Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]([CH2:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2F)([OH:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)C=O.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(Cc2cc(Cl)ccc2F)CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc2c(c1)CC1(CCN(Cc3ccccc3)C1)O2
Temperature: 25 °C
Yield: 46 %

Procedure:
To a suspension of sodium hydride (NaH) (55%, 612 mg, 14.0 mmol) in toluene (10 mL) was added a solution of 1-benzyl-3-(5-chloro-2-fluorobenzyl)pyrrolidin-3-ol (1.3 g, 4.06 mmol) in toluene (20 mL) and the reaction mixture was kept on stirring at reflux, after 5 minutes dimethylformamide (10 mL) was added and the reaction mixture was refluxed for 90 minutes, cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% ammonium hydroxide, NH4OH) to give the subtitled compound (560 mg).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([CH2:4][C:5]([CH3:20])=[C:6]([CH:13]=[CH:14][C:15]([CH3:19])=[CH:16][CH2:17][OH:18])[C:7]2([CH3:12])[CH3:11])[O:2]1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([CH2:4][C:5]([CH3:20])=[C:6]([CH:13]=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=[O:18])[C:7]2([CH3:11])[CH3:12])[O:2]1
Reactant: CC(C=CC1=C(C)CC2OCCOC2C1(C)C)=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC(C=CC1=C(C)CC2OCCOC2C1(C)C)=CC=O
Reaction time: 24 h

Procedure:
500 g. of manganese dioxide was added in 3 portions over 9 hours to a solution of 42 g. of crude 5-(4-ethylenedioxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienol in 1 l. of benzene. During this period a suspension formed. The suspension was then stirred under nitrogen for 24 hours. Filtration and evaporation of the solvent yielded a light yellow oil which was used for the next steps without further purification. The yellow oil was purified by chromatography on silica gel G. The yellow oil was identified as 5-(4-Ethylenedioxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienal.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:24])=[CH:21][N:20]=1
Reactant: O=C(O)c1ccc(-c2ccccc2F)nc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2F)nc1

Procedure:
Using the procedure outlined in Example 104, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.19 mmol) and 6-(2-fluorophenyl)-nicotinic acid (D74) (50 mg, 0.23 mmol) as a yellow solid. MS(ES): MH+ 344, M-H+ 342
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[N:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:17][CH:16]=1)=[N:11][C:10]([C:40]1[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 78.6 %

Procedure:
Following general procedure II, tert-butyl 1-[5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)pyrimidin-2-yl]pyrrolidin-3-ylcarbamate (120 mg, 0.25 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (110 mg, 0.38 mmol) to afford the product (120 mg, 80%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 12.02 (s, 1H), 9.12 (s, 1H), 8.28-8.20 (m, 3H), 7.93 (d, J=8.8 Hz, 1H), 7.39 (s, 2H), 4.72 (br s, 1H), 4.36 (br s, 1H), 3.86 (br s, 1H), 3.65 (br s, 2H), 3.40 (br s, 1H), 2.80 (s, 3H), 2.28 (br s, 1H), 2.03-1.93 (m, 1H), 1.48 (s, 9H); ESI MS m/z 610 [M+H]+
Reaction SMILES: Br.[N:2]1([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=O)[CH:20]=[CH:19][C:18]=2[CH:17]=[CH:16]1>>[N:13]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:2]1[CH2:7][CH2:6][N:5]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:21]2[N:22]=[C:23]3[C:18]([CH:17]=[CH:16][C:15](=[O:14])[NH:24]3)=[CH:19][CH:20]=2)[CH2:4][CH2:3]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Br
Product: O=c1ccc2ccc(OCCCCN3CCN(c4ncccn4)CC3)nc2[nH]1

