Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][C:39](O)=[O:40])=[CH:29]1>ClCCl>[CH3:1][CH:2]1[N:6]([C:39](=[O:40])[CH2:38][CH2:37][C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:28][CH:29]=2)[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1
Reactant: CC1NCC2(CCN(C)CC2)O1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1OC2(CCN(C)CC2)CN1C(=O)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,8-dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (991.2 mg, 5.8 mmol) in dichloromethane (110 ml) at room temperature were added dicyclohexylcarbodiimide (1.61 g, 7.8 mmol) and 3-indolepropionic acid (1.43 g, 7.6 mmol). The resulting solution was stirred at room temperature overnight. A white solid precipitated during the reaction. After filtration the solvent was evaporated and the crude product was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 90/10/1). After evaporation and drying under vacuum, AF711 (716 mg, 99.6% chemical purity) was obtained as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.50, 8.46 (2 br s, 1H, NH indole), 7.61 (d, J=7.55 Hz, 1H, CHC arom), 7.33 (d, J=7.85 Hz, 1H, CHCNH arom), 7.18 (app t, J=7.24, 7.85 Hz, 1H, CHCHC arom), 7.11 (app t, J=7.55, 7.24 Hz, 1H, CHCHC arom), 7.02 (d, J=1.86 Hz, 1H, CHNH indole), 5.32, 5.15 (2q, J=5.09 and J=5.16 Hz, 1H, CHCH3), 3.99, 3.22 (2d, J=11 and J=9.5 Hz, 1H, CHHNCO), 3.19 (m, 1H), 3.13-3.08 (m, 1H), 3.03, 2.97 (2d, J=9.5 and J=11 Hz, 1H, CHHNCO), 2.72-2.60 (m, 2H), 2.51-2.20 (m, 4H), 2.25, 2.23 (2s, 3H, NCH3), 1.78-1.64 (m, 2H), 1.43, 1.31 (2d, J=5.15 and J=5.15 Hz, 3H, CH3CH), 1.39, 1.28 (2m, 1H), 1.14 (m, 1H) ppm; 13C NMR (CDCl3, 500 MHz) δ 170.50, 169.85 (C), 136.30, 136.25 (C), 127.07, 126.99 (C), 121.93 (CH), 121.85 (CH), 119.24 (CH), 118.55, 118.52 (CH), 114.73 (C), 111.20, 111.12 (CH), 84.69, 84.06 (CH), 77.98 (C), 54.18 (CH2), 52.18 (CH2), 51.86 (CH2), 45.89, 45.83 (CH3), 36.38 (CH2), 34.98 (CH2), 32.99, 32.41 (CH2), 22.70, 20.50 (CH3), 20.96, 20.73 (CH2) ppm.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=O)C.C(O)(=O)C.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].ClCCCl>[CH2:25]([N:32]1[CH:7]2[CH:6]([CH2:11][CH:10]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][CH2:8]2)[CH2:5][C:4]1=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC1CC(Cc2ccccc2)CCC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=C1CC2CC(Cc3ccccc3)CCC2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
A mixture of 8 g of (5-benzyl-2-oxo-cyclohexyl)-acetic acid ethyl ester, 3.4 g of acetic acid, 3.75 g of benzylamine, 50 mL of 1,2-dichloroethane and 7.7 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 100 mL chloroform and 40 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with 50% ethyl acetate in hexane gave 5 g of 1,5-dibenzyl-octahydro-indol-2-one.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[I:17]N1C(=O)CCC1=O>C(#N)C.ClCCl>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:15])[C:14]([I:17])=[C:10]2[N:9]=[C:8]([CH3:16])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2cc(C)nn12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Yield: 97.1 %

Procedure:
Dissolve 7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (2.14 g, 9.84 mmol) in anhydrous acetonitrile (25 mL) and add 6 portions (0.5 g each) of N-iodosuccinimide (3.0 g, 13.3 mmol) at 10 min intervals. Stir the reaction for 4 h. Strip off the acetonitrile and dilute the resulting oil with dichloromethane (100 mL). Wash the orange solution with saturated ammonium chloride solution (2×50 mL). Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a dark red oil. Purify using flash chromatography, eluting with 100% pentane/0% (20% ethyl acetate/pentane) to 0% pentane/100% (20% ethyl acetate/pentane) in a step gradient of 50% increments to give an orange oil (3.28 g, 97%). 1H NMR (400 MHz, CDCl3): 6.44 (s, 1H), 3.59 (m, 1H), 2.61 (s, 3H), 2.49 (s, 3H), 1.86-1.76 (m, 4H), 0.85 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.[ClH:26].O1CCOCC1.C(OCC)C>C(O)(C)C.O1CCOCC1>[ClH:26].[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(Oc2cccc(C#N)c2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(Oc2cccc(C#N)c2)ccc2[nH]ncc12
Yield: 69 %

