Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:9]3[CH:8]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:3]1.[Li+].[OH-].[OH-].[Na+]>C1COCC1.CO.O>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:9]3[CH:8]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Temperature: 50 °C

Procedure:
To a suspension of ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-1) (51 mg, 0.14 mmol) in THF:MeOH:H2O 3:2:1 (3 mL) was added LiOH (29 mg, 0.7 mmol). The reaction was heated to 50° C. for 48 hours then cooled to room temperature and neutralized to pH 6 with 1M NaOH. The mixture was reduced to dryness and purified by column chromatography on silica gel with DCM/MeOH gradient as eluant to yield 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (X-3). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1 H), 8.15 (d, J=7.6 Hz, 1 H), 7.36-7.29 (m, 1 H), 7.09-7.04 (m, 2 H), 7.00-6.92 (m, 2 H), 6.24 (dd, J=2.4, 7.6 Hz, 1 H), 5.41 (d, J=52.8 Hz, 1 H), 5.06 (t, J=8.4 Hz, 1 H), 4.29-3.92 (m, 2 H), 2.94-2.82 (m, 1 H), 2.24-2.05 (m, 1 H). MS m/z 344.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:21])=[O:22])=[CH:16][CH:15]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccnc2cc(Br)ccc12
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Product: O=S(=O)(O)c1ccc(Nc2ccnc3cc(Br)ccc23)cc1

Procedure:
7-Bromo-4-chloroquinoline and p-aminobenzenesulphonic acid are reacted in a similar manner to that described in Example 14(a) to give 4-(7-bromo-4-quinolylamino)-benzenesulphonic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[C:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH:51]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:12]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:26])=[O:25])[C:5]3=[N:6][CH:7]=2)[CH:38]=[CH:37][C:36]=1[C:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(CCc4ccccc4)n3)c3cc(Br)cnc32)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(CCc4ccccc4)n3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 57.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-phenethyl-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 63A) (160 mg, 0.307 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 70) (307 mg, 0.769 mmol) using potassium phosphate (195 mg, 0.918 mmol), tricyclohexyl phosphine (13 mg, 0.046 mmol) and Pd2(dba)3 (28 mg, 0.030 mmol) in dioxane/water (15/3 ml) to afford 126 mg (57.2% yield) of the pure product after column purification using 35% ethyl acetate in hexane as eluent. MS: m/z=718.3 (M+1).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]=[CH:17][N+:18]([O-])=O>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][NH2:18]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Br
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.2 %

Procedure:
To a stirred suspension of lithium borohydride (0.39 g; 18.0 mmol) in 25 mL THF at ambient temperature was added chlorotrimethylsilane (3.9 g; 36.0 mmol), dropwise over 2 minutes. Gas was evolved and the mixture warmed slightly. After stirring for 20 minutes, gas evolution had ceased, and argon gas was bubbled through the mixture for 2 minutes to try to remove the remaining trimethylsilane that had formed. A solution of 2-bromo-4-chloro-1-(2-nitrovinyl)benzene (1.18 g; 4.5 mmol) in 20 mL tetrahydrofuran was then added dropwise with stirring at ambient temperature over 4 minutes. The resulting mixture was stirred and heated to reflux. After 2 hours, the heat was removed, and after cooling to ambient temperature, the mixture was cooled in an ice bath and carefully quenched with 25 mL methanol. The solvent was evaporated, and the residue was partitioned between 50 mL of 20% KOH and 25 mL of dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 0.92 g of 2-(2-bromo-4-chlorophenyl)ethanamine as a cloudy yellow oil. MS (apci, pos) m/z=234.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6](=[NH:8])[CH3:7])[CH2:4][CH2:3]1.Br[C:10](=[CH:13]OC(C)C)[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.O>[CH:2]1([N:5]2[C:10]([CH:11]=[O:12])=[CH:13][N:8]=[C:6]2[CH3:7])[CH2:4][CH2:3]1
Reactant: CC(C)OC=C(Br)C=O
Reactant: CC(=N)NC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ncc(C=O)n1C1CC1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Ethyl acetimidate hydrochloride (5.0 g, 40 mmol) and cyclopropylamine (2.3 mL, 40 mL) were dissolved in 45 mL of EtOH and heated to 85° C. in a sealed pressure vessel overnight. The mixture was cooled and concentrated to provide N-cylcopropyl-acetamidine hydrochloride as a viscous oil. N-Cyclopropyl-acetamidine hydrochloride (1.00 g, 7.43 mmol) and 2-bromo-3-isopropoxy-propenal (Shilcrat, S. C. et al. J. Org. Chem., 1997, 62, 8449-8454) (1.45 g, 7.50 mmol) were dissolved in 13 mL of CHCl3 and 1.6 mL of water. Then K2CO3 (1.5 g, 11 mmol) was added and the mixture was stirred overnight. The reaction was partitioned between CH2Cl2 (60 mL) and water (30 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (40 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered, concentrated, and chromatographed to provide 400 mg of 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:8][O:9][CH2:10][CH:11]=O.C1CCCCC1>O>[CH3:8][O:9][CH2:10][CH:11]1[O:6][CH2:5][C:2]([CH3:7])([CH3:1])[CH2:3][O:4]1
Reactant: COCC=O
Reactant: CC(C)(CO)CO
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCC(C)(C)CO1
Yield: 79 %

