Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCC1C=CC(CC[O:11]C2C=CC(CC3SC(=O)NC3=O)=CC=2)=NC=1.Cl.C(O)[C@H]1[O:33][C@H:32]([O:34][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:31]([OH:46])[C@@H:30](O)[C@@H:29]1[OH:48]>>[C:32]([OH:33])(=[O:34])[CH:31]([CH2:30][C:29]([OH:48])=[O:11])[OH:46]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: Cl
Product: O=C(O)CC(O)C(=O)O

Procedure:
Compound A (24.8 g), sucrose (Osaka-Toka. Co., Ltd., 28.7 g), crystalline cellulose (Avicel PH-101, Asahi Kasei Corporation, 8.0 g) and L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd., 12.5 g) were thoroughly mixed to give a dusting powder. Malic acid crystal (Wako Pure Chemical Industries, Ltd.) was sieved with a round sieve to give malic acid crystal on 30 mesh (aperture 0.50 mm). The malic acid crystal (150 g) was fed into a centrifugal fluidized-bed granulator (CF-mini, Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution (6 w/v %) of hydroxypropylcellulose (HPC-SL, NIPPON SODA CO., LTD.). The obtained spherical granules were dried under reduced pressure in a constant temperature vacuum drying oven (DP43, YAMATO SCIENTIFIC CO., LTD.) at 40° C. for 16 hr, and sieved with a round sieve to give granules at the range of 16-30 mesh (aperture 0.50-1.00 mm). The granules (450 mg) were filled in No. 0 gelatin capsules (Capsugel) to give capsules having the following composition per capsule.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(C)O
Reactant: BrCc1ccc(I)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)OCc1ccc(I)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a suspension of sodium hydride (55% in liquid paraffin) (315 mg, 7.3 mmol) in THF (2 ml) was dropped a solution of methyl 2-hydroxyisobutyrate (0.84 g, 7.1 mmol) in THF (2 ml). The reaction mixture was stirred for 30 minutes at 60° C. Thereto was dropped a solution of 4-iodobenzyl bromide (2.0 g, 6.7 mmol) in THF (4 ml) at 60° C. The mixture was stirred for 5 hours at 60° C. Therein were added ethyl acetate and a saturated ammonium chloride solution. After stirring for 5 minutes the mixture was separated by a separating funnel. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (1.93 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28]([N:6]([CH2:5][C:4]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2Cl)c(OC)c1
Yield: 21.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150 mg, 0.611 mmol) prepared in Example 14a, 2-Chloro-4,5-difluorobenzenesulfonyl chloride (302 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (58.8 mg, 21%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:17]O>O1CCCC1.[Pt]>[CH2:10]([N+:8]([O-:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCN(C)CCCCCCC
Reactant: OO
Agent: [Pt]
Solvent: C1CCOC1
Product: CCCCCCC[N+](C)([O-])CCCCCCC
Temperature: 25 °C

Procedure:
To a solution of 6.6 g of diheptylmethyl amine in 25 ml tetrahydrofuran (THF) was added 12 ml 30% hydrogen peroxide. The reaction mixture was refluxed for 24 hours, cooled to room temperature and then stirred with 0.2 mg platinum black overnight. After filtering the reaction mixture through Hyflo® filter-aid, the THF was removed in vacuo. The aqueous solution was extracted with 100 ml ether. The aqueous portion of the extraction was allowed to stand for several days to allow most of the water to evaporate. The resulting solution was found to be 40% water and 60% diheptylmethyl amine oxide by NMR analysis.
Reaction SMILES: [H-].[K+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[C:13]([N+]([O-])=O)=[C:14]([CH:21]=[CH:22][CH:23]=1)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[CH3:11][C:12]1[C:13]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:14]([CH:21]=[CH:22][CH:23]=1)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: SCc1ccccc1
Reactant: Cc1cccc(C(=O)OC(C)C)c1[N+](=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)OC(C)C)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of dry tetrahydrofuran (125mL) and 35% potassium hydride in oil (6.3 g) was slowly added benzyl mercaptan (6.1 mL) at 0° C. under an inert atmosphere. After 15 minutes, 3-methyl-2-nitrobenzoic acid, 1-methylethyl ester (11.23 g) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between 6N sodium hydroxide (25 mL) and ethyl acetate (150 mL). The organic phase was dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel eluted with 5% ethyl acetate in hexanes to give 13.7 g of the title compound as a yellow oil, nD 1.5642.
Reaction SMILES: CS(O[CH2:6][C:7]([F:19])([F:18])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.CN(C=O)C.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K]>O>[CH2:11]([O:10][CH2:9][CH2:8][C:7]([F:19])([F:18])[CH2:6][N:29]1[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC(F)(F)CCOCc1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CCOCc1ccccc1
Temperature: 120 °C

