Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[O:15][CH3:16])=[C:5]([CH3:7])[N:6]=1.C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:26]([NH2:25])=[S:27])=[CH:10][C:9]=2[O:15][CH3:16])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1-c1sc(C)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(N)=S)ccc1-c1sc(C)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenylamine (100 mg, 0.43 mmol) in tetrahydrofurane (4 mL) was added drop wise under stirring and under an atmosphere benzoyl isothiocyanate (63.6 ul, 0.45 mmol). The reaction was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (177 mg, 1.28 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (90 mg, 72%). MS ISP (m/e): 294.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.81 (s, 1H, NH), 7.35 (s, 1H), 7.21 (d, 1H), 7.01 (s, 1H), 3.76 (s, 3H), 2.59 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:20])=[CH:22][CH:23]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1nc2ccccc2s1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-1,3-benzthiazole (40 mg, 0.27 mmol) in methylene chloride (1 ml) and pyridine (100 μl) was treated with 4-n-butylbenzoyl chloride and stirred at 25° C. for 30 minutes. After this time, the reaction was treated with NaOH (0.5 ml, 5.0 M) and the resulting mixture stirred overnight. The resulting precipitate was collected by filtration and recrystallized from water to give 2-(4-n-butylbenzamido)-1,3-benzthiazole as pale yellow needles. (47 mg, 53%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: Brc1cnc2ccnn2c1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: c1ccc(-c2nn3c(c2-c2cnc4ccnn4c2)CCC3)nc1
Yield: 26.2 %

Procedure:
To a microwave tube, add 6-bromo-pyrazolo[1,5-a]pyrimidine (0.175 g, 0.884 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (0.25 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol), 2M aqueous potassium carbonate (0.5 mL, 1.0 mmol) and dimethylsulfoxide (1.5 mL). Irradiate the reaction in a microwave reactor set at 110° C., 50 Watts, 10 min with external cooling. Dilute the reaction mixture with diethyl ether (250 mL) and extract the product into 0.1M aqueous hydrochloric acid (450 mL). Make the aqueous solution basic by adding 5M aqueous sodium hydroxide (25 mL) and extract with dichloromethane (300 mL). Filter the organic layer and concentrate under reduced pressure. Recrystallize the resulting solid from ethyl acetate, filter, rinse with ethyl acetate, and dry at 100° C. under vacuum to obtain 70 mg (26%) of the title compound as a tan solid. MS (electrospray, m/z) 302.9 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.Cl.[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.CCOC(C)=O>[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=CC1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2CC2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (0.19 g, 3.02 mmol) and tetrahydro-pyran-4-carbaldehyde (0.26 g, 2.26 mmol) is added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.4 g, 1.51 mmol) in DMF (5.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 364 [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:20][C:5]2[CH2:6][N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.NC1SC2CN(C(OCC3C=CC=CC=3)=O)CCC=2C=1C(=O)C1C=CC=CC=1>>[NH2:1][C:2]1[S:20][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(C(=O)OCc1ccccc1)C2
Agent: Nc1sc2c(c1C(=O)c1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2

Procedure:
The procedure of Example 8 was followed except that a corresponding amount of 2-amino-3-(4-chloro-benzoyl)-6-benzyloxycarbonyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, prepared as in Example 9, was used in place of 2-amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: [N:1]#[C:2]Br.[I:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:10]N)=[O:9].[OH-].[NH4+:16]>CO>[NH2:16][N:1]1[CH2:2][N:10]=[C:8]([C:7]2[CH:12]=[CH:13][CH:14]=[C:5]([I:4])[CH:6]=2)[O:9]1
Reactant: NNC(=O)c1cccc(I)c1
Reactant: N#CBr
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NN1CN=C(c2cccc(I)c2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyanogen bromide (1.06 g, 10.0 mmol) in 10 mL of methanol was added dropwise to an ice-cold suspension of 3-iodobenzhydrazide (2.62 g, 10.0 mmol, Intermediate 7, Step A) in 20 mL of methanol. After 30 min, the mixture was allowed to warm to room temperature and was then warmed at reflux for 1.5 h. The resultant solution was cooled to 0° C., and neutralized to pH 9 with concentrated aqueous ammonium hydroxide. The resultant precipitate was collected, washed with methanol, and dried in vacuo to afford the product as an off-white powder. LC/MS 288.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=O.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH3:12])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C(=O)O)c1ccccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)N1CCN(Cc2ccccc2)CC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
2-(2-Fluorophenyl)propanoic acid (7.7 g, 0.046 mol), 1-benzylpiperazine (8.0 g, 0.045 mol), triethylamine (4.6 g, 0.046 mol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (9.6 g, 0.050 mol) were dissolved in dichloromethane (150 ml) and stirred at room temperature for 18 h. The solution was evaporated and the residue diluted with water and extracted with brine, dried and evaporated. Chromatography on silica gel with dichloromethane-methanol (97:3) yielded 4-benzyl-1-[2-(2-fluorophenyl)propanoyl]piperazine (5.54 g, 38%) as an oil.
