Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[CH:21]([Cl:24])(Cl)Cl>>[Cl:24][CH2:21][C:3]1[C:4]([CH3:9])=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClC(Cl)Cl
Reactant: Cc1ncccc1CO
Product: Cc1c(CCl)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared essentially according to the procedure of I. M. Bell et al., J. Med. Chem. 41, 2146–2163 (1998). To a stirred solution of the crude 3-hydroxymethyl-2-methyl-pyridine of Step B (1.35 g, 9.53 mmol) in chloroform (50 mL) was added 90% m-chloroperbenzoic acid (2.0 g, 10.4 mmol). After stirring overnight at room temperature, an additional quantity of 90% m-chloroperbenzoic acid (1.0 g, 5.2 mmol) was added. The reaction mixture was stirred for an additional 3 hours and then quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. Purification by flash chromatography using a solvent system of 3% methanol in chloroform provided 0.85 g of the title compound as a brown-orange amorphous solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[C:24]([C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:17]3[C:24]([C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:32])=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)cc1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl(4-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)benzyl)carbamate (0.18 g, 0.41 mmol) in DCM (1.5 mL) was added 0.5 mL of TFA. The mixture was heated at 50° C. for 1 hour. The solvent was removed under reduced pressure. The residue was washed with DCM and dried on high vacuum give a yellow solid. M.p.=255-257° C.; 400 MHz 1HNMR (DMSO-d6) δ 13.05 (s, 1H), 11.43 (s, 1H), 8.48 (s, 1H), 7.98-7.96 (m, 3H), 7.85 (d, J=8.4 Hz, 2H), 7.70 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 4.03 (q, J=5.2 Hz, 2H); LCMS [M+H] 344.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>N1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH:14]2[O:13][C:5]3=[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[C:4]3[CH2:15]2)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]4)[CH2:18][CH2:19]1)=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CN1CCNCC1)C2
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(CC3Cc4cc(C)c5c(c4O3)CCC(=O)N5)CC2)cc1OC
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 5-methyl-2-(1-piperazinomethyl)-2,3,6,7,8,9-hexahydrofuro-[2,3-f]quinoline-7-one (1.474 g) in pyridine (40 ml), a solution of 3,4-dimethoxybenzoyl chloride (1.003 g) in pyridine (20 ml) was added dropwise while cooling on ice. Subsequently, stirring was continued at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was combined with water, and extracted with chloroform. The extract was washed with sodium bicarbonate water and water in this order, and dried and concentrated. The residue was crystallized from chloroform--n-hexane to obtain 2.163 g of a free base of the title compound as colorless prisms (mp. 190°-191° C.).
Reaction SMILES: C=O.[CH2:3]([O:5][C:6](=[O:26])[CH:7]([CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH3:12])[C:8](O)=O)[CH3:4].C(NCC)C.CCOC(C)=O>C(Cl)Cl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH:11]([CH3:12])[C:7]([C:6]([O:5][CH2:3][CH3:4])=[O:26])=[CH2:8])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C(=O)O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCNCC
Product: C=C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Formaldehyde (132 mg, 1.65 mmol, 37% in water) was added to a solution of of crude 2-[1-(1-tert-butoxycarbonyl-piperidin4-yl)-ethyl]-malonic acid monoethyl ester (416 mg) in methylene chloride (2 mL) at 0° C. Diethylamine (153 μL, 1.47 mmol) was added dropwise and the mixture was stirred at room temperature over night. EtOAc was added and the mixture was washed with water and saturated NaHCO3, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (toluene/EtOAc, 3:1) to give 4-(2-ethoxycarbonyl-1-methyl-allyl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 49% over two steps).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][C:30]#[N:31])(=[O:28])=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:29](/[S:26]([NH:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:28])=[O:27])\[C:30]#[N:31])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C(C)C)c1O

Procedure:
M44 was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanomethylsulfonamide under similar conditions as decribed for M40.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>C1C=CC=CC=1>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: O=C=Nc1nnc(C2CCCCCC2)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCCCC2)s1

