Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([OH:16])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:10]([OH:16])([CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CC(O)(CCl)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CC(O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 90 °C
Yield: 47 %

Procedure:
1.62 g (0.04 mole) of a 60% w/v dispersion of sodium hydride in mineral oil were added to 60 ml of dimethylformamide. Whilst the mixture was being stirred in an ice bath, 2.91 g (0.04 mole) of 1,2,4-triazole were added, and the mixture was stirred for a further 30 minutes at room temperature. At the end of this time, 5.5 g (0.021 mole) of 1 chloro-2-(4-fluorophenyl)-3-trimethylsilyl-2-propanol (prepared as described in Example 40) were added to the reaction mixture, which was then heated for 30 minutes at 90° C. whilst stirring. The reaction mixture was cooled and then poured into 200 ml of ice-water, and the resulting mixture was extracted with 300 ml of ethyl acetate. The organic extract was washed three times, each time with 100 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to afford a crude oily product. 2.9 g (yield 47%) of the title compound, melting at 118 119° C., were obtained by purification of this crude oily product by silica gel column chromatography, using mixtures of ethyl acetate and hexane in proportions of 1:5, 1:1 and 2:1 as the eluent.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:46][O:47][CH2:48][CH:49]=[CH2:50])[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C1(OC)C=CC=CC=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:46][O:47][CH2:48][CH:49]=[CH2:50])[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3ccccc3)CS[C@H]12)c1nsc(N)n1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS/C=C\c3ccccc3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
To a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-phenylvinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (748 mg) in a mixture of methylene chloride (2.24 ml), anisole (0.37 ml) and thioanisole (0.37 ml) was added trifluoroacetic acid (1.5 ml) under ice-cooling. The mixture was stirred for 30 minutes at the same temperature and poured into diisopropyl ether (50 ml). The resulting precipitate was collected, washed with diisopropyl ether and dissolved in a mixture of ethyl acetate and an aqueous solution of sodium bicarbonate at pH 7. The aqueous layer was separated, adjusted to pH 6.2 with diluted hydrochloric acid and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in diisopropyl ether to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-phenylvinylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (207 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:29]([F:31])([F:32])[F:30])[CH:11]=3)=[O:22])=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: NC1(C2CC2)CC1
Reactant: C#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1cc2cn[nH]c2c(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 530 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-5-ethynyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of N,N-dimethylformamide, is added 465 mg (3.48 mmol) of bicyclopropyl-1-ylamine hydrochloride and 485 μL (3.48 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 3:7) affords 200 mg (31% over two steps) of the product as white solid; LC/MS:554/556 (M+H)+, m.p.: 246-248° C.
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[Si:1]([C:8]1[S:9][C:10]([C:19]2([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:23][CH2:24]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1nccs1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 100 mL 3-necked round-bottom flask, was placed a solution of 2-(tert-butyldimethylsilyl) thiazole (1.58 g, 7.94 mmol, 1.00 equiv) in tetrahydrofuran (40 mL). This was followed by the addition of n-BuLi (3.7 mL, 1.20 equiv) dropwise with stirring at −78° C. in 1 hr. After half-hour, the benzyl 4-oxopiperidine-1-carboxylate (1.85 g, 7.94 mmol, 1.00 equiv) was added dropwise with stirring at −78° C. in 0.5 hr. The reaction mixture was stirred for 2 h at −78° C. in a liquid nitrogen bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate, and the combined organic layers washed with 2×100 mL of brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 2 g (58%) of benzyl 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)-4-hydroxypiperidine-1-carboxylate as yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([O:13]C)=[C:11]([O:15]C)[C:10]([Cl:17])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[BrH:18]>>[BrH:18].[Cl:2][C:3]1[C:12]([OH:13])=[C:11]([OH:15])[C:10]([Cl:17])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2
Reactant: COc1c(Cl)c2c(c(Cl)c1OC)CNCC2
Agent: Br
Agent: Cl
Product: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2