Reaction SMILES: [OH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[CH2:12](O)[CH3:13]>>[OH:1][C:2]1([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(O)CCNCC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The 4-hydroxypiperidine-4-carboxylic acid (118 mg) obtained in the step (a) of Example 68 was dissolved in 1 N hydrochloric acid/ethanol (5 ml) solution, and the resulting solution was stirred at room temperature for 17 hours and then under reflux for 6 hours. The reaction mixture was concentrated to obtain crude ethyl 4-hydroxypiperidine-4-carboxylate. This crude ethyl 4-hydroxypiperidine-4-carboxylate was used in the following reaction without purification.
Reaction SMILES: [C:1]1([CH3:9])[C:2](C=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:10]([CH2:12][C:13]([OH:15])=[O:14])#[N:11].[C:16](O)(=O)C.C([O-])(=O)C.[NH4+]>C(O)C>[C:10]([C:12](=[CH:9][C:1]1[CH:6]=[CH:5][C:4]([CH3:16])=[CH:3][CH:2]=1)[C:13]([OH:15])=[O:14])#[N:11]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C=O
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
Tolualdehyde (400 g), cyanoacetic acid (311 g), acetic acid (60 ml) and ammonium acetate (25.6 g) were refluxed in ethyl alcohol (1.6 l) for 4 hours with heating. After the reaction, the mixture was concentrated to 600 ml by removing ethyl alcohol under a reduced pressure, followed by pouring into 1 liter of ice water to separate crystals. The separated crystals were collected by suction filtration and recrystallized from 2 liters of ethyl alcohol to obtain 560 g of 2-cyano-3-(4-methylphenyl)acrylic acid which melted at 210° to 215° C. The resulting compound (320 g) and thionyl chloride (252 g) were dissolved in acetonitrile (200 ml) with heating for 1 hour. After the reaction, the acetonitrile and the thionyl chloride were distilled off under a reduced pressure, and the resulting solid was added to a solution consisting of hydroxyethyl methacrylate (244.8 g), pyridine (149 g) and acetonitrile (2 l). The reaction was carried out for 2 hours while keeping the reaction temperature below 40° C. After the reaction, the reaction solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized from ethyl alcohol (3 l) to obtain 360 g of the desired compound which melted at 74° to 75° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1.[SH:23][C:24]1[NH:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[CH3:9][C:8]1[C:3]([CH2:2][S:23][C:24]2[NH:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CO
Reactant: Sc1nc2ncccc2[nH]1
Product: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CSc1nc2ncccc2[nH]1

Procedure:
The same reaction as in Example 1 was carried out using 2-hydroxymethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine in place of 2-hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine and 2-mercaptoimidazo[5,4-b]pyridine in place of 2-mercaptobenzimidazole to give 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)imidazo[5,4-b]pyridine as crystals, melting point 180° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:16])[N:37]([O:38][CH3:39])[CH3:36])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Reactant: CNOC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 72 h
Yield: 88069.2 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (14 g, 0.0573 mol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (10.06 g, 0.0573 mol) and N-methyl morpholine (5.79 g, 0.0573 mol) in tetrahydrofuran was stirred for 2 hours at room temperature. N,O-Dimethylhydroxylamine hydrochloride (5.59 g, 0.0573 mmol) and triethylamine (5.59 g, 0.0573 mol) were added and the mixture was stirred for 3 days. The reaction mixture was evaporated and ethyl acetate was added. The reaction mixture was washed with 1 N aqueous hydrochloric acid and then washed with saturated aqueous sodium bicarbonate. [4-(Methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (14.5 g, 88%) was obtained as a tan tar after drying (magnesium sulfate) and evaporation.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:24][C:10]=13)[CH2:2]2.CCN(CC)CC.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][OH:50]>C(Cl)Cl>[OH:50][CH2:49][CH2:43][O:42][C:41](=[O:47])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1)OCCO
