Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)c1
Yield: 53.8 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-Nitrophenyl boronic acid (0.86 g, 5.2 mmol) according to Example 45 procedure A. Purification by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) afforded the desired compound (0.60 g, 1.4 mmol, 55%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.42–1.82 (8H, m), 2.02–2.04 (2H, q), 5.01 (2H, s), 6.88 (1H, d), 7.28–7.71 (8H, m), 8.08–8.13 (2H, m), 8.38 (1H, d), 9.69 (1H, s); MS (ESI(−ve)) m/z 426 (M−H)−.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:15]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccnc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.6 %

Procedure:
A mixture of 4-nitro-phthalonitrile (3.46 g, 20 mmol), pyridin-3-ol (1.90 g, 20 mmol), K2CO3 (8.29 g, 60 mmol), and DMF (50 ml) was stirred at ambient temperature overnight. The reaction mixture was then combined with another batch of the same reaction performed on the same scale. Subsequently, the solid components were removed by filtration and the filtrate was concentrated in vacuo. To the residue was added water and the mixture was extracted with EtOAc. The organic phase was then washed with brine, dried, and evaporated in vacuo. The residue was recrystallized from EtOAc/MeOH to give 8.3 g of the title compound; 1H NMR (CDCl3): δ=8.56 to 8.59 (m, 1H), 8.45 to 8.47 (m, 1H), 7.76 (d, 1H), 7.42 to 7.44 (m, 2H), 7.22 to 7.32 (m, 2H).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([O:77]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([O:46]CC4C=CC(OC)=CC=4)=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[CH:43]=[CH:42][S:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([OH:77])=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[CH:43]=[CH:42][S:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C=Cc4ccsn4)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Yield: 82 %

Procedure:
After 400 mg of p-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethoxycarbonyl)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylate were dissolved in 4 ml of methylene chloride and 2 ml of anisole, 8 ml of trifluoroacetate was added therein under ice-cooling, and the reaction solution was reacted for 90 min. as it was. The residue obtained by evaporating off methylene chloride and trifluoroacetate was powdered by using ethyl ether. The powder obtained by filtering off was further added to 24 ml of trifluoroacetate under ice-cooling, and then 6 ml of water was added therein, and the reactants were reacted for 30 min. as they were, and further reacted for 2 hrs. at the room temperature. The residue obtained by evaporating off trifluoroacetate and water under the reduced pressure was powdered by adding ethyl ether and filtered off to give 190 mg of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[ [(R S)-(carboxy)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylic acid.trifluoroacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([CH3:23])([CH3:22])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([CH3:22])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a mixture of 4-hydroxy-3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.5 g, 20.0 mmol) and triethylsilane (5.0 mL) at 25° C. was added trifluoroacetic acid (2.5 mL) dropwise. The resulting mixture was stirred at 25° C. for 4 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 24%) as a white solid: LC/MS m/e calcd for C20H23NO2 (M+H)+: 310.40, observed: 310.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]([CH3:17])=[CH:6][C:7]=1[NH:8][CH:9]([CH2:14][O:15][CH3:16])[CH2:10][CH2:11][O:12][CH3:13].[N:19]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[Cl:18][C:3]1[C:2]2[N:1]=[N:19][N:8]([C@H:9]([CH2:14][O:15][CH3:16])[CH2:10][CH2:11][O:12][CH3:13])[C:7]=2[CH:6]=[C:5]([CH3:17])[N:4]=1
Reactant: COCCC(COC)Nc1cc(C)nc(Cl)c1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COCC[C@@H](COC)n1nnc2c(Cl)nc(C)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-amino-2-chloro-6-methyl-4-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (4.1 g, 14.98 mmol) was dissolved in a mixture of CH2Cl2 (40 mL) and 50% acetic acid (40 mL) and cooled to 0° C. in an ice bath. To that a solution of NaNO2 (1.84 g, 26.86 mmol) in water (10 mL) was added dropwise and the reaction was stirred at 0° C. for 30 min and at 25° C. for 1.5 h. Then the acetic acid was neutralized with solid NaHCO3 and water (80 mL) was added. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were combined and washed with brine (50 mL), dried and stripped in vacuo. The residue was chromatographed on silica gel (40% EtOAc/hexanes eluent) to give the product (4.05 g, 56% overall for the eight steps). NMR(CDCl3)d 7.25 (s, 1H), 5.04-5.13 (m, 1H), 3.98 (dd, 1H, J1=9.9 Hz, J2=8.4 Hz), 3.84 (dd, 1H, J1=10.2 Hz, J2=4.4 Hz), 3.39 (dt, 1H, J1=9.9 Hz, J2=4.8 Hz), 3.25 (s, 3H), 3.17 (s, 3H), 2.91 (dt, 1H, J1=9.5 Hz, J2=4.0 Hz), 2.68 (s, 3H), 2.22-2.6 (m, 2H).
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:8]=[N+:9]=[N-:10].[Na+].CS(C)=O>>[CH:1]1([N:8]=[N+:9]=[N-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCCCC1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
Cyclohexyl bromide (2.74 mL, 0.023 mol) was added to a stirred solution of 0.5M sodium azide in DMSO (50 mL, 0.025 mol) at room temperature, under an atmosphere of nitrogen. The reaction mixture was heated to 75° C. behind a blast shield and stirred for 5 h. The reaction mixture was then cooled with an ice-bath, quenched by the addition of water (75 mL) and extracted with diethyl ether (3×125 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude oil (2.4 g) which was used without further purification.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:14]=1.C(O)(=[O:28])C>O>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:28])=[CH:15][CH:14]=1
Reactant: Clc1ccc(Cc2ccccn2)cc1
Reactant: CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccccn1

