Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:22].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C1COCC1>[C:30]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:22])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(OC)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(OC)cc3n2)c1O
Temperature: -5 °C
Reaction time: 2 h

Procedure:
In a 100 ml round bottom 3-neck flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.24 g (10.8 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-methoxy-2H-benzo[d][1,2,3]-triazol-2-yl)phenol in 60 ml anhydrous THF. Triethylamine (1.2 ml) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (1.40 g, 13.4 mmol) was added dropwise and the mixture was stirred for 2 hr at 0° C. followed by 20 hours at ambient temperature. The salts were filtered off and the filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in ethanol to give a light yellow solid. 1H NMR (CDCl3) delta: 11.20 (s, 1H, phenol OH), 7.80 (m, 1H, Ar—H benzotriazole), 7.77 (s, 1H, Ar—H phenol), 7.17 (m, 1H, Ar—H benzotriazole), 7.14 (s, 1H, Ar—H phenol), 7.10 (m, 1H, Ar—H benzotriazole), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.38 (s, 2H, Ar—C1-12), 3.92 (s, 3H, Ar—OCH3, phenol), 3.88 (s, 3H, Ar—OCH3, benzotriazole), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:39](=[CH:38][CH:37]=[C:36]([CH3:35])[CH:41]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc([N+](=O)[O-])c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([OH:12])=O)(=[O:3])[CH3:2].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:78])([F:77])[C:49]1[CH:50]=[C:51]([C:59]([CH3:76])([CH3:75])[C:60]([N:62]([CH3:74])[C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][NH:65][CH2:64]2)=[O:61])[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>C1COCC1>[C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([N:65]1[CH2:66][C@@H:67]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@H:63]([N:62]([CH3:74])[C:60](=[O:61])[C:59]([C:51]2[CH:50]=[C:49]([C:48]([F:78])([F:47])[F:77])[CH:54]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:52]=2)([CH3:76])[CH3:75])[CH2:64]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: CC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1C[C@H](O)C[C@H]1C(=O)N1C[C@@H](N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Reaction time: 48 h
Yield: 29 %

Procedure:
To a stirred solution of (2S,4R)-1-acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid (commercially available) (7.5 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 7.6 mg (29%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4](OC)=[O:5].[CH3:13][NH2:14]>>[CH3:13][NH:14][C:4](=[O:5])[CH2:3][C@H:2]([OH:1])[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C[C@H](O)c1cccs1
Reactant: CN
Product: CNC(=O)C[C@H](O)c1cccs1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
115 g of methyl (3S)-3-hydroxy-3-(2-thienyl)propanoate are initially charged and admixed with 618 ml of a 2 molar methanotic methylamine solution. This mixture is stirred at 60° C. for 4 h, cooled and then concentrated under reduced pressure. In this way, 118 g of N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (purity 86%; 88% of theory) are obtained. The crude product may be used in the next stage or else recrystallized from methylene chloride and hexane. This delivered 93 g of N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (76% of theory) as white crystals. As an alternative, the purification may also be done by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]([OH:20])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.[CH2:21]([O:23][C:24](=[O:27])[CH2:25]Br)[CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2O)c(Cl)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)CC)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (i) using the product from step (iv) and ethylbromoacetate. Yield 2.23 g
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:7]=2[N:8]=1
Reactant: COc1ncc2nc(N=C(SC)SC)sc2n1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of dimethyl 5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (100 mg, 0.349 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (80 mg, 0.349 mmol) and cesium carbonate (228 mg, 0.698 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids were collected by filtration to afford (R)—N-(5-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (78 mg, 64% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.12 (br. s., 1H) 8.63 (s, 1H) 3.95-4.18 (m, 4H) 3.71 (d, J=9.77 Hz, 1H) 3.41 (d, J=15.26 Hz, 1H) 2.74-3.10 (m, 5H) 2.11-2.27 (m, 2H) 1.71-1.86 (m, 1H) 1.50-1.70 (m, 2H). MS (LC/MS) R.T.=1.66; [M+H]+=347.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:35]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:30][CH2:31][N:32]([C:35]([CH:37]3[CH2:42][CH2:41][N:40]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][N:3]=4)[CH2:39][CH2:38]3)=[O:36])[CH2:33][CH2:34]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: Clc1ccncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Yield: 60.8 %