Reaction time: 0.02 h

Procedure:
4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (7.96 g) from the previous step was reacted in 0.5 g portions. Into a 50 mL round-bottomed flask with stopper and magnetic stir bar was added amine (0.5 g) and methylene chloride (7.5 mL). With good stirring Et3N (0.5 mL) was added, followed by a clear, colorless solution of triphosgene (0.22 g) in methylene chloride (2.5 mL). After 1 min at room temperature, an aliquot of the reaction mixture was diluted in MeOH to form the methyl carbamate. Analysis by HPLC indicated methyl carbamate peak with a retention time of 2.315 min (91%) and an amine starting material peak with a retention time of 1.650 (1.9%). After 8 min total reaction time ethylene glycol (1.38 mL) was added at once. The cloudy solution turned into a clear, yellow solution. Stirring at room temperature continued for 75 min, at which time HPLC analysis indicates a new peak with a retention time of 2.032 min (88%). The 32 0.5 g runs were combined and the combined product was divided into two portions. Each portion was diluted with methylene chloride (400 mL), and washed with water (4×100 mL), dried with brine (100 mL), and then dried over Na2SO4. Concentration under reduced pressure and combination of the two portions gave 8.77 g of 83.3% pure material. This was triturated with methylene chloride to give 1.2 g of {4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-carbamic acid 2-hydroxy-ethyl ester. Repeated chromatography of mother liquors with gradient of 0-5% MeOH in methylene chloride gave an additional 5.6 g of desired product, for a total of 6.8 g (70%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[C:21]12([C:31](O)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/2=[N:8]\[C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(N)sc1C
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(Cc2ccc(C(C)(C)C)cc2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, 1-bromomethyl-4-tert-butylbenzene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.24 (s, 9 H) 1.54-1.73 (m, 6 H) 1.82 (d, J=2.50 Hz, 6 H) 1.92-2.01 (m, 3 H) 2.10 (s, 3 H) 2.13 (s, 3 H) 5.39 (s, 2 H) 7.19 (d, J=8.42 Hz, 2 H) 7.36 (d, J=8.42 Hz, 2 H); MS (ESI) m/z 437 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6])([O-:14])=[O:13]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g of 3-fluoro-4-methyl-benzoic acid are initially introduced into 100 ml of concentrated sulphuric acid, and a mixture consisting of 26 g of 98% strength nitric acid and 40 g of concentrated sulphuric acid is added dropwise at 20°-25°, while cooling with ice. The mixture is subsequently stirred at room temperature for 1 hour. The batch is then poured onto ice-water and the crystals are filtered off with suction and washed thoroughly with water. After drying and recrystallization from toluene, 48 g (74.3% of theory) of 2-nitro-4-methyl-5-fluorobenzoic acid of melting point m.p.: 163°-5° C. are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)=[O:28]
Reactant: COCCOCC(=O)O
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCCOCC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 0.045 ml 2-(2-methoxyethoxy)acetic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The reaction mixture is quenched with 3 ml water and 5 ml dichloromethane. The organic phase is separated, the water phase extracted with 2 ml dichloromethane. The combined organic phases are dried and evaporated. 335 ml of yellow oil is obtained, which is further purified by preparative HPLC-methods.
