Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)#[N:27]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(C#N)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 286 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 4-cyanobenzene sulfonyl chloride. The compound of example 286 was used directly without isolation, for the preparation of compound of example 287.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=2)=[CH:2]1.Cl.[CH3:27][O:28][C:29](=[O:34])[CH:30]([CH2:32][OH:33])[NH2:31].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(CC)CC)C>[OH:33][CH2:32][CH:30]([NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:9][C:10]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:29]([O:28][CH3:27])=[O:34]
Reactant: C[Si](C)(C)CCOCOc1cc(OCc2ccsc2)ccc1C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of 4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxymethoxy)benzoic acid (6 g), (RS) serine methyl ester hydrochloride (2.7 g), 1-hydroxybenzotriazole (2.6 g), triethylamine (2.4 mL), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (3.6 g) and DMF (100 mL) is stirred at ambient temperature for 16 hours. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (150 mL) and 1N HCl (100 mL). The organic phase is washed with water (2×100 mL) then dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and cyclohexane (3:7 v/v) then with a mixture of ethyl acetate and cyclohexane (1:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give methyl (RS)-3-hydroxy-2-[4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxymethoxy)benzoyl]aminopropionate (6.5 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][NH:25][C:24]4=[O:29])=[N:21][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:30]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][N:25]([CH3:30])[C:24]4=[O:29])=[N:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)CC4C)nc3)CC2)c(C)c1

Procedure:
Using 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-5-methylimidazolidin-2-one (166 mg) described in Example 426 and methyl iodide (31 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (123 mg) was obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[N+:33]([O-:35])=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO.[OH-].[Na+]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[N+:33]([O-:35])=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared by the hydrolysis of the compound of Example 203 under basic conditions (aq. NaOH/EtOH), producing a light yellow solid:, mp 165° C.(dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.15-1.52 (m, 3H), 1.46-1.62 (m, 2H), 2.32 (m, 1H), 2.80 (m, 1H), 3.45(br, 1/2H), 4.00 (br, 1/2H), 4.44 (br, 1/2H), 4.800 (br, 1/2H), 6.83 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.09 (dd, J=2.0, 14.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.20 (d, J=15.5 Hz. 1H), 7.35 (d, J=15.5 Hz, 1H), 7.73 (m, 1H), 8.52 (m, 1H). MS (ESI) m/z 469 (M−H)+, 471 (M+H)+. Anal. calcd. for C23H21N2l O7SNa.NaOH.2.7 H2O: C, 47.54; H, 4.75; N, 4.82. Found: C, 47.18; H, 4.36; N, 4.89.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH2:17]([NH2:19])[CH3:18]>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:19][CH2:17][CH3:18])=[N:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCN
Reactant: CCn1c(=O)[nH]c(=S)c2[nH]c(C3CC3)nc21
Solvent: O
Product: CCNc1nc(=O)n(CC)c2nc(C3CC3)[nH]c12

Procedure:
5.91 g of 8-cyclopropyl-3-ethyl-6-thioxanthine and 100 ml of 70% ethylamine in water were heated in a 450 ml reactor to 150° C. After 6 hours the solution was filtered and evaporated to dryness. The residue was suspended in methanol, collected, washed and dried to give the title compound (5.67 g) as an off-white solid mp 260°subl./301-5° C. The hydrochloride salt was also obtained as an off-white solid mp 205-50° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][N:11]([CH3:13])[CH2:10][NH:9][C:8]2=[N:14][N+:15]([O-:17])=[O:16])[CH2:2]1.[H-].[Na+].[CH3:20]I>CN(C=O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][N:11]([CH3:13])[CH2:10][N:9]([CH3:20])[C:8]2=[N:14][N+:15]([O-:17])=[O:16])[CH2:2]1
Reactant: CI