Procedure:
4-Chloropyrimidine (1.72 g) and triethylamine (5.3 ml) were added to a solution of 4-(1-(6-chloronaphth-2-ylsulphonyl)piperazin-4-ylcarbonyl)piperidine (4 g) in ethanol (100 ml) and the mixture heated on a steam bath overnight. The mixture was cooled to give a precipitate which was collected to filtration and recrystallised from acetonitrile to give 1-(6-chloronaphth-2-ylsulphonyl)-4-[1-[4-pyrimidinyl]piperidin-4-ylcarbonyl]piperazine (2.88 g); mp 218-219° C.;
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](CC(N)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[C:36]([O:35][C:33](=[O:34])[CH2:32][N:25]1[CH2:26][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:24]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)OC(C)(C)C)C3)ccc1-2

Procedure:
Following a similar procedure to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using tert-butyl bromoacetate, {3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid tert-butyl ester was isolated as a colourless oil (97 mg, 33%). LCMS: RT=3.63 min, [M+H]+=482
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:11][O:12][CH2:13][C:14](OCC)=[O:15].Cl>C1C=CC=CC=1.O>[CH3:11][O:12][CH2:13][C:14]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:15]
Reactant: CCOC(=O)COC
Reactant: CC1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
In 50 ml of benzene was suspended 2.5 g of 60% sodium hydride. While cooling the suspension, a mixture of 5.6 g of 4-methylcyclohexanone and 5.4 g of ethyl methoxyacetate was dropwise added thereto. After stirring at room temperature for 2 hours, 20 ml of water was added thereto and the pH was rendered 3 with concentrated hyrochloric acid. The benzene phase was separated and the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined with each other followed by washing with a sodium chloride aqueous solution. After drying, the mixture was concentrated to give 7.4 g of crude 2-methoxyacetyl-4-methylcyclohexanone. The crude product was used at the following step. (2) 4-Cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl-7-methyl-3-oxoisoquinoline
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH3:6])=[O:4])=[O:2].[O:8]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:8]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][C:17]=1[C:1](=[O:2])[C:3]([O:5][CH3:6])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1=C(COc2ccccc2)OCCC1
Reactant: COC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)C1=C(COc2ccccc2)OCCC1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
35 g (0.29 mol) of methoxalyl chloride are added dropwise to 31 g (0.16 mol) of 6-phenoxymethyl-2,3dihydropyran (Example 7c), 39.5 g (0.5 mol) of pyridine and 2.5 g (0.02 mol) of p-dimethylaminopyridine in 200 ml of methylene chloride. During this procedure, the reaction mixture warms up to 30°-35 ° C. Stirring is carried out overnight and the reaction mixture is then poured onto water. The aqueous phase is separated off and the organic phase is extracted once again with water. The organic phase is then dried over MgSO4 and evaporated down. The residue is purified by column chromatography using hexane/ethyl acetate mixtures. 16 g of starting material and 8.5 g (0.031 mol=19%, pale yellow oil) of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C1C=CC=CC=1>[N:20]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]=12
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: Nc1ncccn1
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3cccnc3n2)cc1
Yield: 46.3 %

Procedure:
A mixture of 48 g of ethyl 4-(chloroacetyl)phenylacetate, 100 ml of ethanol and 38 g of 2-aminopyrimidine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and concentrated to give a brown oil. To the oil is added benzene, and the crystalline precipitate is filtered off and recrystallized from ethyl acetate to give 26 g of ethyl 4-(imidazo[1,2-a]-pyrimidine-2-yl)phenylacetate as pale brown crystals melting at 155°-158°C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[C:13]1([CH:19]([Mg]Cl)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20])[CH3:12]
Reactant: CC([Mg]Cl)c1ccccc1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)C(C)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (92) prepared above at −78° C. After stirring at −78° C. for 3 hours, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=19/1) to give 1,1-diethoxy-3-phenylbutan-2-one (93) as a colorless oily substance (330 mg, 1.37 mmol, 13.7%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].[BH4-].[Na+]>ClCCl.CO>[OH:1][CH:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1N=C(c2cccc(C(F)(F)F)c2)OCC1O
Temperature: 0 °C