Procedure:
The compound 1-methanesulfonyloxy-2,2-difluoro-4-benzyloxybutane (21.8 g 74.1 mM), dry DMF (100 mL), and potassium phthalimide (15.26 g, 10% excess) are stirred and heated under nitrogen, at 120° C. for 5 days. Following the addition of water (500 mL), the mixture is extracted with ether. The organic phase is washed with 1N CCl followed by water (twice), dried (Na2SO4) and concentrated to a volume of about 100 mL. Upon addition of petroleum ether, crystallization occurs. After chilling for 3 hours at 5° C., beige crystals of the compound N-(4-benzyloxy-2,2-difluorobutyl)phthalimide are obtained, filtered and washed with petroleum ether: 18 g (70%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10][NH2:11].[CH3:12][Si:13]([CH3:32])([CH3:31])[CH2:14][CH2:15][O:16][CH2:17]N1C2=NC=CC=C2C=C1C(OC)=O.Cl.S1C2C=CN=CC=2C=C1CN>>[CH3:12][Si:13]([CH3:32])([CH3:31])[CH2:14][CH2:15][O:16][CH2:17][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10][NH2:11]
Reactant: COC(=O)c1cc2cccnc2n1COCC[Si](C)(C)C
Reactant: NCc1cc2cccnc2[nH]1
Agent: Cl
Agent: NCc1cc2cnccc2s1
Product: C[Si](C)(C)CCOCn1c(CN)cc2cccnc21

Procedure:
Intermediate H′ was prepared from methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H′-1) following similar procedures for synthesizing intermediate D from D-2, as described above. MS (m/z): 278 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C@H:9]1[CH2:32][O:31][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C@H:9]1[CH2:32][O:31][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@H:21]([OH:23])[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3
Yield: 82.6 %

Procedure:
A mixture of the product from step A (2.60 g, 4.41 mmol) and a solution of tetrabutylammonium fluoride (1 M, 1.52 mmol) in THF (3 mL) was stirred at ambient temperature overnight, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. The extract was purified by chromatography (silica, gradient 10% to 40% ethyl acetate in hexane) to give an oil (1.32 g, 82%): LCMS (+APCI) m/z 363 (M+H).
Reaction SMILES: [N:1]1([C:7](=[O:23])[CH2:8][CH:9]([CH2:13][CH:14]2[CH2:16][CH:15]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](O)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:24][CH:25]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:26]([C:28]1[O:29][CH:30]=[CH:31][N:32]=1)[OH:27]>>[N:1]1([C:7](=[O:23])[CH2:8][CH:9]([CH2:13][CH:14]2[CH2:16][CH:15]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([NH:24][CH:25]([C:26]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[O:27])[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1
Reactant: NC(CCc1ccccc1)[C@H](O)c1ncco1
Product: O=C(NC(CCc1ccccc1)C(=O)c1ncco1)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1

Procedure:
It is similarly prepared according to general procedure given for example X above but using 4-Morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyric acid and (S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22]Cl)[CH:21]=1.[H-].[Na+]>>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:21]=1
Reactant: ClCc1cncc(Br)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine (intermediate A-3 [A]) was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow solid. MS: 385.2, 387.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][O:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([Cl:1])[CH:3]=1)[CH:7]=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cc(Cl)cc(O)c1O
Reactant: BrCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)cc(OCCCOCc2ccccc2)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 5-chloro-2,3-dihydroxy-benzaldehyde (3.1 g, 17.7 mmol) in anhydrous DMSO (20 mL) was added NaH (60% in mineral oil, 1.50 g, 35.4 mmol) portion-wise and the mixture was stirred for 30 minutes. The solution was cooled to 0° C. and a solution of 3-benzyloxy-1-bromopropane (3.1 mL, 17.7 mmol) in DMSO (3 mL) was added dropwise over 10 minutes period. The ice bath was removed. After overnight, the solution was diluted with EtOAc (100 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (2:1 hexanes-EtOAc mobile phase) generating the title compound (5.3 g, 16.6 mmol, 94%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.81 (s, 1H), 9.87 (s, 1H), 7.42-7.28 (m, 5H), 7.17 (s, 1H), 7.08 (s, 1H), 4.53 (s, 2H), 4.17 (t, J=6.2 Hz, 2H), 3.69 (t, J=5.8 Hz, 2H), 2.15 (t, J=6.2 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:35][CH2:34][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)C(O)=O.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([Cl:31])[CH:28]=1)[C:24]([NH:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:13](=[O:12])[C:54]3[CH:53]=[CH:49][CH:48]=[C:47]([C:46]([F:57])([F:56])[F:45])[CH:55]=3)[CH2:35][CH2:34][C:18]=2[N:19]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cc(Cl)cc(Cl)c3)ncc2C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ncc2c(n1)CCN(C(=O)c1cccc(C(F)(F)F)c1)C2)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Trifluoroacetic acid 5.0 ml (65 mmol) was added to a solution of 2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 404 mg (0.954 mmol) in CH2Cl2 (7 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After removal of the solvent, the intermediate (3,5-dichloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml) and DIPEA 340 μl and 3-trifluoromethylbenzoic acid 200 mg (1.05 mmol) were added. After cooling the reaction mixture to 0° C., EDCI 201 mg (1.05 mmol) and HOAt 20 mg (0.15 mmol) were added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product 3,5-dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 260 mg (0.53 mmol, 55% of theoretical) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1.[CH3:19][CH2:18][CH:17]([C:2]([NH2:3])=[O:1])[CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCN=C=O
Agent: O=c1[nH]c2ccccc2o1
Solvent: C1COCCO1
Product: CCCC(CC)C(N)=O