Procedure:
5,8-Dichloro-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.0 g, 3.35 mmol) was suspended in aqueous HBr (48%, 10 mL) and refluxed for 5 hours before evaporation. The remaining residue was evaporated twice from toluene to give 1.05 g (quant) of the title compound as a pale solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[C:17]([O:25]CC)=[CH:18][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[C:17](=[O:25])[CH:18]=[C:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=CC(=O)C(=O)OC)c1ncnc2c1ncn2Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(O)=CC(=O)c1ncnc2c1ncn2Cc1ccccc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Methyl 4-(9-benzyl-9H-purin-6-yl)-4-ethoxy-2-oxo-but-3-enoate (9) (100 mg, 0.20 mmole) obtained in above step was stirred at room in CH2Cl2 (20 mL) and treated with FeCl3.6H2O (0.125 g, 0.40 mmole). The reaction mixture was stirred at 40° C. for 5 h. Chloroform was distilled off and the resulting residue was treated with 1 N HCl (50 mL) for 1 h and then extracted with EtOAc (4×20 mL). The extract was dried over anhydrous sodium sulfate and the EtOAc distilled off to give a brownish residue which was purified by ion exchange chromatography (diethylamino sephadex anion exchange resin, CH3CN:H2O, (1:1) eluent). Yield 5.2 mg. Mp 166-167° C. 1H NMR (CDCl3) δ 3.99 (s, 3H, CH3), 5.54 (s, 2H, benzylic CH2), 7.35-7.41 (m, 5H, aromatic), 7.9 (s, 1H, olefinic CH), 8.3 (s,1H, purine C8—H), 9.19 (s,1H, purine C2—H). 13C NMR (CDCl3) δ 47.7, 53.4, 101.4, 128.0, 128.0, 128.9, 129.3, 131.8, 134.5, 147.4, 152.3, 154.3, 162.1, 172.8, and 185.7. FAB-HRMS: [M+H]+ calcd. for C17H15N4O4 339.1093, found 339.1083.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13](F)=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>CCO.O>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COCCNc1ccc(C(=O)c2cc(Br)cnc2N)cn1
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A solution of (2-amino-5-bromo-pyridin-3-yl)-(6-fluoro-pyridin-3-yl)-methanone, 2-methoxyethylamine (1 equiv.) and triethylamine (1.2 equiv.) in absolute EtOH (0.17 M) was sealed in a Smith process vial. The reaction was run in a Personal Chemistry® microwave reactor at 160° C. for 900 s. The mixture was diluted with water, and the resulting precipitate was filtered off, washed with water, and dried in vacuo to give (2-amino-5-bromo-pyridin-3-yl)-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone as a yellow solid (86% yield). 1H NMR (DMSO-d6): δ 8.28 (d, J=2.5 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.69 (dd, J=2.0, 9.0 Hz, 1H), 7.64 (broad s, 1H), 7.12 (broad s, 2H), 6.59 (d, J=9.5 Hz, 1H), 3.51 (t, J=4.5 Hz, 2H), 3.47 (t, J=4.5 Hz, 2H), 3.26 (s, 3H); HPLC/MS m/z: 351, 353 [MH]+.
Reaction SMILES: C([N:8]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])C1C=CC=CC=1>Br>[P:14]([CH2:13][NH:8][CH2:9][C:10]([OH:12])=[O:11])([OH:17])([OH:16])=[O:15]
Reactant: O=C(O)CN(Cc1ccccc1)CP(=O)(O)O
Agent: Br
Product: O=C(O)CNCP(=O)(O)O
Temperature: 0 °C
Yield: 40.6 %

Procedure:
N-Benzyl-N-phosphonomethylglycine (65 g.) prepared by the method of Example 1 was dissolved in aqueous hydrobromic acid (46 - 48% w/w, 400 ml.) and the pale yellow solution heated under reflux for 16 hours. The oily layer of benzyl bromide which separated was extracted with petroleum ether (b.p. 60°-80°, 200 ml.) and the pale yellow hydrobromic acid solution evaporated to dryness under reduced pressure. The light brown crystalline product was dissolved in ethanol (300 ml.) and the solution quickly filtered and allowed to stand at room temperature. After a few minutes a white solid began to separate. After cooling at 0° C for 3 hours, the solid (approximately 20 g. m.p. 222° C decomp.) was collected and recrystallised from water to yield N-phosphonomethylglycine (17.2 g 41%) This material became coloured and softened at 230° - 235° C but did not decompose until 314° C. This material was analysed. Found: C, 21.13; H 4.52; N 8.49% Calculated for C3H8NO5P: C, 21.31; H, 4.77; N, 8.28% The melting point of analytically pure N-phosphonomethyglycine, purified by slow precipitation from strongly acid aqueous solution, has been reported in Belgian Pat. No. 774,349 to be 230° C (decomp.) A sample of N-phosphonomethylglycine was purified by precipitation from strongly acid (HCl) aqueous solution and was found to have a melting point of 230° (decomp.) This material was found to have nuclear magnetic resonance spectrum identical with that of the material recrystallised from water and having a melting point of 314° (decomp.) The solvent used for studying the nuclear magnetic resonance spectrum was deuterium oxide. The infra-red spectra of Nujol mulls of the two materials (m.p. 230° and m.p. 314°) were examined and found to be very similar with some minor differences in peak heights. The solubility of the two forms in water was determined at various temperatures by adding the finely powdered solids to deionised water until saturated. The results are given below.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CC(O)=O>[CH2:2]([O:3][C:4]([C@H:6]1[CH2:12][CH2:11][C@H:9]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-cyclohexanonecarboxylic acid ethyl ester (5.0 g, 29.0 mmol) and tert-butyl carbazate (3.9 g, 29.4 mmol) in dichlorometane (250 mL) and AcOH (4 mL) was added NaBH(OAc)3 (18.7 g, 88.0 mmol) gradually at 0° C. After addition, the mixture was stirred at the same temperature for 3 h, then allowed to warm to room temperature and stirred for 20 h. The reaction mixture was poured into saturated aqueous Na2CO3 solution and extracted with DCM. The DCM extracts were washed with brine×2 and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound D1-1 (3.0 g, 36%) as a white solid.
Reaction SMILES: [F:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:1][C:2]([CH3:36])([CH3:37])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)amide (93 mg, 0.176 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.54 ml, 7.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.7 ml, 10.5 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-6% MeOH) then triturated with ethyl acetate to afford 34 mg (46%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amide as a light yellow powder. MS: (M+H)+=399; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.90 (br. s., 1H), 9.12 (s, 1H), 8.45-8.54 (m, 2H), 8.25 (d, J=9.8 Hz, 1H), 7.68 (dd, J=9.8, 2.3 Hz, 1H), 7.09 (td, J=9.1, 2.3 Hz, 1H), 4.30-4.48 (m, 1H), 4.15 (s, 3H), 1.29-1.52 (m, 9H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][CH2:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[Cl:5][CH2:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: Nc1nnc(CCl)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(CCl)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-chloromethyl-2-amino-1,3,4-thiadiazole (10 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours resulting in the formation of a precipitate. The reaction mixure is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the desired product 5-chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid.
Reaction SMILES: [CH2:1]([C:16]([OH:18])=O)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:19]([NH2:34])[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Na+].[Cl-]>CN(C)C=O.O.C(N(CC)CC)C>[CH2:19]([NH:34][C:16]([CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4])=[O:18])[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)=CCCC(C)=CCNC(=O)CC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a mixture of farnesyl carboxylic acid (7.15 g) and farnesylamine (6.95 g) in 20 ml of dimethylformamide was added at 0° C. to a solution of diphenylphosphorylazide (7.62 g) in 7 ml of dimethylformamide. Next, to this mixture was added a solution of triethylamine (3.20 g) in dimethylformamide (3 ml). The reaction mixture was kept at room temperature overnight and poured into water (900 ml). After adding table salt, this mixture was extracted with ethyl acetate. The organic phase was worked up as usual manner and gave pale yellow oil. This material was purified by silica gel chromatography by using a mixture of methanol:benzene (2:1) as the eluent and gave 11.20 g of the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][OH:30])[CH:25]=[CH:26][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][OH:30])[CH:25]=[CH:26][CH:27]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCO)c1
Reactant: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 92.3 %

