Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[N:10]=[CH:11][N:12]=[C:4]2[CH:3]=1.[OH-:13].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([OH:13])[N:5]2[N:10]=[CH:11][N:12]=[C:4]2[CH:3]=1
Reactant: CSc1nc(Cl)cc2ncnn12
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: Oc1nc(Cl)cc2ncnn12

Procedure:
7-Chloro-5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidine (181 mg, 0.91 mmol) was dissolved in MeOH (4 ml). 2N KOH (8 ml) was added and the mixture was stirred at reflux for 2 hours. The solvents were removed by a rotavap. The residue was added 4N HCl in dioxane and stirred for an hour before it was concentrated. Water was added and the mixture was extracted with DCM to give 7-Chloro-[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (35 mg) as a solid. [M+H] calc'd for C5H3ClN4O, 171; found, 171.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:18])[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[N:8]=2)[CH2:3][CH2:2]1.N([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)=[N+]=[N-].[H-].[Na+]>>[CH:1]1([C:4]2[N:5]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[N:39]([C:40]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:38]=[N:37][N:36]=4)=[CH:27][CH:28]=3)[C:6](=[O:18])[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[N:8]=2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1[nH]c(C2CC2)nn1-c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: O=c1n(-c2ccccc2[N+](=O)[O-])nc(C2CC2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 59 %

Procedure:
The alkylation of 5-cyclopropyl-2,4-dihydro-2-(2-nitrophenyl)-3H-1,2,4-triazol-3-one with 5-[4'-bromomethyl)biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 4, Step D, except that a 20% excess of sodium hydride and 20% excess of the alkylating agent were used. After work-up, the crude product mixture was flash chromatographed on silica gel (124 mL for 0.467 mmole, eluted with 0.5% MeOH/CH2Cl2) to give a 59% yield of the desired material as a yellow foam, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 723 (M+1)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reaction time: 0.33 h

Procedure:
The product from step (vi) (0.6 g) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The reaction mixture was stirred for 20 min, the solvents were evaporated and the product purified via SCX resin, eluting with ammonia in MeOH solution (3.5%). Yield 380 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Oc1cccc(Cl)c1-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 2′,6-dichloro-biphenyl-2-ol (10.0 g, 41.8 mmol) in DMF was added sodium hydride (60% in mineral oil, 2.5 g, 62.7 mmol) and allyl bromide (5.4 mL, 62.7 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 30% ethyl acetate in hexanes provided 11.6 g (100%) of 2-allyloxv-2′,6-dichlorobiphenyl as a light yellow oil
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:19][Mg]Br.[Cl-].[NH4+].Cl>C1COCC1.O.C(OCC)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH2:19]
Reactant: C[Mg]Br
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=C1c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 50 °C
Reaction time: 0.21 h

Procedure:
7-Bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (21.5 g, 65.4 mmol) was suspended in dry THF (300 mL) under nitrogen in an ice bath. Methylmagnesium bromide (3.0 M in diethyl ether, 36 mL, 108 mmol) was added in ˜12 mL portions allowing 10-15 minutes between additions. The mixture was stirred for a 15 minutes after the final addition. Saturated ammonium chloride (50 mL) was added carefully followed by diethyl ether (200 mL), ethyl aceate (200 mL), water (400 mL) and 2 N HCl (50 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude alcohol was dissolved in dry THF (300 mL) and treated with HCl (4.0 M solution in 1,4-dioxane, 16 mL, 64.0 mmol). The mixture was heated to 50° C. and stirred for 30 minutes. The crude reaction mixture was evaporated to dryness under reduced pressure. The crude tar was triturated with diethyl ether (200 mL) and stirred in an ice bath. A cream coloured solid precipitated within a few minutes. After 10 minutes the mixture was filtered through a sintered glass frit and dried under high vacuum to give the desired 7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:27])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=386.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CCc1conc1-c1ccc(F)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1conc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of methyl 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (3.50 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 30 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.89 g, yield 92%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.30 (1H, t, J=5.2 Hz), 1.74–1.94 (2H, m), 2.62–2.74 (2H, m), 3.64–3.76 (2H, m), 7.18–7.31 (1H, m), 7.50–7.60 (1H, m), 7.74 (1H, dd, J=2.2, 7.0 Hz), 8.29 (1H, s).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C[Si](C)(C)NC(N[Si](C)(C)C)=O.C(O)C>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 84 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of N,N′-bis(trimethylsilyl)urea. 0.481 g Styrene and 0.549 g methyldichlorosilane were introduced into a glass tube, and an ethanol solution containing 0.124 mg N,N′-bis(trimethylsilyl)urea (6.2 wt %) was added with a microsyringe. 1 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a septum and then placed in a 100° C. oil bath where it was heated for 20 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 89% and a phenethylmethyldichlorosilane yield of 84%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 21:1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])(=[O:3])[CH3:2].C1(C=CC(O)=CC=1)[OH:14].C(O)(=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:5]1(=[O:14])[O:4][C:1](=[O:3])[CH2:2][CH2:6]1.[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])(=[O:3])[CH3:2]
Reactant: Oc1ccc(O)cc1
Agent: C=CC(=O)O
Agent: CCOCCOCCOC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1CCC(=O)O1
Temperature: 115 °C