Procedure:
100 mg (0.74 mmol) of 3H-benzooxazol-2-one were reacted in analogy to Example 1 with 113 mg (0.888 mmol) of 1-isocyanatohexane in dioxane at 80° C. Yield: 163 mg (84%), M+H+: 263.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:26])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH2:22]([O:21][C:19]([C:17]1[N:18]=[C:11]2[N:12]([C:13]([Cl:26])=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:10]2)[N:16]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1nc2cc(-c3ccc(Cl)cc3Cl)nc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: CCOC(=O)c1nc2cc(-c3ccc(Cl)cc3Cl)nc(Cl)n2n1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
1311 mg (3.7 mmol) of ethyl 7-(2,4-dichlorophenyl)-5-hydroxy[1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate (Example 132A) are introduced into phosphoryl chloride (15 ml), 2.54 g (11.1 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 12 h. The reaction mixture is slowly poured, while stirring vigorously, into saturated sodium bicarbonate solution (150 ml) and ice, and solid sodium bicarbonate (approx. 10 g) is added until a pH of 8 is reached. The solid is filtered off with suction. 635 mg (93% of theory) of the product are obtained.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[Cl:18][CH:3]([C:2](=[O:1])[CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of benzyl 3-oxobutanoate (15 g, 78 mmol) in chloroform (150 mL) at 0° C. was added sulfuryl chloride (6.35 mL, 78 mmol) during a period of 20 min. The ice bath was removed and reaction mixture was allowed to warm to room temperature and stirred for 4 h. The solvent was evaporated and the crude product was diluted with EtOAc (250 mL). The organic layer was washed with H2O (100 mL), separated, dried over MgSO4 and concentrated to give the desired product as a light yellow oil (17.6 g, 99% yield). 1H NMR (CDCl3) δ 2.31 (s, 3H), 4.80 (s, 1H), 5.25 (s, 2H), 7.30-7.42 (m, 5H). LCMS, [M−H]+=225.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:25]=1[CH3:35])(=[O:12])=[O:11].[NH:36]1[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1]/[C:2](/[CH:7]=[CH2:6])=[C:3](/[C:4]([Cl:8])=[CH2:5])\[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([N:36]2[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]2)=[O:34])[C:25]=1[CH3:35])(=[O:12])=[O:11]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=C/C(Cl)=C(/CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(CCC(=O)N3CC[C@@H](O)C3)c1C)C(=O)N2)C(=C)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (267 mg), (R)-pyrrolidin-3-ol (2 eq.), HATU (1.2 eq.) and TEA (0.2 mL) in DMF (2 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 16 mg of the titled compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=1>>[CH3:20][C:6]1[N:5]([C@H:3]([CH3:4])[CH2:2][O:1][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:8]([CH:7]=1)=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2
Reactant: Oc1cccnc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)COc1cccnc1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and 3-pyridinol: MS (ES) m/z 360 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH2:15])=[N:3]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:23](=[O:25])[CH3:24])=[N:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a solution of trans-1-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) and triethylamine (104 μL, 0.746 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (70.5 μL, 0.746 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/hexane) to give the title compound (63.2 mg, yield 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[CH:5]2[C:19]1[C:28]([OH:29])=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].ClCI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[C:5]12[C:19]2[C:28](=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[O:29][CH2:30]1
Reactant: O=C([O-])[O-]
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1Cc1ccccn1
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccccn2)c2ccc(Br)cc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of 5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (2.00 g, 4.40 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added cesium carbonate (4.30 g, 13.2 mmol) and chloroiodomethane (0.85 g, 4.9 mmol). The solution was stirred at ambient temperature for 16 h and poured into water (100 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate extracts were washed with brine (2×35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane/diethyl ether (2/5, 14 mL) to afford 5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.44 g, 72%) as a beige solid: mp>250° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.57-8.52 (m, 1H), 7.69-7.61 (m, 1H), 7.33-7.27 (m, 3H), 7.26-7.16 (m, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.16 (d, J=15.8 Hz, 1H), 4.97-4.87 (m, 2H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.2, 155.1, 149.6, 144.9, 141.1, 138.4, 137.2, 134.2, 131.7, 127.0, 122.9, 121.7, 120.4, 116.1, 111.7, 111.1, 99.5, 80.0, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 465.0 (M+1), 467.0 (M+1).