Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[C@@H:23]([CH3:27])[N:22](C(=O)C(C)(C)C)[CH2:21]5)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:34])[C:6]([C:35]([O:37]CC)=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.O>Cl>[OH2:14].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[C@@H:23]([CH3:27])[NH:22][CH2:21]5)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(=O)C(C)(C)C)[C@@H]4C)ccc2c1=O
Agent: Cl
Solvent: O
Product: C[C@H]1NCc2cc(-c3ccc4c(=O)c(C(=O)O)cn(C5CC5)c4c3OC(F)F)ccc21
Yield: 182.1 %

Procedure:
In 68 ml of conc. hydrochloric acid is suspended 34 g of ethyl (R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate, and the suspension is heated under reflux for 3 hours, after which 340 ml of water is added to the resulting mixture and 170 ml of the solvent is removed from the mixture by distillation under atmospheric pressure over 3 hours. The reaction mixture is cooled and thereafter 17 ml of ethanol is added to the mixture, after which the crystals deposited are collected by filtration. The resulting (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride is suspended in 340 ml of water and the pH of the mixture is adjusted to 7.5 with 2 moles/liter sodium hydroxide solution, after which the crystals deposited are collected by filtration to obtain 25.55 g of (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid monohydrate.
Reaction SMILES: [N+:1]([O-])([N+]([O-])=O)=[O:2].C([O-])(=O)C.[Na+].[Cl:12][CH2:13][CH2:14][NH:15][C:16]([N:18]=[N+:19]=[N-:20])=[O:17].CC(O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:13][CH2:14][N:15]([N:1]=[O:2])[C:16]([N:18]=[N+:19]=[N-:20])=[O:17]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: [N-]=[N+]=NC(=O)NCCCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NC(=O)N(CCCl)N=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Nitrogen tetroxide (0,3 mole) was slowly added to a suspension of anhydrous sodium acetate (0.6 mole) in 300 ml of carbon tetrachloride at -10° C. After warming to 0° C., 2-chloroethylcarbamoyl azide (0.2) was slowly added with a spatula to the stirred suspension. A white precipitate was formed (AcOH). After 15 minutes, the reaction mixture was poured into ice water. The separated organic phase was extracted twice with 50 ml of a cold solution of NaHCO3 (1 molar) and was then washed neutral with 2×50 ml of ice cold water saturated with NaCl. It was then dried over anhydrous sodium sulfate. No attempt was made to isolate N-(chloroethyl)-N-nitrosocarbamoyl azide as it is potentially explosive. The NMR spectroscopic examination of the CCl4 solution (internal standard TMS) showed the complete absence of an NH- signal and showed a pattern which is typical for the A2B2 system of the nitrosated 2-chloroethylamino group. δ=3.50 ppm (t, 2H, --CH2 -- N--NO); 4.15 ppm (t, 2H, Cl--CH2 --).
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:25][CH3:26])[CH:8]=1)=[O:6])C>C(O)(=O)C>[CH2:25]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([F:18])=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:11]=2)[C:16](=[O:17])[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1)[CH3:26]
Reactant: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 83.5 %

Procedure:
To a mixture of glacial acetic acid (170 ml) and concentrated hydrochloric acid (170 ml) was added 4.3 g of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 10 ml of water and adjusted to pH 7.5 with diluted sodium hydroxide solution. The precipitated crystals were carried out by the same way in the Example 1 to give 3.3 g (84% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. mp: 220.5°-222° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3](C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.CN1CCOCC1.CN(C=O)C.[C:49]1([CH3:67])[CH:54]=[CH:53][C:52]([S:55]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:57])=[O:56])=[CH:51][CH:50]=1>>[C:49]1([CH3:67])[CH:50]=[CH:51][C:52]([S:55]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[C:60]([CH3:62])([CH3:63])[CH3:61])(=[O:56])=[O:57])=[CH:53][CH:54]=1.[C:49]1([CH3:67])[CH:50]=[CH:51][C:52]([S:55]([NH:58][C@H:59]([C:64]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:66])[C:60]([CH3:61])([CH3:62])[CH3:63])(=[O:56])=[O:57])=[CH:53][CH:54]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)(C)C)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C(=O)O)C(C)(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-tert-butylglycine was prepared from L-tert-butylglycine using the procedure described in Method 1. The title compound was prepared by coupling in DMF N-(toluene-4-sulfonyl)-L-tert-butylglycine with an L-phenylalanine ester in the presence of BOP and NMM. Conventional deesterification provided the title compound.
Reaction SMILES: [C:1]1([CH:7]([CH3:19])[CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]1([CH:7]([CH3:19])[CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CNC(=O)c1ccc(Cl)nn1)c1ccccc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccccc1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-phenylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.2% yield). 1H NMR (500 MHz, CDCl3) δ 7.97, 7.80, 7.68, 7.57, 7.50, 7.30, 7.24, 7.20-7.12, 6.92, 3.98, 3.80, 3.74-3.60, 3.53, 3.28, 3.00, 1.28.
Reaction SMILES: CN(C)C=O.[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>O>[C:6]1([S:12][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccccc2)cc1
Reaction time: 3 h
Yield: 28.2 %