Procedure:
Under nitrogen, 3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile (299 mg, 0.897 mmol) was dissolved in a mixture of isopropyl alcohol (6 ml) and 1,4-dioxane (6 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (6 ml), and the resulting mixture was stirred at room temperature for 23 hours. After diethyl ether (30 ml) was added thereto and stirred, the precipitate was collected by filtration, washed with diethyl ether and then dried under reduced pressure to obtain 3-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrile hydrochloride (176 mg, yield 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)=[C:12]([NH:25][C:26]3[C:27]4[CH:35]=[CH:34][CH:33]=[N:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:11]=2)=[CH:4][C:3]=1[CH3:37].C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(NC3C=CC(C)=CC=3)=O)=NC=NC=2N=1)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)=[C:12]([NH:25][C:26]3[C:27]4[CH:35]=[CH:34][CH:33]=[N:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:11]=2)=[CH:4][C:3]=1[CH3:37]
Reactant: COc1ccc(Sc2ccc(C(=O)Nc3ccc(F)c(C)c3)cc2Nc2ncnc3ncccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Product: Cc1cc(NC(=O)c2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4ncccc34)c2)ccc1F

Procedure:
The product from Example 261A was reacted according to the procedure from Example 150 substituting the product from Example 261A for the product from Example 138 to provide a residue which was purified by trituration from methanol to provide the title compound as an off white solid (30.4 mg, 82%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.22 (s, 1 H), 10.01 (s, 1 H), 9.20 (d, J=3.68 Hz, 1 H), 9.12 (d, J=8.82 Hz, 1 H), 8.92 (s, 1 H), 7.83-8.00 (m, 4 H), 7.64 (dd, J=7.17, 2.39 Hz, 1 H), 7.50-7.60 (m, 1 H), 7.29-7.34 (m, 2 H), 7.12 (t, J=9.19 Hz, 1 H), 7.02 (d, J=8.46 Hz, 1 H), 6.80-6.85 (m, 2 H), 2.23 (d, J=1.84 Hz, 3 H); MS (ESI+) m/z 498.1 (M+H)+, (ESI−) m/z 496.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (115 mg), 2-hydroxy-5-methoxybenzaldehyde (385 mg), and 4-dimethylaminopyridine (321 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively obtain 180 mg of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15]([O:22]C)(=[O:21])[CH2:16][CH2:17][C:18]([CH3:20])=O.N1CCCC1>C1(C)C=CC=CC=1>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH2:13][C:18]([CH2:17][CH2:16][C:15]([OH:22])=[O:21])([CH3:20])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: COC(=O)CCC(C)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)O)CC2=O
Reaction time: 1 h

Procedure:
To a mixture of 20.0 g (103 mmole) of 2,4-dihydroxy-3-propylacetophenone and 15.5 g (134 mmole) of methyl levulinate in 100 ml of dry toluene was added by syringe 21.5 ml (ca. 260 mmole) of pyrrolidine. After stirring for one hour the solution was heated on a steam bath for four hours and allowed to cool. The toluene solution was washed with water and 2N NaOH. The basic solution was acidified and extracted with diethyl ether, which in turn was extracted with saturated sodium bicarbonate. The basic aqueous extract was neutralized with dilute hydrochloric acid and again extracted with diethyl ether. After drying, the solution was concentrated at reduced pressure to an oil which crystallized to the title compound, m.p. 152°-153°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:22][CH2:21][O:20][CH3:19])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Br)cc(O)cc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Br)c2c(c1)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
A mixture of Example 104B (100 mg, 0.44 mmol), Cs2CO3 (163 mg, 0.5 mmol) and 2-bromoethyl methyl ether (0.045 mL, 0.46 mmol) in DMF (2.2 mL) was warmed to 60° C. for 4 hours, stirred at room temperature overnight, and partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to give 128 mg of the desired product. MS (ESI(+)) m/e 286,288 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:23]([OH:26])(=[O:25])[CH3:24]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[C:23]([O-:26])(=[O:25])[CH3:24]
Reactant: CC(=O)O
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: CC(=O)[O-]
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g of olanzapine base in 150 ml acetone was added slowly 1.o6 g of acetic acid at room temperature and the mixture was stirred overnight at 4° C. The crystals were isolated by filtration, washed with 20 ml acetone and 20 ml of ether and dried overnight at 40° C. in vacuo. Yield: 3.32 g (56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:14]([CH:17]=[CH:18][CH3:19])([O-:16])=[O:15]>>[CH3:19][CH:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:13])=[O:12])[CH:5]=2)[NH:1][CH:2]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: NC(=O)Cc1ccc2[nH]ccc2c1
Reactant: CC=C[N+](=O)[O-]
Product: CC(C[N+](=O)[O-])c1c[nH]c2ccc(CC(N)=O)cc12
Reaction time: 24 h