Procedure:
A mixture of 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time to the mixture is stripped of benzene under reduced pressure yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I.O>C1COCC1.C(OCC)(=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-nitroindole (500 mg, 3.1 mmol) in THF (15 mL) at 0° C. was treated portionwise with NaH (290 mg, 9.3 mmol), stirred for 30 minutes, treated dropwise with methyl iodide (0.95 mL, 15.5 mmol), warmed to room temperature for 18 hours, treated sequentially with water and ethyl acetate (200 mL), and washed with brine (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to provide the desired product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]([O:39][C:40]([C:42]1([NH2:51])[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])[CH3:38].CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C(Cl)Cl>[CH2:37]([O:39][C:40]([C:42]1([NH:51][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:2]([CH3:1])=[O:3])[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])[CH3:38]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CS(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccccc2S(C)=O)Cc2ccccc2C1

Procedure:
To a 40 mL vial containing a stirring bar, 2-(methylsulfinyl)benzoic acid (0.449 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) is added. The 2-aminoindane-2-carboxylic acid ethyl ester ([500 mg, 2.44 mmol) is added followed by DIPEA (0.95 mL, 8.0 mmol). The reaction is allowed to stir for 94 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.2 g of yellow foam. This material is dissolved in 10 mL of DCM and purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 100% EtOAc over 8 column volumes and then hold for 5 column volumes. 25 mL fractions are collected. Fractions 9 through 18 are combined and evaporated in vacuo to a constant weight to give 0.75 g of amorphous off-white solid.
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)C>CO>[N:9]1[CH:8]=[C:7]([CH2:6][C:5]([NH2:1])=[O:4])[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=12
Reactant: CCOC(=O)Cc1cnc2ccccn12
Reactant: N
Solvent: CO
Product: NC(=O)Cc1cnc2ccccn12
Temperature: 100 °C

Procedure:
Bubble ammonia through a solution of (imidazo[1,2-a]pyridin-3-yl)acetic acid ethyl ester (10.0 g, 48.96 mmol) in methanol (30 ml) at 0° C. Heat the reaction mixture in a sealed tube at 100° C. for 2 hours. Concentrate the reaction mixture under reduced pressure. Triturate with ethyl acetate to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[S:10]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11])C#N.[OH-:18].[Na+].ClCl.[CH2:22]([OH:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:23]([CH:7]=[CH:8][C:9]=1[S:10]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11])[C:22]([OH:18])=[O:24]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1ccc(S(=O)(=O)N2CCCC2)c(Cl)c1
Agent: ClCl
Agent: [Na+]
Product: O=C(O)c1ccc(S(=O)(=O)N2CCCC2)c(Cl)c1
Yield: 89 %

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(pyrrolidin-1-ylsulfonyl)benzonitrile and sodium hydroxide solution in ethanol. Yield: 89% of theory; C11H21ClNO4S (289.74); mass spectrum: (M+H)+=290/292 (chlorine isotope).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[C@@H:19]([CH3:21])[CH2:18][C:17]([O:22][CH3:23])=[CH:16]3)[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=[CH:10]2)(=[O:5])=[O:4].C1C=C(Cl)C=C([C:35](OO)=[O:36])C=1.C[OH:40]>>[F:27][C:2]([F:1])([F:26])[S:3]([O:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[C@@H:19]([CH3:21])[CH2:18][C:17]([O:36][CH3:35])([O:22][CH3:23])[C@@H:16]3[OH:40])[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=[CH:10]2)(=[O:5])=[O:4]
Reactant: CO
Reactant: COC1=Cc2c(c(OS(=O)(=O)C(F)(F)F)nc3ccc(OC)cc23)[C@@H](C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc2nc(OS(=O)(=O)C(F)(F)F)c3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Temperature: 23 °C
Yield: 63 %