Reactant: CN1CNC(=N[N+](=O)[O-])N(CC2CCOC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CN(C)C(=N[N+](=O)[O-])N(CC2CCOC2)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A mixture comprising 3.00 g of 1-{(tetrahydro-3-furanyl)methyl}-2-(nitroimino)-5-methylhexahydro-1,3,5-triazine, 0.54 g of sodium hydride and 40 ml of DMF was stirred at 50° C. for 30 minutes. Then, 2.08 g of methyl iodide were added thereto, followed by stirring at 70° C. for 2 hours. The reaction fluid was poured into a saturated saline solution and the mixture was extracted with methylene chloride several times. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The crude oily matter thus obtained was purified by column chromatography to obtain 1.43 g of 1-{(tetrahydro-3-furanyl)methyl}-2-(nitroimino)-3,5-dimethylhexahydro-1,3,5-triazine.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O-2].[Mg+2].O.[CH:13]([O:26][C:27](N=[N+]=[N-])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH:13]([O:26][C:27]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: [N-]=[N+]=NC(=O)OC(c1ccccc1)c1ccccc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OC(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
To a mixture consisting of 13.1 g. of L-leucine, 6 g. of magnesium oxide, and 150 ml. of water is added a solution of 25.3 g. of benzhydrylazidoformate in 150 ml. of dioxane, and the resulting mixture is stirred at room temperature for 2 days. It is then filtered, and the filtrate is concentrated to remove the dioxane. The aqueous concentrate is acidified with solid citric acid, and the acidified mixture is extracted with ethyl acetate. The extract is dried and evaporated to dryness to give an oily residue of N-benzhydryloxycarbonyl-L-leucine, which is suitable for use without further purification. To a mixture of 32 g. of this intermediate product, 25 g. of pentachlorophenol, and 300 ml. of ethyl acetate, at 5° C., is added 20 g. of dicyclohexylcarbodiimide, and the resulting mixture is kept at 5° C. for 5 hours and filtered. The filtrate is concentrated to small volume, and the concentrate is treated with petroleum ether to give a precipitate of N-benzhydryloxycarbonyl-L-leucine pentachlorophenyl ester, which is isolated and crystallized from ethanol-water; m.p. 84°-86° C.; [α]D25 -27.8° (2% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]([O-:14])=O)=[C:7]2O.[NH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[NH2:17]>S(Cl)(Cl)=O.C(O)C>[F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:14])[N:16]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=4)[NH:17][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C([O-])c1nnc2c(F)cccc2c1O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 8-Fluoro-4-hydroxycinnoline-3-carboxylate from the previous stage (1.00 g, 4.95 mmol) was dissolved in thionyl chloride (50 ml). The solution was heated to reflux for 2-3 h until no further gas evolution was observed. The reaction mixture was cooled to room temperature and excess thionyl chloride was removed under vacuum. The crude intermediate was azeotroped with toluene (3×25 ml). A dark brown solid was obtained, which was taken up in ethanol (25 ml). 4-Hydrazinobenzoic acid (640 mg, 4.21 mmol) was added and the mixture was stirred at room temperature overnight. The solids were collected by filtration, slurried in 1 M HCl (100 ml), filtered, washed with hexane (50 ml) and dried under vacuum. A brown solid was obtained (890 mg of crude product). LCMS: m/z [M+H]+ 325.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reaction time: 1 h

Procedure:
20 mg of Pd/C (10%) is prehydrogenated for 20 minutes in 2 ml of absolute methanol. To it are added 200 mg (0.53 mmole) of the compound from Example 1 in a mixture of 2 ml of absolute methanol and 0.8 ml of ethyl acetate, and the mixture is hydrogenated for 1 hour at 20° C. The catalyst is filtered off, and the solvent is evaporated under vacuum in a rotary evaporator. The residue is pure in TLC and crystallizes upon drying under high vacuum.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[O:18][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:25][N:23]([CH2:22][C:19]1[O:18][C:17]([CH2:16][S:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11])=[CH:21][CH:20]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(CSCCNC(=S)NC(=O)c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccc(CSCCNC(N)=S)o1
Temperature: 65 °C

Procedure:
