Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16](=[O:24])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH:9]1[CH2:25][OH:26])=O)(C)(C)C.C(OCC)(=O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[OH:26][CH2:25][CH:9]1[CH2:10][CH:11]([C:14]2[NH:15][C:16](=[O:24])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3ccccc3c(=O)[nH]2)CC1CO
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(C2CCNC(CO)C2)cc2ccccc12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The obtained 3-(1-t-butoxycarbonyl-2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one (616 mg) was dissolved in ethyl acetate, and 4N hydrogen chloride-ethyl acetate solution (2.0 ml) was added to the solution, and the mixture was stirred at room temperature for 6.5 hr. The reaction mixture was concentrated, and the precipitated crystals were washed with diethyl ether and dried under reduced pressure to give 3-(2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (433 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>>[N:18]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1cc(-n2cccn2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (74 mg, 0.285 mmol) and pyrazole (28 mg, 0.425 mmol) similar to Example 166 and was isolated as a white solid (mp 151–152° C., 67 mg, 0.230 mmol, 81%). 1H NMR (CDCl3) 9.71 (s, 1H), 8.77 (m, 3H), 8.19 (s, 1H), 7.88 (m, 1H), 7.47 (m, 1H), 6.61 (dd, J=1.5, 2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:51]([O:55][C:56]([C:58]1[C:59]2[CH2:67][CH2:66][CH2:65][CH2:64][C:60]=2[S:61][C:62]=1[NH2:63])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.C(Cl)Cl>[C:51]([O:55][C:56]([C:58]1[C:59]2[CH2:67][CH2:66][CH2:65][CH2:64][C:60]=2[S:61][C:62]=1[NH:63][C:13](=[O:15])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Yield: 75.1 %

Procedure:
(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetic acid (638 mg, 2.57 mmol) was suspended in a solution of DCM (10 mL) and DMF (1 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.17 g, 3.08 mmol) and N,N′-diisopropylethylamine (537 μL, 3.08 mmol) added, followed by 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid tert-butyl ester (651 mg, 2.57 mmol). The resultant mixture was stirred at RT overnight. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography using DCM as eluent, to afford the title compound as a yellow solid (0.93 g, 1.93 mmol, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6](=C=O)[C@@H:7]([C:19](=O)[NH2:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:9]([NH:8][CH:7]([C:19]#[N:20])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CCOC(=O)CC(=C=O)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)CCC(C#N)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a suspension of 21.45 g of N-carbobenzoxy-carbonyl-L-isoglutamine ethyl ester in 200 mL of dry tetrahydrofuran kept at 0° C. to -5° C. in an ice-bath 11.82 mL of pyridine is added. To the above solution 9.84 mL of trifluoroacetic anhydride in 100 mL of tetrahydrofuran is added dropwise at such a rate that the bath temperature is maintained. The solution is stirred for 2 hours at this temperature. The solution is evaporated to dryness and the oil is dissolved in ethyl acetate. The organic layer is washed with 1.0N hydrochloric acid and sterile water. The solution is dried and evaporated in vacuo to give; an oil to give 14.8 g of ethyl γ-(N-carbobenzoxy)amino-γ-cyanobutanoate, 17.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([N:21]3[CH2:26][CH2:25][CH:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.[BH4-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([C:15]2[C:16]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]([OH:29])[CH3:28])[CH2:23][CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:14]1
Reactant: CC(=O)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanone (96.75 mg, 0.25 mmol) in MeOH (10 mL) was added NaBH4 (37 mg, 1 mmol). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the product (racemic)-1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol (76 mg, 0.20 mmol, yield 78%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN1CCOCC1.[CH3:34][N:35]([CH3:52])[C:36]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:40][C:39](=[CH:42][C:43](O)=[O:44])[CH2:38][CH2:37]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH:21]1[CH2:26][CH2:25][N:24]([C:43](=[O:44])[CH:42]=[C:39]2[CH2:38][CH2:37][C:36]([N:35]([CH3:52])[CH3:34])([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:41][CH2:40]2)[CH2:23][CH2:22]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
1-hydroxybenzotriazole (405 mg, 3.0 mmole), 5-chloro-3-piperidine-4-yl-1H indole (352 mg, 1.5 mmole) and N-methylmorpholine (0.333 ml, 3.0 mmole) were added in succession under argon to a solution of (4-dimethylamino-4-phenylcyclohexylidene)-acetic acid (444 mg, 1.5 mmole) in dry dimethylformamide (10 ml). The solution was cooled in an ice bath and dicyclohexylcarbodiimide (618 mg, 3.0 mmole) was added. The reaction mixture was stirred for 7 days at RT, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Oily products thereupon precipitated out, which could not be separated by filtration. The reaction mixture was extracted with DCM (3×50 ml), water (300 ml) and 5M sodium hydroxide (7 ml, 35 mmole) were added to the aqueous phase, and the whole was kept for 16 hours at 5° C. 1-[4-(5-chloro-1H-indol-3-yl)piperidine-1-yl]-2-(4-dimethylamino-4-phenylcyclo-hexylidene)-ethanone thereupon precipitated out as a yellow solid (167 mg, 23%) with an m.p. of 115°-119° C.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])=[CH:7][CH:6]=1)([O-])=O>O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCS2(=O)=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCCS2(=O)=O)cc1