Procedure:
A solution of (S)-7,8-dihydro-2,9-dimethoxy-7-methyl-6-phenanthridinol trifluoromethanesulfonate (ester) (12, 3.00 g, 7.40 mmol, 1 equiv) and m-CPBA (5.10 g, 14.9 mmol, 2.00 equiv) in methanol (120 mL) was heated at reflux for 1 h. After cooling to 23° C., the reaction solution was partitioned between 1:1 saturated aqueous sodium bicarbonate solution:saturated aqueous sodium thiosulfate solution (200 mL) and dichloromethane (200 mL). The aqueous layer was separated and extracted further with dichloromethane (2×200 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (25% ethyl acetate-hexanes initially, grading to 40% ethyl acetate-hexanes) away from structure 14 to afford (7S,10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-6,10-phenanthridinediol 6-(trifluoro-methanesulfonate) (13) as a yellow foam (2.12 g, 63%). ##STR24##
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:16]C(C)=O.O>CO>[CH3:16][O:12][C:11](=[O:13])[C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(I)cc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Dissolve 5-iodo-isophthalic acid (5 g, 15.6 mmol), NaOH (600 mg, 14.8 mmol) in a mixture of methanol (100 mL), acetone (20 mL) and water (2 mL). Stir at room temperature overnight. Concentrate and redissolve the residue in diethyl ether (100 mL) and water (100 mL). Separate the aqueous layer and wash with diethyl ether (50 mL). Acidify the washed solution with 5 N HCl to about pH=1. Stir for 30 min at room temperature and filter off solid. Wash the solid with water and dry to give the title compound (3.7 g, 77%).
Reaction SMILES: Cl.[Br:2][C:3]1[S:4][C:5]([CH2:8][NH2:9])=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C>ClCCl>[Br:2][C:3]1[S:4][C:5]([CH2:8][NH:9][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:19])=[O:18])=[CH:6][N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NCc1cnc(Br)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCc1cnc(Br)s1)c1ccccc1Cl

Procedure:
In analogy to example 1, step 1, 2-bromo-5-aminomethyl-thiazole hydrochloride was reacted with 2-chlorobenzenesulfonylchloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-(2-bromo-thiazol-5-ylmethyl)-2-chloro-benzenesulfonamide as an off-white solid. MS: 367.0 ([M+H]+)
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.[NH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].C(NCC(O)=O)(=O)C>COCCOC>[C:1]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=C(O)CNCC(=O)O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), DME (90 mL), and CO2 (CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. for 30 min. HPLC analysis of this stream gave an 89% yield of (XVI), 1% (XIV), and 8% (XVIII).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[C:25]1C=CC(C(Cl)=O)=C[CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:25]#[C:26][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-bromo-4′-fluorobenzophenone: fluorobenzene (6.89 g, 71.7 mmol), 4-bromobenzoyl chloride (7.86 g, 35.8 mmol), and aluminum chloride (4.78 g, 35.8 mmol) were combined and stirred for 24 h at room temperature. The resulting mixture was poured over ice, and then filtered. The solid was dissolved in hot ethanol, treated with decolorizing charcoal, and filtered; white crystals of the title compound formed upon cooling of the ethanol solution and were isolated by filtration.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
A suspension of 37.2 g of methoxymethyl-triphenylphosphonium chloride in 250 ml of t-butyl methyl ether is treated at room temperature while gassing with argon with 13.4 g of potassium t-butylate and stirred for 1 hour. Subsequently, the reaction mixture is treated at about 20° C. with a mixture of 9.49 g of 4-cyanobenzaldehyde and 100 mol of t-butyl methyl ether and stirred for a further 1 hours. Thereafter, the reaction mixture is partitioned in diethyl ether/water. The aqueous phase is extracted several times with diethyl ether. The organic phases are washed with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with petroleum ether and toluene/hexane (vol. 3:1) gives 4-(2-methoxyvinyl)benzonitrile.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2]O.[CH2:6]([OH:12])[CH2:7][CH2:8][CH2:9]CC.[CH3:13]O>>[OH:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:2][C:1]([O:5][CH3:13])=[O:4]
Reactant: O=C(O)CO
Reactant: CCCCCCO
Reactant: CO
Product: COC(=O)CCCCCO
Temperature: 270 °C