Reaction SMILES: B(Br)(Br)Br.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[N:6]1.C([O-])(O)=[O:15].[Na+].[Na+].[Cl-].CCCCCC.[C:27](OCC)(=[O:29])[CH3:28]>ClCCl.O>[CH2:27]([O:29][C:7]1[C:8]2[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=2[O:5][N:6]=1)[CH3:28]
Reactant: CCOC(C)=O
Reactant: O=C([O-])O
Reactant: c1ccc2oncc2c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: CCOc1noc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron tribromide (1.0M solution in dichloromethane; 1.39 ml, 1.39 mmol) was added to a stirred, −78° cooled solution of benzisoxazole from part © (179 mg, 928 μmol) in dichloromethane (4 ml) under an argon atmosphere. The reaction mixture was gradually warmed to room temperature over approx. 2 hours, and stirred overnight. Tlc (silica, 2:1 hexane/ethyl acetate) showed new polar material as well as unreacted starting material. The reaction was worked up by adding water (5 ml) and ice. The aqueous phase was neutralised by addition of saturated NaHCO3 solution, and saturated with NaCl. The aqueous phase was extracted into dichloromethane (3×60 ml), then the organic extracts combined and washed with brine (10 ml) and dried (NaSO4). The product was purified by chromatography on silica (18 g; eluent 2.5%, 5%, then 15% ethyl acetate/hexane). The first compound to elute was unreacted 3-ethoxy-6-methoxy-1,2-benzisoxazole, (46 mg), followed by 3-ethoxy-6-hydroxy-1,2-benzisoxazole 108 mg (65%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[CH:10]=[C:11]([CH3:13])[CH3:12]>CCOCC>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][P:14]([O:15][CH3:16])(=[O:19])[O:17][CH3:18]
Reactant: COP(=O)(CC=C(C)C)OC
Reactant: Oc1cccc(O)c1
Solvent: CCOCC
Product: COP(=O)(CCC(C)(C)c1ccc(O)cc1O)OC

Procedure:
55.0 parts of resorcinol, 17.8 parts of dimethyl prenylphosphonate and 5.0 parts of Fulmont 23 (trademark) are stirred at 125° C. for 18 hours. The cooled reaction mixture is then diluted with ether, filtered free of catalyst, and poured into 500 parts of water. The oil which separated out is then washed by decantation with water and extracted with ether. Following further washes with sodium bicarbonate solution and water, the ether solution after concentration yields dimethyl 3-(2,4-dihydroxyphenyl)-3-methyl-butane-phosphonate, m.p. 142°-3° C., with the following percentage composition by weight.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH:8]1(CC(O)=O)[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH:13]=[CH:12][CH:11]=[C:10]3C1.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(Cl)Cl>[CH:7]1([CH2:6][NH2:3])[C:10]2=[C:19]3[C:14](=[CH:13][CH:12]=[CH:11]2)[CH:15]=[CH:16][CH:17]=[C:18]3[CH2:8]1
Reactant: O=C(O)CC1Cc2cccc3cccc1c23
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: NCC1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 250 ml three-necked flask, triethylamine (3.49 ml, 2.50.10−2 mol, 1.15 eq.) is added dropwise to a solution, cooled to 0° C., of the acid obtained in Step D (4.62 g, 2.18. 10−2 mol) in a mixture of acetone (95 ml) and water (5.4 ml). Ethyl chloroformate (2.71 ml, 2.83.10−2 mol, 1.30 eq.) is then slowly added at 0° C.; evolution of gas is visible. The mixture is stirred at 0° C. for 30 minutes; after it has been established, on TLC (CH2Cl2), that the starting material has disappeared, a solution of sodium azide (1.89 g, 2.83.10−2 mol, 1.30 eq.) in water (9.2 ml) is added at 0° C. The mixture is maintained at that temperature for one hour. The mixture is poured into an ice/water mixture and is then extracted with ether. The ethereal phases are washed with water, then dried over Na2SO4 and evaporated in vacuo without heating. The acyl azide is taken up in 50 ml of anhydrous toluene and then heated at 80° C. until nitrogen is no longer evolved. After evaporating off the toluene, the oil corresponding to the isocyanate is heated at 100° C. together with a 20% hydrochloric acid solution (52 ml) for 3 hours; the mixture is stirred for one night at ambient temperature. The reaction mixture is diluted with water, filtered through filter paper and extracted with ether. The aqueous phase of pH=1 is rendered basic using solid sodium carbonate and is then extracted three times with dichloromethane. The combined organic phases are washed with water and dried over K2CO3. After evaporating off the solvent under reduced pressure, the amine is obtained in the form of an oil (820 mg). The solid, having been filtered and taken up in dichloromethane, is treated in the same manner as the filtrate. The amine so obtained is converted into the hydrochloride after being solubilised in ether and treated with a 4N ethereal hydrogen chloride solution. After drying, the title product is obtained in the form of a white solid.