Procedure:
To a solution of 2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.50 g, 1.6 mmol) (prepared according to Example 10, Step A) and 2-(3-aminophenyl)ethanol (0.30 g, 2.2 mmol) (prepared according to Example 2, Step A) in 1,4-dioxane (13.6 mL) was added p-toluenesulfonic acid monohydrate (0.11 g, 0.58 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc and H2O successively to give the desired product as a light brown gum (0.61 g, 92%). LCMS for C22H26ClN4O2 (M+H)+: m/z=413.1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.1 %

Procedure:
To a mixture of benzyl alcohol (32.0 g), 2-chloro-3-cyanopyridine (37.3 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60%, oil, 12.92 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(benzyloxy)nicotinonitrile as an oil (39.13 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:16]([O:18]CC)=[O:17])=[C:6]1[S:15][CH2:14][CH2:13][N:7]12.C(O)C.O.C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:16]([OH:18])=[O:17])=[C:6]1[S:15][CH2:14][CH2:13][N:7]12
Reactant: CCOC(=O)c1c2n(c3ccc(Cl)c(Cl)c3c1=O)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1c2n(c3ccc(Cl)c(Cl)c3c1=O)CCS2
Yield: 63.3 %

Procedure:
Ethyl 6,7-dichloro-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylate (1.0 gram, 2.9 mmol) obtained in Example 3 was suspended in a mixture of 2.0 grams of sodium hydroxide, 140 ml of ethanol and 60 ml of water, the mixture was heated to reflux for thirty minutes, acidified with acetic acid when it was still hot, crystals separated out were collected by filtration, washed with water, and dried and recrystallized from dimethyl formamide to give 580 mg (62.8 percent) of the title compound. Melting point 305° to 310° C. (decomposition). Elementary analysis calculated as C12H7Cl2NO3S: C 45.59, H 2.23, N 4.43; Found: C 45.85, H 2.19, N 4.37.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:39]>N1C=CC=CC=1>[CH3:1][N:2]1[C:7](=[S:39])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1C(=O)c2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Solvent: c1ccncc1
Product: CN1C(=S)c2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 150 °C

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (36.1 mg, 0.055 mmol) and P4S10 are placed in a Biotage microwave vial, and then 1 mL of pyridine is added. The reaction mixture is heated in a microwave at 150° C. for 2.5 h. Pyridine is removed under high vacuum. The obtained crude product is purified by a semi-preparative HPLC to give 3.2 mg of pure product as pale yellow solids. MS (ESI) m/z 506.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([OH:16])[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[CH:2].[ClH:17]>>[ClH:17].[C:1]([C:3]1([OH:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(O)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Product: C#CC1(O)CCCNC1

Procedure:
3-Ethynylpiperidin-3-ol hydrochloride was prepared from tert-butyl 3-ethynyl-3-hydroxypiperidine-1-carboxylate and hydrogen chloride using the procedure outlined in Example 3-30.