 82%) as an orange solid. ISP mass spectrum, m/e: 261.2 (M+1 calculated for C14H13ClN2O: 261).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[OH:17])/[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].CC(C)=O.S(OC)(OC)(=O)=O>O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[O:17][CH3:18])/[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccccc1/C(=N\O)C(N)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CO/N=C(/C(N)=O)c1ccccc1COC(C)=O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of (E)-2-(2-acetoxymethylphenyl)-2-hydroxyiminoacetamide (428 mg), potassium carbonate (301 mg) and acetone (3.6 ml) was stirred at room temperature. To the mixture was added dropwise 95% dimethyl sulfate (0.20 ml). The mixture was stirred at room temperature for 4.5 hours. Water (10 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Water (30 ml) was added, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (440 mg). The crude product was crystallized from ethyl acetate-hexane, the crystallization mother liquor was concentrated and purified by silica gel thin layer chromatography (ethyl acetate:hexane=4:1) to obtain the title compound (432 mg in total, yield 95.6%, colorless crystals).
Reaction SMILES: [N+]([C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[N+:14]([O-:17])(O)=[O:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[N+:14]([C:9]1[CH:8]=[CH:7][C:6]([CH3:10])=[CH:5][CH:4]=1)([O-:17])=[O:15]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
The process according to the invention is preferably used for the production of dinitrotoluene by the two-stage reaction of toluene with nitric acid in the presence of sulphuric acid, wherein in the first stage toluene is nitrated to form mononitrotoluene (MNT) using waste acids from the second stage, in which mononitrotoluene is nitrated to form dinitrotoluene (DNT) using concentrated waste acid from the first stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[N:26]=1.C(N(CC)CC)C.CN(C)C=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[N:26][C:20]=4[CH2:21][CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Clc1ccc2c(n1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(Cl)nc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.03 g (0.12 mmol) 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.12 mmol 2-chloro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine hydrochloride and 0.51 mmol triethyl amine (TEA) in 1.5 ml dimethylformamide (DMF) 0.14 mmol TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) was added and the reaction mixture was stirred at RT for 1 h. Water was added to the reaction mixture. The precipitate was collected and dried. Yield: 0.018 g (36% of theory). ESI-MS: m/z=406 (M+H)+; Rt(HPLC): 1.29 min. (Method J).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(N)c1C#N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5.1 grams (0.020 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine (prepared as in Step E of Example 9) and 4.2 mL (0.030 mole) of trimethylsilylacetylene in 40 mL of acetonitrile is stirred, and 10.5 mL (0.078 mole) of triethylamine, 0.1 gram of copper(I) iodide, and 0.3 gram of bis(triphenyl-phosphine)palladium(11) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours and then is warmed to 70° C., where it stirred for about 7.5 hours. The reaction is monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl)pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18](Cl)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:17])[F:16])=[CH:6][CH:5]=1)[CH3:2].[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.N1C=CC=CC=1>C1C=CC=CC=1.CCOCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:24]=3)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:16])[F:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: CCOc1ccc(C2(C(=O)Cl)CC(F)(F)C2(F)F)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C2(C(=O)OCc3cccc(Oc4ccccc4)n3)CC(F)(F)C2(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carbonyl chloride (0.76 gm, 1.54 mmole) in dry benzene (10 ml) was added a solution of 2-hydroxymethyl-6-phenoxypyridine (0.305 g) and pyridine (0.12 g) in dry benzene (15 ml). The mixture was stirred at room temperature for 16 hours then diluted with ether, washed twice with water, dried over Na2SO4 and concentrated in vacuo. Purification by high pressure liquid chromatography gave the ester as a colourless oil. IR (film) λmax 1741, 1606, 1591, 1575, 1500, 1490, 1450 cm-1. N.m.r. (250 MHz) δ (CDCl3) 1.42, t, 3H, J=7 Hz, CH3 ; 2.90-3.08, m, 1H, cyclobutyl H; 3.44-3.64, m, 1H, cyclobutyl H; 4.02, q, 2H, J=7 Hz, CH2CH3 ; 5.10, 5.16, ABq, 2H, J=14.5 Hz, CH2 -O; 6.71-7.64, m, 13H, aromatic H's. Mass spectrum, m/z 476 (M+ +1), 456 (M+ -19).