Procedure:
A reflux condenser, a thermometer, a bleed tube, and a stirrer were set to a four-necked flask. In order to prepare a reaction solution, 919 parts by mass of bisphenol A epoxy resin (jER1004 (item number) available from Mitsubishi Chemical Corporation, epoxy equivalent weight: 919), 470 parts by mass of diethylene glycol monoethyl ether acetate, 0.2 parts by mass of hydroquinone, 72 parts by weight of acrylic acid, and 3 parts by mass of triphenyl phosphine were added to the four-necked flask. The reaction solution was heated at 115° C. for 12 hours with air bubbled therein to cause the addition reaction. Subsequently, into thus-obtained solution in the four-necked flask, 249 parts by mass of succinic acid anhydride and 195 parts by mass of diethylene glycol monoethyl ether acetate were added, and then thus-obtained solution was heated at 110° C. for 5 hours to react them. Consequently, a 65 mass % solution (carboxyl group containing resin solution C-1) of resin containing a carboxyl group was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(CO)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
In dichloromethane (5 mL) was dissolved (6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanol (340 mg, 1.80 mmol) obtained in Step 2. Dess-Martin periodinane (915 mg, 2.16 mmol) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution and the mixture was stirred at room temperature for 1 hour. Extraction with dichloromethane and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 6-(2-methyl-1H-imidazol-1-yl)nicotinaldehyde (292 mg, 87% yield).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[NH:5])C.[CH3:12][NH:13][NH2:14]>N1C=CC=CC=1>[CH3:12][NH:13][NH:14][C:4]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[NH:5]
Reactant: CCOC(=N)c1ccc(Br)s1
Reactant: CNN
Solvent: c1ccncc1
Product: CNNC(=N)c1ccc(Br)s1
Yield: 161.9 %

Procedure:
The 5-bromo-thiophene 2-carboximidic acid ethyl ester (3BW) (13 g, 34.3 mmols) was dissolved in pyridine (100 ml). Methylhydrazine (2.7, 51.45 mmols) was added with stirring and the resulted mixture was allowed to stir overnight. The reaction mixture was concentrated under reduced pressure, and added ether, filtered, washed with ether three times and dried to provide the titled compound (4BW) (13 g).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[C:6]2[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].[OH-].[Li+].O>C1COCC1>[CH3:1][C:2]1([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of methyl 3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2H-1-benzofuran-5-carboxylate (510 mg, 1.35 mmol), sodium hydroxide (0.33 g, 7.9 mmol), lithium hydroxide (0.33 g, 7.9 mmol) and water in THF is stirred at room temperature for 5 days. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. 10 ml of water and 10 ml of ethyl acetate are added. The mixture is acidified with concentrated hydrochloric acid solution to pH 1. After separation of the phases by settling, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The solid obtained is washed with heptane.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH:7]2[CH2:20][CH2:21][N:22]([C:23](=[O:45])[CH:24]([NH:31][C:32](=[O:44])[CH:33]([N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH3:34])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:6]12)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:20][CH2:21][N:22]([C:23](=[O:45])[CH:24]([NH:31][C:32](=[O:44])[CH:33]([N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH3:36])[CH3:34])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:6]12)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C21
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
A solution of 18 (0.4 g, 0.64 mmol) in MeOH (20 mL) was treated with 10% Pd/C (wet, 216 mg) and reduced under an H2 atmosphere (50 psi) using a Parr apparatus. After 1.5 h, the mixture was filtered through a nylon filter cartridge and the solids were washed with MeOH. The filtrate was concentrated to afford 19 (0.31 g) as an orange-colored oil which was used without further purification. Mass spectrum, m/z [495.4] (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[C:3]=1[OH:13].CI.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[C:3]=1[O:13][CH3:16]
Reactant: COCc1ccc(OC)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COCc1ccc(OC)c(Br)c1OC
Reaction time: 2.5 h
Yield: 51.2 %