Procedure:
A mixture of 520 g (5 moles) of 2,2-dimethyl-1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxy-acetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb AC 10 under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 632 g (79% yield) of 2-methoxymethyl-5,5-dimethyl-1,3-dioxane of boiling point 96° C./60 mbar were obtained.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[F:13][CH2:14][CH:15]([OH:18])[CH2:16][F:17].[OH-].[Li+]>>[F:13][CH2:14][CH:15]([CH2:16][F:17])[O:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OC(CF)CF
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OC(CF)CF)nc1
Temperature: 25 °C
Yield: 47 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 47% yield starting from ethyl 6-chloronicotinate and 1,3-difluoro-2-propanol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at ambient temperature over night; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.19 (dd, 1 H), 6.99 (d, 1 H), 5.62-5.80 (m, 1 H), 4.77-4.87 (m, 2 H), 4.65-4.75 (m, 2 H); MS (ESI) m/z 216[M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:13][C:14]([F:25])([F:24])[C:15]1[C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1>>[F:24][C:14]([F:13])([F:25])[C:15]1[C:20]([C:21]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: CCOC(=N)c1ccccc1Cl
Reactant: O=C(Cl)c1cnccc1C(F)(F)F
Product: CCOC(=NC(=O)c1cnccc1C(F)(F)F)c1ccccc1Cl

Procedure:
starting from ethyl o-chlorobenzimidate and 4-trifluoromethyl-nicotinoyl chloride there is obtained ethyl N-(4-trifluoromethyl-nicotinoyl)-2-chlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(o-chlorophenyl)-1-methyl-5-(4-trifluoromethyl-3-pyridyl)-1H-1,2,4-triazole, 1H-NMR(CDCl3): 3.85 (s, N-CH3), 7.6-8.1 (5 aromatic H), 8.9-9.2 (2 aromatic H); mass spectrum: 338 (100), 319 (5), 166 (94), 138 (95);
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])[N:5]=[C:4]([NH:25][CH:26]=[O:27])[N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH:26]=[O:27])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOP(=O)(COCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(COCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A solution of 4-chloro-6-[2-(diethoxyphosphorylmethoxy) ethoxyamino]-2,5-diformamidopyrimidine (2.8 g, 6.6 mmol) in diethoxymethyl acetate (20 ml) was heated at 120° C. for 2 hours. After cooling to ambient temperature, excess solvent was removed under reduced pressure, the residue dissolved in methanol (20 ml) and 0.880 ammonia (6.5 ml) and the solution stirred at ambient temperature for 1 hour. The solvent was evaporated to leave an oil which was chromatographed on silica gel (eluted with dichloromethane: methanol, 98.2) to give the title compound as a pale yellow oil (2.4 g, 90%). IR: νmax (film) 3480, 3120, 2995, 1710, 1610, 1580, 1510, 1440, 1390, 1330, 1240, 1050, 1030, 970, 920, 780 cm-1 ; 1H NMR δH [(CD3)2SO] 1.23 (6H, t, J=7 Hz, (OCH2CH3)2), 3.87 (2H, d, J=8 Hz, OCH 2P), 3.87 (2H, m, N-OCH2CH2), 4.03 (4H, m, (OCH2CH3)2), 4.56 (2H, m, N-OCH2CH2), 8.75 (1H, s, H-8), 9.38 (1H, br.s, CHO), 11.30 (1H, br.s, D2O exchangeable NHCHO). Found: C, 38.19; H, 4.79; N, 16.74%. C13H19N5O6PCl requires: C, 38.29; H, 4.70; N, 17.17%. Found: m/z 408.0827 (MH+). C13H20N5O6PCl requires: m/z 408.0840 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[CH:12]=2)[C:7]1=[O:17])[CH3:2].[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1N2CCN(CC2)C1>ClC1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Clc1ccccc1
Product: CCOC(=O)CN1C(=O)c2ccc(N=C(c3ccccc3)c3ccccc3)cc2C1=O
Yield: 52.4 %