Reaction SMILES: C(S[C:4](S(CC)=O)([CH:19]([F:21])[F:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])C.Cl(O)(=O)(=O)=[O:27].O>C(#N)C>[C:12]1(=[O:13])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([CH:19]([F:21])[F:20])=[O:27])[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]12
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CCSC(CCCN1C(=O)c2ccccc2C1=O)(C(F)F)S(=O)CC
Solvent: CC#N
Solvent: O
Product: O=C(CCCN1C(=O)c2ccccc2C1=O)C(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 10 mmole of [((ethylsulfinyl)methyl)-thio]ethane in 20 ml of tetrahydrofuran is treated with 10 mmole of sodium hydride at 25° C for 2 hours after which 10 mmole of N-(3-bromopropyl)phthalimide in 5 ml of tetrahydrofuran is added. The reaction mixture is stirred overnight at 25° C then quenched with brine and extracted with chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromotography on silica gel to give N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide. To a solution of 22 mmole of N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide in 20 ml of tetrahydrofuran is added under nitrogen at 0° C a solution of lithium diisopropylamide in 23 mmole of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 25° C then is saturated with difluorochloromethane. Stirring is continued for 2 hours at 40° C. After quenching with brine, the reaction mixture is extracted with ether. The organic phase is decanted, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-ethylthio-4-ethylsulfinyl-4-difluoro-methylbutyl)phthalimide. To a solution of 30 mole of N-(4-ethylthio-4-ethylsulfinyl-4-difluoromethylbutyl)-phthalimide in 33 ml of acetonitrile is added at 0° C 1.1 ml of a 70% aqueous solution of perchloric acid. After stirring for 2 hours at 0° C the reaction mixture is poured into 60 ml of water then extracted with chloromethane. The organic phase is washed with brine, dried, filtered and the filtrate concentrated under reduced pressure to afford difluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccccc3)c12
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (85 mg, 0.25 mmol) was mixed with K2CO3 (68 mg, 0.5 mmol), phenylboronic acid (31 mg, 0.25 mmol), Pd(Ph3)4 (14 mg, 0.01 mmol), 1 mL of 1,2-dimethoxyethane and 2 drops of water. The mixture was heated and stirred in an 85° C. oil bath for 2 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Filtration followed by removal of the solvent in vacuo gave the crude product (71 mg), which was purified by column chromatography to give 53 mg (77% yield) of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:4]=2[CH2:3]1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>[OH-].[Na+]>[I:17][C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:3][C:4]=2[CH:16]=1
Reactant: ClC1Cc2cc(I)ccc2Sc2ccccc21
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: Ic1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
10.1 g of 10-chloro- 10,11-dihydro-2-iodo-dibenzo[b,f]-thiepin and 23.3 g of piperazine are held at 120°-130° C for 1 hour. The mixture is cooled, diluted with 2-N sodium hydroxide and extracted with ether. The organic phase is washed with water until neutral and extracted with 500 ml of 2-N hydrochloric acid. The aqueous phase is made alkaline and extracted with chloroform. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. There is obtained 1-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-yl)-piperazine as a brown oil.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:17][C@@:18]1([CH2:35][F:36])[CH2:22][CH2:21][N:20]([C:23]2[C:31]([F:32])=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25](F)[C:24]=2[F:34])[CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN([C:40](=[CH2:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])C.C(N(CC)CC)C.[CH:54]1([NH2:57])[CH2:56][CH2:55]1>C(#N)C>[CH:54]1([N:57]2[C:25]3[C:26](=[CH:30][C:31]([F:32])=[C:23]([N:20]4[CH2:21][CH2:22][C@@:18]([CH2:17][N:9]([CH2:10][C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:2][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)([CH2:35][F:36])[CH2:19]4)[C:24]=3[F:34])[C:27](=[O:28])[C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:46]2)[CH2:56][CH2:55]1
Reactant: C=C(C(=O)OCC)N(C)C
Reactant: NC1CC1
Reactant: O=C(Cl)c1cc(F)c(N2CC[C@](CF)(CN(Cc3ccccc3)Cc3ccccc3)C2)c(F)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@](CF)(CN(Cc4ccccc4)Cc4ccccc4)C3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
(S)-4-(3-(N,N-Dibenzylaminomethyl)-3-fluoromethylpyrrolidin-1-yl)-2,3,5-trifluorobenzoyl chloride hydrochloride (0.97 g) was dissolved in acetonitrile (8 ml). Ethyl N,N-dimethylaminoacrylate (0.27 g) and triethylamine (0.4 g) were dissolved in acetonitrile (1 ml) and dropwise added thereto with stirring at room temperature. The mixture was stirred at room temperature for 1 hour and at 50° C. for 4 hours. The reaction mixture was cooled to room temperature and cyclopropylamine (0.11 g) was added. The mixture was stirred at room temperature for 3 hours and the reaction mixture was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Dry dimethylformamide (3 ml) and potassium carbonate (0.26 g) were added to the residue, and the mixture was stirred at 60° C. for 8 hours. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=30:1) to give the object compound as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:29])([F:28])[C:4]([F:27])([F:26])[C:5]([F:25])([F:24])[C:6]([F:23])([F:22])[CH2:7][O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-])=O)=[C:11]([F:20])[C:10]=1[F:21].O.O.[Sn](Cl)Cl.[OH-].[K+]>C(O)C.O>[OH:1][CH2:2][C:3]([F:28])([F:29])[C:4]([F:27])([F:26])[C:5]([F:24])([F:25])[C:6]([F:22])([F:23])[CH2:7][O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([NH2:17])=[C:11]([F:20])[C:10]=1[F:21]
Reactant: O=[N+]([O-])c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Temperature: 0 °C
Yield: 94.7 %

Procedure:
A solution of the 4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluoronitrobenzene (2.0 g) in ethanol (50 mL) was treated with tin (II) chloride dihydrate (9.9 g) at 60° C. for 18 hrs. under a nitrogen atmosphere. The mixture was diluted with ice water, basified with potassium hydroxide (10.1 g) in water (80 mL) and extracted with ethyl ether. The extracts were washed with water and brine, dried (K2CO3), and concentrated to an oil. The oil was purified by chromatography to give 4-(6-Hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluorobenzeneamine as an oil (1.77 g).