Procedure:
To an ice-cooled suspension of 26.0 g 5,6-dihydro-5-oxo-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)-phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in B above) in 300 ml dichloromethane and 300 ml methanol was added 2.3 g sodium borohydride in portions. The resultant mixture was stirred for 45 min and then quenched with 200 ml 1M HCl and diluted with 1 l dichloromethane. The phases were separated and the organic phase was washed with 200 ml 1 M HCl and 100 ml saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to give 5,6-dihydro-5-hydroxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.[CH:26](=O)[C:27]1[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:29].C(N(CC)CC)C>CO>[OH:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[CH:26]=[N:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12
Reactant: O=Cc1ccccc1O
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N=Cc4ccccc4O)C(=O)N23)cc1
Reaction time: 5 h
Yield: 90.1 %

Procedure:
In 50 ml of methanol was dissolved 4.05 g(10 mmol) of 4-methoxybenzyl 7 β-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride, and 1.28 ml(12 mmol) of salicylaldehyde and 1.39 ml(10 mmol) of triethylamine were added thereto. The reaction mixture was stirred for 5 hours. The resulting precipitate was filtered, washed with 50 ml of methanol and dried to give 4.26 g of the desired compound(90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:37])[CH2:5][CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[S:29][N:28]=4)[CH2:23][CH2:22]3)=[C:15]([Cl:18])[CH:16]=2)[CH2:11][C:10]1=[O:36])=[O:8].[CH2:38](O)C.Cl>O>[ClH:18].[CH2:2]([O:3][C:4](=[O:37])[CH2:5][CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[S:29][N:28]=4)[CH2:23][CH2:22]3)=[C:15]([Cl:18])[CH:16]=2)[CH2:11][C:10]1=[O:36])=[O:8])[CH3:38]
Reactant: CCO
Reactant: COC(=O)CCC(=O)N1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21
Agent: Cl
Solvent: O
Product: CCOC(=O)CCC(=O)N1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21

Procedure:
The product of Example 5, (611 mg, 1.1 mmol) was mixed with ethanol (27 mL) and concentrated hydrochloric acid (0.5 mL) and the mixture boiled under reflux for 24 h in the temperature range 78-80° C. Distilled water (20 mL) was added to the hot reaction mixture and solids removed during the hot filtration. The filtrate was cooled further and product solids were isolated by filtration, washed with distilled water (20 mL), and dried under vacuum to yield 200 mg (32%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][C:48]([CH3:54])([CH3:53])[CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][C:48]([CH3:54])([CH3:53])[CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 3,3-dimethylbutanoyl chloride (0.050 g, 0.372 mmol) followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 701 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11].C(O)=O>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([N:2]([CH3:1])[CH:3]4[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]4)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNC1CCN(C)CC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)C3CCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using N,1-dimethylpiperidin-4-amine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (42 mg, 0.088 mmol, 70.6%) as a white solid. MS: 431 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (d, J=11.6 Hz, 2H) 1.78-1.95 (m, 2H) 2.35 (s, 3H) 2.78 (s, 3H) 2.92-3.83 (m, 7H) 4.34 (br. s., 1H) 7.43 (d, J=8.3 Hz, 1H) 7.48 (s, 1H) 7.76-7.88 (m, 2H) 8.06-8.11 (m, 1H) 8.38 (br. s., 1H) 8.43 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH:1]1([N:10]2[C:18](=[O:19])[NH:17][C:16]3[C:11]2=[N:12][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[N:14][C:15]=3[C:20]([O:22]C)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:41]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=1NC1C2C(=CC=CC=2)CC1>ClCCl>[CH:1]1([N:10]2[C:18](=[O:19])[NH:17][C:16]3[C:11]2=[N:12][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[N:14][C:15]=3[C:20]([NH2:41])=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(NC2CCc3ccccc32)c1N
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2C1CCc2ccccc21
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCc2ccccc21
Yield: 85 %

Procedure:
Methyl 9-(2,3-dihydro-1H-inden-1-yl)-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate (0.192 g, 0.360 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.467 g, 2.88 mmol) in dichloromethane (15 mL) were reacted according to General Procedure F and purified using biotage chromatography (0 to 45% EtOAc in hexanes) to afford the title compound (0.171 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 7.76 (d, J=7.99, 1H), 7.64 (s, 1H), 7.36 (d, J=7.59, 1H), 7.32 (t, J=7.99, 1H), 7.24 (m, 1H), 7.12 (s, 1H), 7.11 (s, 1H), 6.92 (dd, J=7.99, 2.39, 1H), 6.05 (t, J=7.19, 1H), 3.94 (s, 3H), 3.33 (s, 9H), 3.06 (m, 1H), 2.67 (m, 1H), 1.23 (m, 3H), 1.08 (m, 18H).