Procedure:
A mixture of 1H-indole-5-acetamide (0.41 g) and 1-nitropropene (0.23 g) was heated at 80° for 24 h and then left at ambient temperature for another 24 h. Chromatography of the thick oil on silica (Merck 7734, 35 g) eluting with ethyl acetate gave a mixture of the title compound and starting material (4:1, 0.26 g) which was used in the next stage without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([P:16]([OH:28])([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7].[C:29](OC(=O)C)(=[O:31])C>C(O)=O>[CH:29]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([P:16]([OH:28])([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])=[O:31]
Reactant: NCCCC(C(=O)N1CCC[C@H]1C(=O)O)P(=O)(O)CCCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCCCC(C(=O)N1CCC[C@H]1C(=O)O)P(=O)(O)CCCCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 1 g (2.44 mmol) of (±)-1-[5-amino-2-[hydroxy-(4-phenylbutyl)phosphinyl]-1-oxopentyl]-L-proline (prepared as described in Example 1) in a mixture of 5 ml of acetic anhydride and 15 ml of 90% formic acid is kept at room temperature for 3 hours, then evaporated to give the title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C>[OH:16]/[N:15]=[C:7](\[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=N/O)c1cccnc1
Yield: 50.7 %

Procedure:
A mixture of ethyl 3-pyridylglyoxylate (6.00 g), hydroxylamine hydrochloride (2.79 g), sodium acetate (4.13 g) and ethanol (80 ml) was heated to reflux for 15 hours. The reaction mixture was concentrated, water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate to obtain ethyl E-2-hydroxyimino-2-(3-pyridyl)-acetate (3.30 g, yield 51%) as colorless crystals. m.p. 172-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[N:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:15]([C:11]2[N:12]([CH3:14])[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]=2)=[O:17])=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2cc(C(=O)O)n(C)n2)cc1
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2cc(-c3ccc(OC)cc3)nn2C)cn1

Procedure:
With a procedure similar to example 16 above, 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid (made by hydrolysis of the corresponding commercially available ethyl ester) and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H25N5O3 (m/e) 395, obsd 396 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>O1CCCC1>[N:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:5]2[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]2[Br:3])=[CH:19][CH:20]=1
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Br)n(Cc2ccncc2)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a suspension of 195 milligrams (mg) (8.13 mM) of sodium hydride in 20 ml of anhydrous tetrahydrofuran was added, in portions, 2 g (8.13 mM) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 1.03 g (8.13 mM) of 4-chloromethylpyridine was added. The reaction mixture was stirred overnight at 50° C. The precipitated sodium chloride was removed by filtration and concentration in vacuo of the filtrate gave 2.5 g (92%) of isopropyl N-(4-pyridylmethyl)-2-bromo-4-methyl-5-imidazole carboxylate as a tan solid.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([N:16]([CH3:30])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:12][CH2:11]1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][N:16]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C@H:13]1[CH2:14][CH2:15][C@H:10]([O:9][CH:7]([CH3:8])[C:6]([OH:31])=[O:5])[CH2:11][CH2:12]1
Reactant: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)O
Reaction time: 3 h

Procedure:
A solution of 300 mg (0.64 mmol) of from trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid tert-butyl ester in 3 ml of CH2Cl2 was treated wit 0.5 ml (6.7 mmol, 10 eq) of trifluoroacetic acid and stirred at 40° during 3 h. Evaporation of the solvent gave 266 mg (quantitative) of trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid as an off-white solid, MS: 408 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12.[F:17][C:18]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:19]=1[NH2:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:20][C:19]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:18]=3[F:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1Cl
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnc2c(Br)cnn2c1Nc1cc(C)ccc1F
Yield: 79.6 %