Procedure:
164 G. (0.55 mol) of sodium dichromate was added to a stirred solution of 101 g. (0.5 mol) of 2-(p-chlorobenzyl)-pyridine in 450 ml. of acetic acid and the resulting mixture was stirred and refluxed for 3 hrs. The resulting dark green solution was cooled and poured into 1500 ml. of cold water. The precipitate which resulted was collected, washed with water and air dried to yield 2-(4-chlorobenzoyl)pyridine as white microprisms, mp. 62°-64° C. (ligroin).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N:9]=O.[Na].C([O:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)C>C(O)C>[CH2:7]([N:6]1[C:2]2=[N:1][C:17]([CH3:19])=[C:16]([C:15]([OH:20])=[O:14])[N:9]=[C:3]2[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1ncc(N=O)c1N
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCn1ncc2nc(C(=O)O)c(C)nc21

Procedure:
49 g. of 5-amino-1-ethyl-4-nitrosopyrazole (0.35 mol.) are added to a solution of 8.05 g. of sodium (0.35 mol.) in 350 ml. of absolute ethanol and this is stirred at room temperature for 30 minutes. After the addition of 50 g. of acetoacetic acid ethyl ester (0.385 mol.) the reaction mixture is heated at reflux temperature for 31/2 hours. The precipitated sodium salt is filtered off, washed with ether and dried at 50°, yield 47.1 g. (59%). By dissolving the sodium salt in water, treatment with charcoal and acidification with concentrated hydrochloric acid, 1-ethyl-6-methyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxylic acid, m.p. 148°-149° (ethanol) is obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[NH:4][C:5](=[O:11])[NH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[F-].[K+].[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([CH2:15][N:22]2[CH2:23][CH2:24][N:25]([C:2]3[C:3](=[O:12])[NH:4][C:5](=[O:11])[NH:6][C:7]=3[CH2:8][CH2:9][CH3:10])[CH2:26][CH2:27]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CCCc1[nH]c(=O)[nH]c(=O)c1N1CCN(Cc2ccccc2)CC1
Temperature: 140 °C
Yield: 58.6 %