Procedure:
In a manner similar to that of other examples above, 2-piperazin-1-yl-pyrimidine hydrobromide was coupled by reductive amination to 4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, MS: APCI: M+1: 381.1 (Exact Mass: 380.20).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]=[CH:9][C:8]2[N:7]=[C:6]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:4][C:3]1=2.[H-].[Na+].CI.[C:30](O)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:11]1[CH:10]=[CH:9][C:8]2[N:7]=[C:6]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (186 mg, 0.57 mmol) in dry DMF (2 mL) was added 60% sodium hydride in mineral oil (29 mg, 0.72 mmol). The reaction was stirred at room temperature for 15 minutes and then methyl iodide was added via syringe (40 μL, 0.70 mmol). After 30 minutes the reaction was diluted with ethyl acetate and some acetic acid was added to neutralize the base. The solution was washed with aqueous NaHCO3 and the organic layer was dried (anhydrous Na2SO4), filtered and the solvent evaporated. The residue was triturated with diethyl ether to give the title compound as a pale yellow solid. The mother liquors were chromatographed on silica gel eluting with a 30-70% ethyl acetate/hexane gradient to give additional product. 1H-NMR (500 MHz, CDCl3): δ 10.02 (1H, s), 8.74 (1H, s), 7.80 (2H, d, J=8 Hz), 7.60 (2H, d, J=8 Hz), 7.37 (1H, d, J=7.6 Hz), 7.28-7.31 (2H, m), 7.19-7.22 (2H, m), 6.85 (1H, d, J=7.6 Hz), 3.67 (3H, s). m/e (m+1): 341.1.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1.ClC1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]1([C:7]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cn1
Yield: 69 %

Procedure:
A mixture of toluene (20 mL) and water (5 mL) was degassed with argon for 5 minutes. Sodium carbonate (1.53 g, 0.01444 mole) was then added and the mixture was degassed with argon for a further 5 minutes. Phenyl boronic acid (1.126 g, 0.00866 mole) and 5-chloro-pyridine-2-carbonitrile (1 g, 0.00722 mole) were added and the resulting mixture was degassed with argon for a further 5 minutes. tetrakis(triphenylphosphine)palladium(0) (1.67 g, 0.00144 mole) was added and the resulting mixture was degassed with argon for a further 5 minutes. The reaction mixture was then heated to reflux for 3 hours. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed with water followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 0.9 g (69%) of 5-phenyl-pyridine-2-carbonitrile. LCMS: 181.07 (M+1)+, 28.90%, 1H NMR (DMSO-d6): δ 9.1 (s, 1H), 8.4-8.3 (m, 1H), 8.2-8.1 (m, 1H), 7.9-7.78 (m, 2H), 7.6-7.4 (m, 3H). To a stirred solution of 5-phenyl-pyridine-2-carbonitrile (0.9 g, 0.005 mol) in a mixture of ethanol (10 mL) and water (5 mL) was added NaOH (1 g, 0.025 mol) and the resulting mixture was stirring overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in water, washed with ether and the aqueous layer was acidified with citric acid. The acidified aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.75 g (75%) of 5-phenyl-pyridine-2-carboxylic acid. LCMS: 200.06 (M+1)+, 97.53%, 1H NMR (DMSO-d6): δ 13 (bs, 1H), 9.1-9.0 (d, 1H), 8.3-8.2 (dd, 1H), 8.2-8.1 (d, 1H), 7.8 (d, 1H), 7.6-7.4 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18]C)=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=[C:35]([N+:41]([O-:43])=[O:42])[C:32]=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:35][N+:41]([O-:43])=[O:42])[C:10]=1[CH:11]=[CH:32][CH2:35][N+:41]([O-:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Product: COc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Yield: 53 %

Procedure:
This compound is obtained according to the operating method described in Example 2a, in which the 2-benzyloxy-3-ethoxy-6-nitrobenzaldehyde is replaced with 2-benzyloxy-3-methoxy-6-nitrobenzaldehyde. A light yellow powder (yield=53%, m.p.=149°-150° C.) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:26][CH2:27][S:28](=[O:31])(=[O:30])[CH2:29][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:26][CH2:27][S:28](=[O:30])(=[O:31])[CH2:29][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Reaction time: 20 h