Procedure:
Titanium tetrachloride (1.99 g) was slowly added to a mixture of (5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (3.48 g), benzophenone (2.81 g) and DABCO (4.72 g) in chlorobenzene (112 ml). Resulting mixture was heated to reflux for 2.5 h. After cooling, reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. Filtrate was concentrated and the residue was purified by silica gel chromatography (25%-40% ethyl acetate in hexanes) to give the title compound (3.03 g). MS-(+)-ion: M+1=413.3.
Reaction SMILES: [N+:1]([C:4]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]3)[CH:17]=2)[CH:12]=1)([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([F:29])([F:30])[F:31])[CH2:24][CH2:23]3)[CH:17]=2)[CH:12]=1)([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-nitro-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (0.099 g, 0.22 mmol) in acetic acid (2.00 mL, Fisher) at 20° C. was added zinc (0.185 g, 2.83 mmol, Aldrich). The mixture was stirred for 45 minutes at room temperature. The mixture was heated at 50° C. and stirred. After 2.5 h, the mixture was diluted in acetic acid, filtered and concentrated to dryness under reduced pressure. Purification was by preparative HPLC. The fractions were dried to give 61 mg (52%) product as TFA salt. MS: m/z=432.10 [M+Na]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 7.62-7.74 (m, 3H), 7.36 (dd, J=8.8, 1.8 Hz, 1H), 7.03-7.12 (m, 2H), 4.21-4.32 (m, 1H), 2.20-2.41 (m, 4H), 1.91-2.19 (m, 5H), 1.72 (s, 3H), 1.35-1.51 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]#[N:24])[CH:17]=1>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:22](/[C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)\[C:23]#[N:24])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: N#CCc1cccnc1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3cccnc3)cc2c1
Yield: 78.1 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 3-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 251 mg, 78%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH:6](=[N:5][CH2:4][CH2:3][NH:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCN
Solvent: c1ccccc1
Product: CNCCN=Cc1ccccc1