Procedure:
A mixture of 53.3 g (0.229 mole) of 5-bromo-6-propyl-2,4(1H,3H)pyrimidinedione and 23.7 g (0.252 mole) of anhydrous potassium fluoride in 176 ml (1.0 mole) of 1-benzylpiperazine was heated under reflux at 140° C. for 14 hours. The reaction mixture was cooled to 80° C. and 100 ml of ethanol was added. The mixture was poured into one liter of ice water. The solid was collected and washed with one liter of water. Recrystallization from ethanol and drying in vacuo at 59° C. for 16 hours gave 44.1 g of the product as an off-white solid; mp 233°-235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]2[C:12]([CH2:13][C:14]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)=[N:17][NH:16][C:15]=32)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:27]=[C:26]2[C:12]([CH2:13][C:14]3[C:18]([C:19]4[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=4)=[N:17][N:16]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:15]=32)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)-c1[nH]nc(-c3ccc(Br)cc3)c1C2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCc1ccccc1)-c1c(c(-c3ccc(Br)cc3)nn1COCC[Si](C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a mixture of Example 267D (11.66 g, 26.1 mmol) and DMF (500 mL) in ice bath was added 95% NaH (0.69 g, 27.41 mmol). The mixture was stirred at room temperature for 0.5 hour and then cooled at 0° C. 2-(trimethylsilyl)ethoxymethyl chloride (4.85 mL, 27.41 mmol) was added to the mixture. After 0.5 hour, the ice bath was removed. The reaction was run at room temperature for another hour, and then poured into water. Ethyl acetate (200 mL×3) was used to extract the product. The organic solution was dried with MgSO4, concentrated, and purified by flash chromatography to give the desired product (10.84 g 72%). MS (DCI/NH3) m/z 577 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccc(F)cc2)CCC(CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
The non-polar diastereoisomer of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexyl]-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone (190 mg, 0.43 mmole) was dissolved in ethyl methyl ketone (10 ml) and chlorotrimethylsilane (0.08 ml, 0.63 mmole) was added. After a reaction time of 1.5 hours the hydrochloride was obtained in a yield of 100% (208 mg) as a colourless solid with an m.p. of 168°-173° C. (Example 40).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(c2cccc([N+](=O)[O-])c2)C1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2cccc(N)c2)C1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Platinum oxide (202.6 mg, 0.89 mmol, 0.05 equiv) was added to a solution of methyl 1-(3-nitrophenyl)-5-oxopyrrolidine-3-carboxylate (4.2014 g, 15.9 mmol, 1 equiv) in ethyl acetate (170 mL). The resulting suspension was placed under a hydrogen balloon and was stirred at 23° C. for 18 hr. The reaction was filtered through celite and was concentrated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.15 (t, 1H, J=2.1 Hz), 7.13 (t, 1H, J=8.1 Hz), 6.78 (dd, 1H, J=8.1 Hz, 1.5 Hz), 6.49 (dd, 1H, J=8.0 Hz, 1.7 Hz), 4.07 (dd, 1H, J=10.0 Hz, 6.8 Hz), 3.99 (dd, 1H, J=10.0 Hz, 8.7 Hz), 3.77 (s, 3H), 3.75 (br s, 2H), 3.29-3.38 (m, 1H), 2.92 (dd, 1H, J=17.3 Hz, 7.8 Hz), 2.84 (dd, 1H, J=17.3 Hz, 9.7 Hz). MS: (+) 235.0 (M+H), 469.5, 703.5; (−) 293.5, 527.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[N:8](C2CCCCO2)[N:7]=1.[N:23]([Sn](CCCC)(CCCC)CCCC)=[N+:24]=[N-:25].Cl>C1(C)C=CC=CC=1.O1CCOCC1>[N:23]1[NH:24][N:25]=[N:16][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)c(-c1ccco1)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: c1coc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1
Yield: 4.7 %

Procedure:
The title compound was prepared from 3-(2-furyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.095 g, 0.307 mmol), azidotributyl tin (0.245 g, 0.202 mL, 0.74 mmol) in toluene (8 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 8 mL of 4.0N solution of hydrogen chloride in 1,4-dioxane. The compound was purified by preparative HPLC (10–100% acetonitrile in H2O, 20 min) (0.008 g, 0.032 mmol, 4.7% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 8.8 (s, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.1 (d, 1H), 6.7 (dd, 1H); ES-MS (m/z) 253 [M+1]+.
Reaction SMILES: C(O[C@H]1C[N:8]([C:10]([O:12][C:13]([CH3:16])(C)C)=O)[C@@H](C(O)=O)C1)C=C.COC[C@H]1CCCN1C(C1C=C(C=C(C2OC=CN=2)C=1)C(OC)=O)=O.O1C=CN=C1.C([Li])CCC.[CH2:55]([Sn:59](Cl)([CH2:64][CH2:65][CH2:66][CH3:67])[CH2:60][CH2:61][CH2:62][CH3:63])[CH2:56][CH2:57][CH3:58]>C1COCC1>[CH2:64]([Sn:59]([CH2:55][CH2:56][CH2:57][CH3:58])([CH2:60][CH2:61][CH2:62][CH3:63])[C:10]1[O:12][CH:13]=[CH:16][N:8]=1)[CH2:65][CH2:66][CH3:67]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C=CCO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: COC[C@H]1CCCN1C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [Li]CCCC
Agent: c1cocn1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncco1
Temperature: -78 °C
Reaction time: 1.2 h