Procedure:
1.0 g of water-moist Raney nickel is added to a solution of 2.60 g (10.7 mmol) of 2-(4-nitrophenyl)isothiazolidine 1,1-dioxide in 50 ml of tetrahydrofuran, and the mixture is hydrogenated at room temperature. The catalyst is filtered off, and the filtrate is evaporated, giving 2-(4-aminophenyl)isothiazolidine 1,1-dioxide as a brownish solid; ESI 213.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[C:10]([Mg]Cl)#[CH:11].S(=O)(=O)(O)O>O1CCCC1>[CH3:6][C:5]([OH:7])([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][CH3:9])[C:10]#[CH:11]
Reactant: C#C[Mg]Cl
Reactant: CCC(C)CCC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C#CC(C)(O)CCC(C)CC
Yield: 93 %

Procedure:
128 g (1 mole) of 5-methyl-heptan-2-one are added in the course of 1 hour, with stirring, to 1 liter of a 1.1 molar solution of ethynyl-magnesium chloride in tetrahydrofuran at 10° C. After allowing about a further hour's reaction, the mixture is worked up. To do so, 2 N sulfuric acid is added, whilst cooling with ice, until two clear phases are present. The organic phase is then separated off and washed neutral with water, if necessary, and the tetrahydrofuran is distilled off at 50° C./67 mbar. The residue is subjected to fractional distillation. 143 g of main fraction, boiling at 50°-52° C./0.01 mbar, are obtained; nD25 =1.4411. This corresponds to a yield of 93%. Scent: predominantly floral, woody, herbal, minty with a spicy, slightly animal after-scent.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[OH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:18]([O:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=2)=[O:19])[CH2:5][CH2:4]1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
To a solution of 4-hydroxypiperidine hydrochloride (3.0 g, 21.8 mmol) in a mixture of methylene chloride (90 ml) and pyridine (15 ml) were added chloroformic acid p-nitrobenzyl ester (15.4 g, 72.0 mmol) and triethylamine (13.1 ml, 93.8 mmol) in an ice bath. The mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, yield 48%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3C[CH2:21][CH2:20][N:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1CCNC1=O>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:21][CH2:20][N:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=C1NCCN1
Product: Cc1cc2nc(N3CCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxoimidazolidin-1-yl)benzo[d]thiazol-6-yl)acetic acid (1.3 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid except using imidazolidin-2-one instead of tetrahydropyrimidin-2(1H)-one. LCMS-ESI+: calc'd for C31H30ClN5O4S: 604.2 (M+H+); Found: 604.2 (M+H+); 1H-NMR 400 MHz, (CD3OD) δ 7.99 (s, 1H), 7.82 (m, 1H), 7.66 (m, 1H), 7.60-7.48 (m, 5H), 7.42 (m, 1H), 5.21 (s, 1H), 4.33 (m, 1H), 4.22 (m, 2H), 4.06 (s, 3H), 3.64 (m, 1H), 2.55 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH2:13][S:12][CH2:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)NC1=C(CSC1)C(=O)N2
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc2c(cc1C)Nc1cscc1C(=O)N2
Reaction time: 8 h

Procedure:
To a slurry of 18.8 g. of 6,7-dimethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 150 ml. of pyridine, stirred in an ice bath, is added 10.1 g. of N-chlorosuccinimide portionwise over 15 minutes. The mixture is heated on a steam bath for 30 minutes, poured into one liter of water and allowed to stand overnight. The solid is filtered, washed with water, 1 N hydrochloric acid, three times with water and diethyl ether and dried giving the desired final product, mp. 233°-238° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[C:7]([CH2:12][CH2:13][CH2:14][OH:15])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][C:52](Cl)=[O:53])=[O:44])[CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])([CH3:29])([CH3:28])[CH3:27].S(=O)(=O)(O)O>C(OCC)C>[C:26]([C:30]1[CH:31]=[C:32]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][C:52]([O:15][CH2:14][CH2:13][CH2:12][C:7]2[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[OH:16])=[O:53])=[O:44])[CH:33]=[C:34]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:35]=1[OH:36])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(CCC(=O)OCCCSCCC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Cc1cc(CCCO)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1cc(CCCOC(=O)CCSCCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c(C(C)(C)C)c1
Yield: 66.7 %