Procedure:
Into a dimethylformamide (DMF) solution (30 mL) of 11.0 g (100 mmol) of benzenethiol is gradually added 14.0 g (132 mmol) of anhydrous Na2CO3 at 85° C. Then 4-chlorobenzaldehyde (11.3 g, 80.0 mol) is added during 20 min. at 85° C. The reaction solution is stirred at this temperature for 3 h. After adding H2O into the reaction mixture, the crude product is extracted with ethyl acetate. The organic layer is washed twice with H2O and with brine, dried over anhydrous MgSO4 and condensed. The residue is applied to column chromatography on silica gel with acetone-hexane (from 1:30 to 1:10) as eluent. 6.05 g of pale yellow oil are obtained (35%). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 7.24 (d, 2H), 7.42-7.44 (m, 3H), 7.53 (dd, 2H), 7.71 (d, 2H), 9.96 (s, 1 H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH2:21][CH3:22])[CH2:4][C@H:5]([CH2:9][N:10]([CH:18]=[O:19])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:6]([OH:8])=O)C.[Cl:23][C:24]1[N:29]=[C:28]([N:30]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:27]([F:44])=[C:26]([NH:45][NH2:46])[N:25]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([NH:45][NH:46][C:6](=[O:8])[C@H:5]([CH2:4][CH:3]2[CH2:1][CH2:22][CH2:21][CH2:20]2)[CH2:9][N:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:18]=[O:19])[C:27]([F:44])=[C:28]([N:30]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[N:29]=1
Reactant: CCCC(CC)C[C@H](CN(C=O)OC1CCCCO1)C(=O)O
Reactant: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NN)c2F)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Reaction time: 8 h
Yield: 57.2 %

Procedure:
(2R)-4-Ethyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}heptanoic acid (0.3764 g, 1.257 mmol), 2-chloro-5-fluoro-6-hydrazino-N-(4-methyl-1-piperazinyl)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.1683 g), NMM (0.298 mL, 2.71 mmol), HOAt (0.074 g, 0.542 mmol), and EDC (0.104 g, 0.542 mmol) were dissolved in DMF (10 mL). The reaction was left to stir overnight. Purification by RP-HPLC provided [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a brown oily solid (0.1688 g). LCMS: (M+H)+=655.4.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2]1.C(O[CH2:16][C:17]([CH2:19][Si](C)(C)C)=[CH2:18])(=O)C>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]=[C:17]1[CH2:19][C@@H:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:18]1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: COC(=O)C=Cc1ccsc1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccsc2)C1
Yield: 86.2 %