Procedure:
Step H (2): Preparation of methyl 3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoate. To a solution of oxazole (2.0 g, 29.0 mmol) in THF (30 mL) was added n-butyl lithium (2.0 M solution in cyclohexanes, 16 mL, 31.9 mmol) at −78° C. slowly. The reaction mixture was stirred at −78° C. for 1.2 h, then tributylstannyl chloride (5.0 g, 15.4 mmol) was added. The reaction mixture was warmed up to rt over 3 h. Hexanes (200 mL) was added and the mixture was washed with H2O, dried over Na2SO4 and concentrated under vacuum to give 5.6 g of the 2-(tributylstannyl)oxazole ready for use.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=[O:37])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH:20]([CH3:35])[C:19]1=[O:36])[CH2:7][CH2:8][N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1.OS([O-])(=O)=O.[K+].C(Cl)Cl>CCO>[OH:17][C@@H:11]1[CH2:10][N:9]([CH2:8][CH2:7][CH:6]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[CH:20]([CH3:35])[C:19]2=[O:36])[C:5]([OH:37])=[O:4])[CH2:16][CH2:15][C:12]21[CH2:14][CH2:13]2
Reactant: COC(=O)C(CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CC1C(=O)N(C(CCN2CCC3(CC3)[C@H](O)C2)C(=O)O)CCN1c1cccc(OC(F)(F)F)c1
Temperature: 60 °C

Procedure:
Sodium borohydride (11 mg, 0.28 mmol) was added at RT to a solution of 4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-butyric acid methyl ester (70 mg, 0.14 mmol) in EtOH (2 mL), then after 16 min another portion of sodium borohydride (11 mg, 0.28 mmol) was added. After 24 h another portion of sodium borohydride (30 mg, 0.80 mmol) was added and the reaction mixture heated at 60° C. for 6 h. After cooling 10% aq. KHSO4 solution and CH2Cl2 were added to the reaction mixture, the organic layer washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; CH2Cl2/MeOH 4:1, then CH2Cl2/MeOH/25% aq. ammonia solution 80:20:1) afforded 4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-butyric acid (41 mg, 60%; light yellow solid, MS: 484.2 (M−H)−) and 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (22 mg, 33%; colorless oil, MS: 472.2 (M+H)+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[OH:38][C@@H:39]([CH2:43][C:44]([OH:46])=[O:45])[C:40]([OH:42])=[O:41]>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:36][CH:37]=2)[CH2:4][CH2:3]1.[C:40]([O-:42])(=[O:41])[CH:39]([CH2:43][C:44]([O-:46])=[O:45])[OH:38]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: O
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to a solution of (2S)-(−)-hydroxybutanedioic acid (L-(−)-malic acid; Fluka, Buchs, Switzerland; 1.34 g, 10 mmol) in water (40 mL). The mixture is heated and the resulting hot solution is filtered and evaporated to dryness under reduced pressure to give a residue which is re-crystallized from ethanol, filtered and dried to give 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, malate as a pale-yellow crystalline solid, having the following analytical properties: Analysis found: C, 62.88; H, 6.04; N, 15.60%; H2O, 0.45%. Calculated for C33H37N7O6-0.16 H2O: C, 62.86; H, 5.97; N, 15.55%; H2O, 0.46%.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)C1C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:27][O:26][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]([CH3:1])[CH:16]3[CH2:15][NH:14][CH2:28][CH:17]3[C:18]=2[CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc2c(c1)C1CNCC1C2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%—two steps) of the subtitle compound. MS calculated for C20H21NO+H: 292, observed: 292.