Procedure:
A solution of methyl 4-[(4aR,10bR)-9-ethoxy-8-methoxy-2,2-dioxido-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoate (380 mg; compound C5) in 1,4-dioxane (10 ml) is treated with an 2 M aqueous solution of sodium hydroxide (1 ml) and the reaction solution is stirred for about 20 h at 45° C. to 50° C. The solution is allowed to come to RT and afterwards a 2 M aqueous solution of hydrogen chloride (1 ml) is added. The mixture is stirred for 20 min at RT, filtered and the filtrate is evaporated to dryness in vacuo. Subsequently, the residue is treated with DCM (30 ml) and the resulting suspension is filtered. The solvent is removed in vacuo to yield the title compound as a solid.
Reaction SMILES: C(OCC)(=O)C.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[O:19][C:18]([CH3:21])([CH3:20])[N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:16]2[CH2:29][F:30])=[CH:11][CH:10]=1)#[CH:8].Cl/[C:32](=[N:38]/[OH:39])/[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:25]([O:24][C:22]([N:17]1[C@H:16]([CH2:29][F:30])[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[O:39][N:38]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=3)=[CH:14][CH:13]=2)[O:19][C:18]1([CH3:21])[CH3:20])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To an ethyl acetate (20 ml) solution of (4S,5R)-tert-butyl 5-(4-ethynylphenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.35 g, 4.0 mmol) is added a dimethylformamide solution of (E)-ethyl 2-chloro-2-(hydroxyimino)-acetate (12.5 ml, 1.5 g, 2.5 equiv). Sodium hydrogen carbonate (3.5 g) is added to the solution and it is allowed to stir overnight at room temperature. The mixture is filtered and diluted with ethyl acetate (100 ml). After washing with water (4×25 ml) the organic phase is concentrated to give the crude product, which is purified on silica gel using a gradient of ethyl acetate in hexanes (0% to 20% ethyl acetate) to give the title compound (567 mg): 1H NMR (400 MHz, CDCl3) 1.43-1.56 (m, 14H) 1.62 (s, 3H) 1.74 (br. s., 3H) 4.50 (q, J=7.24 Hz, 3H) 5.20 (d, J=7.33 Hz, 1H) 6.96 (s, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.86 (d, J=8.59 Hz, 2H), m/z (Cl) 449 ([M+H]+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][C@@H:35]1[C:60](=[O:61])[N:37]2[C:38]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:39]([CH2:42][Cl:43])[CH2:40][S:41][C@H:36]12.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([NH:34][C@@H:35]2[C:60](=[O:61])[N:37]3[C:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:45])=[C:39]([CH2:42][Cl:43])[CH2:40][S:41][C@H:36]23)=[O:29])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C

Procedure:
To 25 ml of N,N-dimethylformamide were added 1.3 g (3 mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid and 1.35 (3 mmol) of diphenylmethyl 7 β-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride. The mixture was cooled to 0° C., and 0.53 g (3.9 mmol) of N-hydroxybenzotriazole hydrate and then 0.80 g (3.9 mmol) of N,N-dicyclohexylcarbodiimide were added thereto.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of 4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 19 supra) (300 mg, 0.64 mmol) and 3-chlorobenzylamine (360 mg, 2.54 mmol) was heated at 130° C., with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford (4-{3-[2-(3-chloro-b enzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 150 mg, 43.5%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC)=[CH:12][CH:11]=1)#[N:9]>O.C(O)C>[CH3:24][S:21]([N:20]=[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=1)[NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:23])=[O:22]
Reactant: NCC(=O)O
Reactant: CSC(=NS(C)(=O)=O)Nc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)N=C(NCC(=O)O)Nc1ccc(C#N)cc1
Yield: 55 %