A mixture of 24.76 g (65.6 mmol) of N-benzoyl-N'-(2-(((5-(dimethylamino)methyl-2-furanyl)methyl)thio)ethyl)-thiourea and 5.6 g (40.5 mmol) of potassium carbonate in 160 ml ethanol and 100 ml water is heated under stirring at 65° C. An additional amount of 3.45 g (25 mmol) potassium carbonate is added after 30 and 75 minutes respectively. After 90 minutes the ethanol is eliminated by vacuum distillation. A reaction mixture is diluted with 200 ml 5% sodium carbonate and extracted with dichloromethane (3×250 ml). The organic compound is washed with 5% sodium carbonate (2×500 ml), dried over anhydrous magnesium sulfate and concentrated to a brown oil. After chromatography on 500 g silica gel in dichloromethane/methanol 9:1, 16.8 g of N-(2-(((5-(dimethylamino)methyl-2-furanyl)methyl)thio)ethyl-thiourea oil is obtained.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][OH:13])([O-:5])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[OH:5][N:3]=[C:6]1[CH:11]=[CH:10][C:9](=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:23]#[N:24])[CH:8]=[C:7]1[CH2:12][OH:13]
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(C(C#N)=C2C=CC(=NO)C(CO)=C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a stirred and cooled (<15° C.) mixture of 134 parts of potassium hydroxide and 940 parts of pyridine were added portion wise 92 parts of 2-nitrobenzenemethanol. Next there were added 132.5 parts of 4-methoxybenzeneacetonitrile and stirring was continued for 4 hours at room temperature. The reaction mixture was diluted with 3000 parts of ice-water and the whole was acidified with 1270 parts of hydrochloric acid. The precipitate was filtered off, stirred overnight in methylbenzene and dried in vacuo at 60° C., yielding 128.8 parts (50.7%) of α-[4-(hydroxyimino)-3-(hydroxymethyl)-2,5-cyclohexadien-1-ylidene]-4-methoxybenzeneacetonitrile (interm. 40).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[Cl:32].[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[Cl:32])[CH2:30][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(Br)c2)CC1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 140.2 ml (1.0 mol) of diisopropylamine were dissolved in 1200 ml of dry THF and cooled to −30° C. 400 ml (1.0 mol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 94.8 g (0.667 mol) of tert-butyl cyclopropanecarboxylate in 750 ml THF was added to the reaction solution, with the temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 208.6 g (0.733 mol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 550 ml of THF was added, the temperature again being kept below −60° C. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added carefully. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 95.5 g (41.4% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:13]=2[C:12]=1[C:26]1[C:27]([CH3:36])=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][CH2:31][CH2:30][CH2:29]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:13]=2[C:12]=1[C:26]1[C:27]([CH3:36])=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][CH2:31][CH2:30][CH2:29]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2c3c(sc2c(=O)n1C)CCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Temperature: 65 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of compound methyl 2-(tert-butoxy)-2-(2-methyl-4-(5-methylchroman-6-yl)-1-oxo-1,2,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-3-yl)acetate (20 mg, 0.04 mmol) in Tetrahydrofuran (THF) (3 mL) and Water (3 mL) was added lithium hydroxide hydrate (20 mg, 0.48 mmol). The mixture was stirred at 65° C. for overnight. The reaction was cooled to room temperature, and solvent was removed by concentrated under reduced pressure to afford an oil, which was acidified with 1N aqueous HCl to pH=3, the resulting precipitate was collected by filtration to afford title product (11.5 mg, 59% yield) as white solid. 1H NMR: (Methanol-d4, 400 MHz) δ 0.99, 1.15 (s, total, 9H), 1.35˜1.52 (m, 2H), 1.69˜1.72 (m, 4H), 1.86 (s, 3H), 2.08˜2.11 (m, 2H), 2.65˜2.75 (m, 2H), 2.85˜2.89 (m, 2H), 3.77, 3.80 (s, total, 3H), 6.72˜6.78 (m, 1H), 6.98˜7.27 (m, 1H). LCMS (m/z) ES+=496 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[S:5]1(=[O:21])=[O:20].[CH3:22][N:23]([CH2:31][CH2:32][NH:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH2:3][CH2:2][N:33]([CH3:34])[CH2:32][CH2:31][N:23]([CH3:22])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[S:5]1(=[O:21])=[O:20]