Procedure:
Into a 50 ml reactor were charged 3.40 g (15.29 mmol) of 3-(3-tert-butyl-2-hydroxy-5-methylphenyl)-1-propanol, 20 ml, of diethyl ether and 1.94 g (16.00 mmol) of N,N-dimethylaniline. The atmosphere in the reactor was replaced with dry nitrogen. To the reactants was added dropwise 7.09 g (16.00 mmol) of 3-[3-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxy]propylthio]propionyl chloride. The reactants were heated and refluxed for 6 hours in the nitrogen stream. After the completion of the reaction, diethyl ether was added and the reaction product was neutralized with 10% sulfuric acid. After liquid separation, washing with saturated aqueous solution of sodium chloride and dehydration with anhydrous sodium sulfate, the organic solvent was removed under reduced pressure. After separation by silica gel chromatography (solvent: chloroform), 6.42 g (10.20 mmol) of the desired product was obtained. The yield was 67%. The physical properties of the product are shown below.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(O)C.C(=O)([O-])O.[Na+]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(Br)cc2)nc2ccccn12
Yield: 37.1 %

Procedure:
Dissolving 4.3 g (16 mmol) of 2,4′-dibromopropiophenon obtained and 1.4 g (15 mmol) of 2-aminopyridine into 50 milliliter of ethanol, adding 1.9 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Washing the organic layer with water, it was dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant syrup was refined by silica gel column chromatography thereby obtaining 1.6 g of 2-(4-bromo-phenyl)-3-methyl-imidazo [1,2-a] pyridine (yield: 37%).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1.[OH-].[Li+].C(OCC)(=O)C.Cl>C1COCC1>[Br:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH:7]=[C:6]2[O:5][CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)COc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(Br)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(OCC(=O)O)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
[5-Bromo-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yloxy]-acetic acid methyl ester (22, 32.0 mg, 0.007 mmol) was dissolved in THF (1.50 mL) and 1M lithium hydroxide (0.4 mL) was added to this solution. After stirring for 30 min at 25° C., ethyl acetate was added and the mixture was acidified with 1M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain a white solid (23, 28 mg, 90% yield). MS(ESI) [M−H+]−=438.0; 440.0.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.7 ml of chloroacetyl chloride was dropwise added to a solution of 3.0 g of aniline hydrochloride and 7 ml of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then washed with water and a saturated aqueous sodium hydrogencarbonate solution in this order, and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from ethyl acetate-n-hexane to obtain 2.45 g of N-(2-chloroacetyl)aniline as a light brown solid. A suspension of 2.45 g of the N-(2-chloroacetyl)-aniline, 2.8 g of 4-methoxymethoxypiperidine, 2.45 g of sodium iodide and 2.3 ml of triethylamine dissolved in 30 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was diluted with ethyl acetate. The dilution was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate: n-hexane=1:1) to obtain 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine as a lightyellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=3)=[C:15]3[N:10]([CH2:11][O:12][CH2:13][CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:30][CH:27]([CH3:29])[CH3:28])[N:18]=3)=[C:15]3[N:10]([CH2:11][O:12][CH2:13][CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCOC3)n1
Reactant: CC(C)N
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCOC3)n1

Procedure:
A solution of 2-(4-fluorophenyl)-4,5-dihydro-3-[2-(methylsulfonyl)-4-pyrimidinyl]-7H-pyrazolo[1,5-c][1,3]oxazine (i.e. the product of Step E) (0.15 g, 0.4 mmol) and isopropylamine (0.95 g, 16 mmol) in 2.5 mL of chloroform in a sealed tube was heated in a microwave reactor for 1 h at 120° C. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography using 0-100% ethyl acetate in hexanes as eluant to give 100 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([OH:24])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:33][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.5 g 4-{2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 23 ml DMF were added 1.87 g benzyl bromoacetate and 5.31 g cesium carbonate. After stirring at room temperature for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4 w/w), 0.1 M HCl and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the following reactions. Yield: 3.6 g
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]3([O:15][CH:8]3[C:7]=2[CH:16]=1)O)#[N:2].[CH2:17]([NH2:20])[CH2:18][NH2:19]>C(O)C>[NH2:19][CH2:18][CH2:17][NH:20][C@@H:8]1[C:7]2[CH:16]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:12])([CH3:13])[C@H:9]1[OH:15]
Reactant: NCCN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21O
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCCN)[C@@H]1O
Yield: 77.8 %

Procedure:
A mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-3-ol (0.927g) and ethylenediamine (2.78g) was heated under reflux in ethanol (70 ml) for 16 h. The solvent was evaporated in vacuo and the residue column chromatographed (Kieselgel 60, gradient elution: 0-9% 880 ammonia-methanol) giving the title compound (0.868g) as a foam.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5]Cl)[CH2:3][Cl:4].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[CH2:9]([O:8][P:7]([CH2:5][C:2](=[CH2:1])[CH2:3][Cl:4])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: C=C(CCl)CCl
Product: C=C(CCl)CP(=O)(OCC)OCC
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
34 parts by weight of 2-methylene propane-1,3-dichloride are heated to 135°C, after which 30 parts by weight of triethyl phosphite are added dropwise with stirring, Ethyl chloride distills off continuously during the dropwise addition. On completion of the dropwise addition, the reaction temperature is increased slowly to 180°C. After 3 to 4 hours at 180°C, the evolution of ethyl chloride is at an end and the reaction is over. The excess dihalide is distilled off in a water-jet vacuum. The resulting 1-chloro-2-methylene propane-3-phosphonic acid diethyl ester is distilled off in a high vacuum.