Procedure:
A mixture of 0.57 g (7.6 mol) of glycine, of 0.3 g (7.6 mmol) of sodium hydroxide in 3 cm3 of water and of 2.0 g (7.6 mmol) of N-(4-cyanophenyl)-N'-methylsulfonyl-S-methylisothiourea in 30 cm3 of 95% ethanol is heated at boiling point for 7 hours. After cooling, the precipitate obtained is filtered and dissolved in 20 cm3 of a 1N sodium hydroxide solution. The solution obtained is washed with dichloromethane (3×10 cm3) and ethyl acetate (2×10 cm3) then acidified to a pH close to 3 with a 6N HCl solution. After cooling, the precipitate obtained is filtered, washed with water (2×5 cm3) and dried in vacuo to give N-[methylsulfonylimino(4-cyanophenylamino)methyl]-2-aminoethanoic acid (yield 55%) having a melting point of 170° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]([F:22])([F:21])[C@H:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Br[C:24]1[CH:25]=[CH:26][C:27]([Cl:31])=[C:28]([CH3:30])[CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:31][C:27]1[CH:26]=[CH:25][C:24]([CH:14]([C@@H:13]([CH3:20])[C:12]([F:21])([F:22])[F:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:29][C:28]=1[CH3:30]
Reactant: CCOC(=O)C[C@@H](C)C(F)(F)F
Reactant: Cc1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(Cl)c(C)c1)[C@@H](C)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
29.2 ml (29.2 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −10° C., and a solution of 4.30 g (23.4 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in 26 ml of abs. toluene was added dropwise. The mixture was stirred for 10 min At −10° C., a solution, prepared beforehand, of 5.0 g (19.5 mmol, 80% pure) of 5-bromo-2-chlorotoluene, 131 mg (0.58 mmol) of palladium(II) acetate and 483 mg (1.23 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 26 ml of abs. toluene was then added dropwise. The resulting reaction mixture was initially stirred at RT for 1 h and then at 80° C. for 4 h. After cooling, the mixture was diluted with ethyl acetate, washed twice with sat. aqueous sodium bicarbonate solution and once with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 7.80 g of the title compound as a crude product which was directly reacted further.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH3:22]O>>[CH3:22][O:16][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: CO
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)c2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 7 h

Procedure:
4,6-Dimethoxy-1-naphthalenecarboxylic acid (98.5 g, 0.425 mole, described in Example 61) was added to an ice-cooled solution of SOCl2 (59.5 g, 0.5 mole) in anhydrous methanol (225 ml). The mixture was heated at reflux for 18 hr. Another portion of SOCl2 (35.5 ml) was added and the reflux was continued for another 7 hr. The mixture was extracted with diethyl ether. The ether extract was washed with water and then aqueous NaHCO3 solution, dried (Na2SO4) and concentrated to dryness. The solid residue was crystallized from methanol (720 ml) to give 64.5 g of 4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester; mp 102°-104° C.; NMR (CDCl3) δ3.9 (s, 6H), 4.0 (s, 3H), 7.7 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)N1CCN(c2ccc(O)cc2)CC1
Reactant: C1COCCN1
Solvent: CO
Product: O=C(CN1CCOCC1)N1CCN(c2ccc(O)cc2)CC1
Temperature: 50 °C

Procedure:
A mixture of 10 parts of 1-(2-chloroacetyl)-4-(4-hydroxyphenyl)piperazine, 6.9 parts of morpholine and 40 parts of methanol is stirred and heated for 2 hours at 50° C. The reaction mixture is evaporated and the residue is stirred with water. The precipitated product is filtered off, dried on the filter and crystallized from 2-propanol, yielding 5.5 parts of 1-(4-hydroxyphenyl)-4-[(4-morpholinyl)acetyl]piperazine; mp. 197.3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([CH:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[OH:10])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[OH:10])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCNCC2)cc1
Yield: 29.8 %

Procedure:
A solution of 36.7 g (0.088 mole) of α,α-bis(4-methoxyphenyl)-1-(phenylmethyl)-4-piperidinemethanol in 500 ml of absolute ethanol was hydrogenated over 1 tsp of 5% Pd/C at 60° C. in a Parr apparatus over the weekend. The mixture was cooled, filtered through Celite®, fresh catalyst added to the filtrate and the process repeated until no starting material was present by mass spectral analysis. The filtrate was concentrated and the residue was partitioned between methylene chloride and a 5% sodium hydroxide solution. The organic layer was dried over sodium sulfate and concentrated to give a solid residue. The solid was recrystallized from 2-propanol to yield 8.6 g (30%) of white solid, mp 153°-155° C.