Procedure:
In the same manner as in Example 1, step 4 and using ethyl 3-bromo-7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (400 mg, 1.31 mmol) obtained in Example 22, step 1 and 2-fluoro-5-methylaniline (0.18 mL, 1.57 mmol), the title compound (410 mg, 91%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30](O)(=[O:32])[CH3:31].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:30]([NH:21][S:18]([CH2:17][CH:14]1[CH2:13][CH2:12][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[CH2:16][CH2:15]1)(=[O:20])=[O:19])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexyl]-methanesulfonamide (Example 3) (64 mg, 0.14 mmol.), acetic acid (0.011 mL, 0.17 mmol.) and dimethylaminopyridine (20 mg, 0.17 mmol.) in dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol.) and the mixture stirred at ambient temperature for 18 hours. After dilution with ethyl acetate (25 mL), and washing with 2N aqueous hydrochloric acid (20 mL) and brine (20 mL), drying (MgSO4) and evaporation left a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:iso-hexane (2:1:1), to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:12][CH2:13][C:14]#[CH:15])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:12][CH2:13][C:14]#[CH:15])=[N:4][C:5]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[N:6][C:7]=1[Cl:8]
Reactant: c1ccc2[nH]ncc2c1
Reactant: C#CCNc1nc(S(C)=O)nc(Cl)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCNc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 0.5 g (1.62 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)-N-(prop-2-ynyl)pyrimidine-4-amine (intermediate 31) in 2 ml of DMSO, 0.19 g (1.62 mmol) indazole and 0.32 g of cesium carbonate were added. The slightly yellow solution was stirred at room temperature for 20 minutes. The reaction mixture was poured onto 10 ml of cold water. The resulting precipitate was filtered, washed with cold water and dried. The desired product was obtained as a white solid 0.31 g (52.8%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][C:10](=[O:12])[N:9]([C@H:13]([C:16]([NH2:18])=[O:17])[CH2:14][CH3:15])[CH2:8]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].FCC1CN([C@@H](CC)C(N)=O)C(=O)C1.O=C1CC(CN2C=NN=N2)CN1[C@@H](CC)C(N)=O.O=C(CCN1CCCC1CN1C=NC=N1)C(N)=O.O=C1CC(CN2C=CN=N2)CN1C(CC)C(N)=O.C(SCC1CN([C@@H](CC)C(N)=O)C(=O)C1)(C)C.C(N)(=O)CCC.O=C1CC(CN2CCSCC2)CN1[C@@H](CC)C(N)=O>C(#N)C>[N:19]([CH2:6][CH:7]1[CH2:8][N:9]([C@@H:13]([CH2:14][CH3:15])[C:16]([NH2:18])=[O:17])[C:10](=[O:12])[CH2:11]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H](C(N)=O)N1CC(COS(C)(=O)=O)CC1=O
Agent: CCC(C(N)=O)N1CC(Cn2ccnn2)CC1=O
Agent: CCCC(N)=O
Agent: CC[C@@H](C(N)=O)N1CC(CF)CC1=O
Solvent: CC#N
Product: CC[C@@H](C(N)=O)N1CC(CN=[N+]=[N-])CC1=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
In a 3 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, 89.7 g (322 mmoles, 1 eq) of {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl methanesulfonate 37 are dissolved in 300 ml of acetonitrile. 27.3 g (419 mmoles, 1.3 eq) of sodium azide are added in one portion, with 150 ml of acetonitrile. The mixture is brought to reflux in 20 min, and stirred overnight. 3.1 g (48 mmoles, 0.2 eq) of sodium azide are added and reflux continued for a total of 44 hours. After cooling down to 10° C., the mixture is filtered, the precipitate washed with 3×50 ml of acetonitrile and the combined organic fractions concentrated to dryness to give 77.3 g of crude 32. It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%. Alternatively, (2S)-2-[4-(fluoromethyl)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[-2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1H-tetrazol -1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1H-1,2,4-triazol-1-ylmethyl -pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1H-1,2,3-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-4-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholinylmethyl)-1-pyrrolidinyl]butanamide 17, are prepared in similar ways, from activated alcohol derivatives, such as mesylates, tosylates or halides.