Procedure:
A mixture of methyl 3-(3-thienyl)acrylate (10.0 g, 59.5 mmol), tetrakis(triphenylphosphine) palladium(0) (5.15 g, 5.6 mmol), 1,2-bis(diphenylphosphino)ethane (1.35 g, 3.4 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (20 g, 107 mmol) in THF (125 mL) under argon was heated to reflux for 24 h. The volatiles were then removed in vacuo and the residue was purified by FC (5% ethyl acetate in hexanes) to afford the title compound (11.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][CH:17]=3)=[CH:30][CH:31]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2ccc3c(c2)OCCC3C(=O)O)cc1
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Methyl 7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3,4-dihydro-2H-chromene-4-carboxylate was dissolved in THF (3 mL) and methanol (3 mL) and treated with 1N NaOH (3 mL), and the reaction was stirred for 1 hour. The reaction was diluted with CH2Cl2 (25 mL) and washed with 2N HCl (25 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 0.5% MeOH/CH2Cl2 containing 0.5% acetic acid to 7.5% MeOH/CH2Cl2 containing 0.5% acetic acid to provide the title compound (0.056 g, 37.8% yield) as a white solid. MS (ESI)=452.1 (M+1).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.Br.[NH2:15][C:16]1([CH3:24])[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C>CN(C)C=O>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:15]([C:16]1([CH3:24])[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CC1(N)CCC(=O)NC1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(N2Cc3cc(Br)ccc3C2=O)CCC(=O)NC1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (3.0 g, 10.0 mmol), 3-amino-3-methyl-piperidine-2,6-dione hydrobromide (2.2 g, 10.0 mmol) and triethylamine (2.0 g, 20 mmol) in N,N-dimethylformamide (10 mL) was heated to 90° C. under nitrogen. After 1 h, the mixture was cooled to rt and the solvent was removed in vacuo. The crude residue was purified by column chromatography (95:5 CH2Cl2: MeOH) providing 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-3-methyl-piperidine-2,6-dione (2.0 g, 61% yield); 1H NMR (DMSO-d6) δ 1.67 (s, 3H), 1.87-1.93 (m, 1H), 2.54-2.80 (m, 3H), 4.64 (d, J=17.9 Hz, 1H), 4.73 (d, J=17.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.1, 1.5 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 10.89 (s, 1H).
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[Bi](Cl)(Cl)Cl.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: Cl[Bi](Cl)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 0.60 ml of antimony pentachloride, 15.18 g of bismuth trichloride and 1.95 ml of trimethyl borate. The mixture was heated at 50° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.81 g. The yield of the desired product was 64%.
Reaction SMILES: C(OC([O:6][CH2:7][CH2:8][CH2:9][Li])C)C.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].[BH4-].[Na+].Cl>CCOCC.CC(O)C.O>[ClH:11].[NH2:24][CH:23]([C:19]1([C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)[CH2:20][CH2:21][CH2:22]1)[CH2:9][CH2:8][CH2:7][OH:6]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [Li]CCCOC(C)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: NC(CCCO)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0.25M solution of 3-[1-(ethoxy)ethoxy]propyllithium [prepared from 3-[1-(ethoxy)ethoxy]propyl bromide (20 g), lithium strips (1.6 g) and ether (75 ml)] was added to a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (4.44 g) in dry ether (100 ml) at 0° C. under argon. The mixture was stirred for 16 hours at ambient temperature and propan-2-ol (50 ml) and then a solution of sodium borohydride (1.5 g) in propan-2-ol (60 ml) were added and the mixture stirred at ambient temperature for 2 days and then heated under reflux for 21/2 hours. The mixture was cooled, poured into water (500 ml) and excess concentrated hydrochloric acid was added. The mixture was heated at 90°-95° C. for one hour, cooled, basified and extracted with ether. The extract was dried and evaporated to given an oil which was treated with a further mixture of sodium borohydride (1 g) and propan-2-ol (50 ml) at reflux for 41/2 hours. The mixture was cooled, and water was added and the resulting mixture extracted with ether. The extract was dried, and evaporated to give an oil which was distilled (170° C./0.65-0.25 mm Hg). The distillate was dissolved in propan-2-ol, 5N-hydrochloric acid was added and the solution evaporated to dryness. The residue was dried by azeotropic distillation with propan-2-ol to give a solid which was triturated with propan-2-ol to give 4-amino-4-[1-(3,4-dichlorophenyl)cyclobutyl]butan-1-ol hydrochloride (m.p. 211° C. (dec)-shrinks 203° C.).
Reaction SMILES: C([C:3]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH:5]=[CH:6][N:7](C)[CH3:8])#N.S(=O)(=O)(O)[OH:22]>>[CH3:20][O:19][C:17](=[O:18])[C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:6]=[N:7][C:8]=1[OH:22]
Reactant: COC(=O)C(C#N)=C(C=CN(C)C)c1ccc(C)cc1
Reactant: O=S(=O)(O)O
Product: COC(=O)c1c(-c2ccc(C)cc2)ccnc1O
Temperature: 0 °C
Yield: 60.9 %