Procedure:
Nylon 6 (0.1 g), glycolic acid as a carboxylic acid (0.380 g) and methanol (3.0 g) were added to a 10 mL volume reactor equipped with a tube (outer diameter: ⅜ inches, inner diameter: 7.53 mm, length: 23 cm), nitrogen substitution was conducted at room temperature, and the reactor was sealed. The reactor was put into an electric furnace heated to 270° C. (pressure: 11.8 MPa), and the change over time was measured. In the measurement, the obtained reaction mixture and 1-hexanol as an internal standard substance were weighed and used as analysis samples for a gas chromatography analysis. An integral value was calculated by a gas chromatography analysis, and a table of a standard curve was prepared and the yield of methyl 6-hydroxycaproate was obtained therefrom. The result is shown in Table 5.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:22]1[CH:23]=[C:24]([S:28]([OH:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:19])([O-:11])=[O:10]>CN(C=O)C>[CH3:7][N:21]([S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N+:9]([O-:11])=[O:10])(=[O:20])=[O:19])[C:22]1[CH:23]=[C:24]([S:28]([OH:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc(S(=O)(=O)O)c1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1cccc(S(=O)(=O)O)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (177 mg, 1.28 mmol), DMF (2 ml) and MeI (60 μl) were added to the compound (230 mg, 0.65 mmol) obtained in Step 1, followed by stirring at 40° C. for 6 hours. Potassium carbonate (44.3 mg) and MeI (40 μL) were supplemented and the mixture was stirred overnight. After the solvent was removed by distillation, the mixture was purified according to the purification step A to give the crude product of 3-{methyl[(2-nitrophenyl)sulfonyl]amino}benzenesulfonic acid (160 mg). This crude product (144 mg, 0.39 m ml) was dissolved in DMF (3 ml), and cesium carbonate (126 mg, 0.39 mmol) and thiophenol (40 μl, 0.39 mmol) were added to the solution. The mixture was stirred at 50° C. overnight. After the solvent was removed by distillation, the mixture was purified in accordance with the purification step A to give the crude product of 3-(methylamino)benzenesulfonic acid (84.1 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][N:38]=2)=[CH:30][CH:29]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][N:38]=2)=[CH:30][CH:29]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCC/C=C/CO
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2ncc(CCCCCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.95 g) is added in small portions to a solution of (E)-hex-2-en-1-ol (0.40 g), 2-(4-hydroxyphenyl)-5-octylthiazole (0.70 g), diethylazodicarboxylate (0.60 g) in dry tetrahydrofuran (40 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.15 g of 2-(4-[(E)-hex-2-enyloxy]phenyl)-5-octyfthiazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(Nc2nc(Cl)ncc2F)n1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H,-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2-amino-6-methylpyridine gave 2-chloro-5-fluoro-N4-(6-methylpyridin-2-yl)-4-pyrimidineamine. 1HNMR(CDCl3): δ 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (d, 1H, J=3 Hz), 7.55 (bs, 1H), 7.69 (t, 1H, J=7.4 Hz), 9.35 (d, 1H, J=7.5 Hz); 19F NMR (CDCl3): −44073; LCMS: purity: 96%; MS (m/e): 239 (M+).
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([C:29]([O:31]C)=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C>CO.C(COC)OC>[C:29]([CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([S:11]([NH:10][C:33]3[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=3)(=[O:13])=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1)[CH3:28])([OH:31])=[O:30]
Reactant: COC(=O)C(C)Oc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(OC(C)C(=O)O)cc1
Reaction time: 72 h
Yield: 40.8 %

Procedure:
2M Sodium hydroxide solution (1 ml) was added to a solution of N-(isobutoxycarbonyl)-2-(4-[1-(methoxycarbonyl)ethoxy]phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.302 g) in methanol (5 ml) and dimethoxyethane (5 ml) and the solution was stirred for 3 days. Volatile material was removed by evaporation and the residue was dissolved in water (15 ml). The solution was washed with ethyl acetate (2×15 ml) and acidified to pH3 with 6M hydrochloric acid. The mixture was extracted with ethyl acetate (2×10 ml) and the extracts were re-extracted with saturated sodium bicarbonate solution (2×10 ml). The aqueous solution was acidified with 2M hydrochloric acid and extracted with ethyl acetate (2×10 ml). The extracts were washed with water (10 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallised from ethyl acetate to give 2-[4-(1-carboxyethoxy)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.098 g), m.p. 149-151° C.; microanalysis found: C, 53.6; H, 4.9; N, 11.7%; C18H18N4O6S.0.2C4H8O2 requires: C, 54.1; H, 4.7; N, 12.1%.