Procedure:
24.1 g (0.098 mole) of 2-bromo-3-methoxy-6-methoxymethylphenol and 27.7 g of methyl iodide are dissolved in 200 ml of acetone in the presence of 14.82 g (0.107 mole) of potassium carbonate. This solution is heated at reflux temperature, with stirring, for 2.5 hours. It is then cooled, the mineral salts are filtered off and the filtrate is distilled to remove the acetone. The residue is taken up in water and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and distilled under reduced pressure. 13.1 g of 1-bromo-2,6-dimethoxy-3-methoxymethylbenzene are obtained. Yield: 51% of theory; B.P.: 92°-115° C./0.005 mbar.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: O=Cc1ccccn1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (100 mg, 0.316 mmol) and 2-pyridine carboxaldehyde (30 ul, 0.316 mmol) similar to Example 15 and isolated as a yellow solid (13 mg, 10%) 1H NMR (CDCl3): 8.68-8.65 (m, 1H), 7.79 (d, J=15.6 Hz, 1H), 7.72 (dd, J=1.7, 7.7 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.31-7.28 (m, 1H), 7.25 (s, 1H), 7.12 (dd, J=3.2, 8.9 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 4.44-4.33 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[Na+].C(S)CCCCCCC.C1C[S+](CC2C=CC(C[S+]3CCCC3)=CC=2)CC1.[Cl-:34].[Cl-].Cl.[CH2:37]([S:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53]SCCCCCCCC)=[CH:49][CH:48]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CO>[CH2:37]([S:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][Cl:34])=[CH:49][CH:48]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: [Cl-]
Reactant: CCCCCCCCSCc1ccc(CSCCCCCCCC)cc1
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCS
Agent: Cl
Solvent: CO
Product: CCCCCCCCSCc1ccc(CCl)cc1
Reaction time: 0.5 h

Procedure:
1.83 g (19 mmol) of sodium t-butoxide and 2.78 g (19 mmol) of octanethiol were stirred into 40 g of methanol at room temperature. After 30 minutes, the clear solution was added in one portion to 6.68 g (19 mmol) of the p-xylylenebis(tetrahydrothiophenium chloride) obtained in accordance with Example 1, in 100 g of methanol. After one hour, the mixture was neutralized using 1N hydrochloric acid, and all the volatile components were removed under reduced pressure. The crude product was taken up in 200 ml of chloroform, the undissolved constituents were filtered off, and the filtrate was evaporated under reduced pressure. The oil was mixed with twice the volume of octane, and distilled off under reduced pressure together with tetrahydrothiophene. This sequence was repeated three times with octane, finally giving 5.31 g, consisting of 90% of product, 5% of starting material and 5% of p-bis(octylthiomethyl)benzene. This reaction was carried out at various temperatures and the product distribution analyzed by 1H-NMR spectroscopy (all data in mol-%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:7]([NH2:26])=[N:8][C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH:1]1([C:4]2[NH:26][C:7]3=[N:8][C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc(N)c(C#CC3CC3)nc2-c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(-c2nc3cc(C4CC4)[nH]c3nc2-c2ccc(C)cc2)cc1

Procedure:
3-(Cyclopropylethynyl)-5,6-di-p-tolylpyrazin-2-amine (step 4)(279 mg, 0.822 mmol) in tert-BuOH (10 ml) was treated with potassium tert-butoxide (184 mg, 1.644 mmol) and heated at reflux for 6 hours. The mixture was diluted with water and extracted with DCM (×3). The combined organic extracts were concentrated under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the titled compound as a beige coloured solid;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:17]2[O:18][CH2:19][C:20]3[N:21]([CH:22]=[CH:23][CH:24]=3)[C:16]2=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31]>O1CCOCC1.CS(C)=O>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:17]2[O:18][CH2:19][C:20]3[N:21]([CH:22]=[CH:23][CH:24]=3)[C:16]2=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cccn1-2
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1cccn1-2
Temperature: 95 °C
Yield: 64.8 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 16, 0.107 g) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.179 g) in dioxane (3 mL) and DMSO (0.3 mL) was degassed and purged with nitrogen. Tris-(dibenzylideneacetone)dipalladium (0) (0.01 g) and tri-tert-butylphosphonium tetrafluoroborate (0.006 g) were added and the mixture was degassed and purged with nitrogen again, then the mixture was heated to 95° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-5% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.074 g) as a sticky yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:20])=O>N1C=CC=CC=1.C(OCC)C>[Cl:20][CH2:2][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(OC(C)C(=O)OC)c(CO)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCc1ccc(OC(C)C(=O)OC)c(CCl)c1
Yield: 100.8 %

Procedure:
By the method of Example 1, Step H, 26.0 grams (0.109 mole) of methyl 2-(2-hydroxymethyl-4-ethylphenoxy)propionate and 14.3 grams (0.12 mole) of thionyl chloride were reacted in the presence of two drops of pyridine in 120 mL of diethyl ether, yielding 28.21 grams of methyl 2-(2-chloromethyl-4-ethylphenoxy)propionate. The NMR spectrum was consistent with the proposed spectrum.