Procedure:
117.0 g (0.54 mol) of 1-cyano-1-methoxycarbonyl-4-(N,N-dimethylamino)-2-(4-methylphenyl)-1,3-butadiene was added to 250 ml of concentrated sulfuric acid at a temperature below 20° C. under stirring, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 l of ice water, and the precipitated material was filtrated out. The filtrate was adjusted to pH 6 with sodium hydroxide aqueous solution to precipitate the aimed product, which was then filtrated out. The material thus precipitated was washed with water and methanol, and was dried to obtain 74.9 g of a white crystal of the aimed product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Cl:11][SiH:12]([Cl:14])[Cl:13]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Si:12]([Cl:14])([Cl:13])[Cl:11])=[CH:5][CH:4]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: COc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 74.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.19 g (0.64 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.39 mmol) of 4-methoxybenzyl chloride, and 2.46 ml (18.2 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.22 g of (4-methoxybenzyl)trichlorosilane (yield; 86%).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[Cl:21][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add 4 M HCl in 1,4-dioxane (10 mL) to 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (6.80 g, 22.76 mmol). Add 1,4-dioxane (40 mL) and subject the reaction to ultrasound then stir at room temperature under nitrogen for 3 hr. Add further HCl in 1,4-dioxane (40 mL) and stir for 1 hr. Add chloroform (400 mL), wash with 2 N sodium hydroxide (200 mL), saturated aq. sodium chloride (100 mL), dry (magnesium sulfate) and concentrate to give 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a yellow oil which crystallized on standing to give a solid (4.0 g, 88%). MS (ES): m/z=199.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.[Br:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:12][C:13]1[CH:18]=[C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)[CH:16]=[C:15]([F:20])[CH:14]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 140 °C
Yield: 27.8 %

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (2.0 g, 17 mmol), 1-bromo-3,5-diflurobenzene (6.6 g, 34 mmol), potassium carbonate (2.4 g, 34 mmol) were combined in DMF (30 mL) under argon. The reaction mixture was heated at 140° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (300 mL), and washed with H2O (3×300 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil which solidified when pumped down under high vacuum. The crude product was purified by column chromatography eluting with 2:8 EtOAc:hexanes to afford 2-[1-(3-bromo-5-fluorophenyl)-1H-pyrrol-3-yl]pyridine (1.5 g, 35% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.61-8.62 (d, 1H), 8.50-8.53 (t, 1H), 8.40 (s, 1H), 8.35-8.36 (d, 1H), 7.78-7.81 (m, 2H), 7.57-7.62 (m, 1H), 7.54-7.57 (d, 1H), 7.43-7.46 (d, 1H), 7.11 (s, 1H), MS 319.1 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH2:14]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:16][C:17]1([C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH2:14][N:20]1[CH2:21][CH2:22][C:17]([OH:16])([C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: CC(C)(C)c1ccccc1OCCCCl
Product: CC(C)(C)c1ccccc1OCCCN1CCC(O)(c2cnc3ccccc3c2)CC1
Yield: 39 %

Procedure:
Beginning with 0.298 gm (1.3 mMol) 3-chloropropyl 2-tert-butylphenyl ether and 0.300 gm (1.3 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.212 gm (39%) of the title compound were recovered as a white, waxy solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=2[N:5]=[CH:6][N:7]=1.O.[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]3[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(N)c3)c12
Temperature: 95 °C

Procedure:
A mixture of ethyl 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1.00 g, 2.81 mmol), 3-aminophenylboronic acid monohydrate (577 mg, 4.21 mmol), 2 M aqueous sodium carbonate (893 mg, 8.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (649 mg, 0.562 mmol) in dioxane (10 mL) and water (2 mL) was purged with argon. The reaction vessel was sealed in a microwave vial and the reaction mixture heated at 95° C. for 2 hours. The resulting mixture was filtered through Celite. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetatehexane to afford ethyl 4-(3-aminophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H29N4O3Si [M+H]+: 413, found 413.