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN(C)C(=O)OC(C)(C)C)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 125 °C

Procedure:
A mixture of 1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (171 mg, 0.461 mmol), tert-butyl methyl[2-(methylamino)ethyl]carbamate (695 mg, 3.69 mmol, 8 equiv.), sodium carbonate (489 mg, 4.61 mmol, 10 equiv.) and N,N-dimethylformamide (5 mL) was sealed and heated at 125° C. for 5 h. After cooling, the reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic layer was washed with brine, dried (anhydrous sodium sulfate), and concentrated. The crude liquid was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (12-g redisep silica gel column, 15-70% ethyl acetate/hexane) to give tert-butyl {2-[{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}(methyl)amino]ethyl}methylcarbamate as a viscous, colorless liquid. Yield: 142 mg (64%). MS (ESI) m/z 479.0 ([M+H]+). HRMS: calcd for C23H31FN4O4S+H+, 479.2123; found (ESI, [M+H]+), 479.2129. HPLC purity 96.6% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.Cl>CN(C=O)C>[C:8]1([NH:14][NH:15][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.54 mL (31.0 mmol) cyclobutanecarboxylic acid chloride were added dropwise at RT to 3.00 mL (30.2 mmol) phenylhydrazine and 4.75 mL (60.0 mmol) pyridine in 30 mL DMF. The mixture was stirred for 1 h at RT and poured onto 200 mL of a 1M hydrochloric acid solution. The precipitated solid was suction filtered, washed with 50 mL water and dried i. vac. The product was extracted with 50 mL ether and suction filtered. The solid was washed with 20 mL ether and dried in the air.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[C:7]([CH3:10])[NH:8][CH:9]=1)=[O:4].[OH-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[C:7]([CH3:10])[N:8]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:9]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1c[nH]c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(C)c1C
Temperature: 7.5 °C
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2,3-dimethyl-1H-pyrrole-4-carboxylic acid methyl ester (Heterocycles 1977, 7, 77) (7.95 g, 51.9 mmol) in THF (160 mL) was added dropwise 50% NaOH (80 mL). The reaction mixture was stirred for 5 minutes and then a solution of p-toluenesulfonyl chloride (11.87 g, 62.3 mmol) in THF (160 mL) was added dropwise to the stirred mixture at room temperature. The mixture was stirred at room temperature for 30 minutes then cooled to 5 to 10° C. and treated dropwise with water (200 mL). The THF was evaporated in vacuo and the aqueous residue was thoroughly extracted with CH2Cl2. The organic extract was washed, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give the required compound (13.6 g, 85%) as a pale yellow solid, m.p. 108°-114° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:41][CH:40]([OH:42])[CH2:39][NH:38][CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:41][CH:40]([OH:42])[CH2:39][NH:38][CH2:37][CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: OC1CNCCNC1
Product: O=C1N=C(N2CCNCC(O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and [1,4]Diazepan-6-ol following General Procedure B.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.CN(C)C=O.Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1>CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:10][N:9]=1
Reactant: Oc1ccc(F)nc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(OCCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add cesium carbonate (3 Eq, 53.05 mmoles; 17.2 g) to a solution of 2-fluoro-5-hydroxypyridine (2.0 g, 1.00 Eq, 17.68 mmoles) in dimethylformamide (0.3 M; 762.37 mmoles; 59.0 mL), followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (17.7 mmoles, 3.7 g) and stir at room temperature overnight. Transfer to a separatory funnel and add EtOAc (500 mL). Wash organic layer, wash with water (300 mL) followed by brine (200 mL). Dry over Na2SO4, filter and concentrate. Purify the crude mixture by HPLC eluting with hexanes/EtOAc 7/3 to give 2-fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine as a pale yellow oil (3.9 g, 16.2 mmoles; 91% yield). LCMS (Low) rt=1.8 min., M+1=242.