Procedure:
20 g. of 2-methylamino-ethylamine in 100 ml. of absolute benzene was stirred with 28.7 g. of benzaldehyde. The mixture warmed up somewhat and became yellow. The benzene was evaporated in vacuo and the residue distilled under reduced pressure in a Hickmann-flask. After a little forerun, the desired fraction distilled at 106°-107°/13 mm. The N-benzylidene-N'-methylethylenediamine was obtained as a colorless oil of nD22 = 1.5452 and a U.V.-absorption maximum at 245 mμ. 25 g. of this product were dissolved in 150 ml. methylene chloride and thereto were added 16.5 g. of triethylamine and while stirring and cooling in an ice bath, 26.7 g. of carbobenzoxy chloride in 100 ml. of methylene chloride in such a way that the temperature did not rise over 20°. The mixture was stirred for 3 hours at room temperature and shaken with 100 ml. of water. The methylene chloride layer was washed three times with water and concentrated in vacuo. The yellow oil obtained was well mixed with 100 ml. of ether and 100 ml. of 6 N sulfuric acid for one hour at room temperature. The layers were separated, the aqueous layer extracted five times more with 30 ml. ether each time. To this ether extracts were added, while cooling on an ice bath, 50 g. of solid potassium hydroxide. The oily product was extracted with methylene chloride, the extract concentrated and the residue distilled under reduced pressure. The desired product distilled, after a short forerun, at 105°-112° /0.04 mm. as a colorless oil of nD24 = 1.5355.
Reaction SMILES: C(Cl)Cl.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N([C@@:13]1(O)[C@@H:19](O)[C@H:18](O)[C@@H:17]([CH2:22]O)O[CH:14]1O)=[N+]=[N-]>C(Cl)(Cl)(Cl)Cl>[C:6]1([CH:13]2[CH2:19][CH2:18][CH2:17][CH:22]=[CH:14]2)[CH:5]=[CH:4][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=N[C@]1(O)C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C1=CC(c2ccccc2)CCC1

Procedure:
TLC Rf=0.67 (10% CH2Cl2/hexane); IR (CCl4) 3088 (m),3063 (m),3025 (s), 2938 (s), 2863 (s), 2838 (s), 1656 (w), 1606 (m), 1543 (m); 1H NMR (CDCl3) δ0.85-2.09 (m, 6H), 3.38 (bs, 1H), 5.70 (dd, J=10.0, 2.1, 1H), 5.86-5.88 (m, 1H), 7.16-7.30 (m, 5H); 13C NMR (CDCl3) δ21.2, 22.7, 32.6, 41.8, 125.9, 127.7, 128.2, 128.3, 130.2, 146.6; LRMS (EI) 159 ((M+1), 15), 158 ((M+), 100), 143 (43), 129 (79); HRMS (EI) calculated for C12H14 158.1096 (M+), found 158.1098. The IR, 1H NMR and 13C NMR, and MS matched spectral data reported by Arnold, D. R. and Mines, S. A., Can. J. Chem. 67:689-698 (1989).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([N:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:43][C@@H:42]1CC=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O.[CH2:58]1[CH2:62][O:61][CH2:60][CH2:59]1>>[CH2:34]([N:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][C@@H:42]1[CH2:58][CH:59]=[CH:60][O:61][CH3:62])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C1CCOC1
Reactant: O=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: O
Product: COC=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Add LiHMDS (1M in THF, 21.38 mL, 21.38 mmol) to (methoxymethyl)triphenyl-phosphonium chloride (7.329 g, 21.38 mmol) in THF (51.0 mL) via syringe at 0° C. and stir. After 30 minutes, add (S)-(1,4-dibenzyl-piperazin-2-yl)-acetaldehyde (4.71 g, 15.27 mmol) in THF (51.0 mL) via syringe. Remove ice bath and stir at ambient temperature. After 4 hours, add water and extract with ethyl acetate twice. Combine the organic solution, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with ethyl acetate:hexane (40:60) to give the title compound: mass spectrum (m/e):337.18 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([C:11]1[C:3]([O:2][CH3:1])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)(=[O:14])[CH3:13]
Reactant: COc1cc2ccccn2n1
Reactant: CC(=O)Cl
Product: COc1nn2ccccc2c1C(C)=O

Procedure:
A mixture of 2-methoxypyrazolo[1,5-a]pyridine (280 mg) acetic anhydride (3 ml) and acetyl chloride (1 ml) was refluxed for 1 hr and the reaction mixture was concentrated under reduced pressure. Water was added to the residue and the solution was made basic with potassium carbonate. The precipitated crystals were collected and washed with water. Recrystallization from n-hexane-ethyl acetate gave colorless needles, mp 158.0°-158.5°. Yield 160 mg.
Reaction SMILES: [CH3:1][CH:2]([S:6]([C:8]1[S:12][CH:11]=[N:10][N:9]=1)=[O:7])[C:3]([OH:5])=O.[NH2:13][CH:14]1[C:28](=[O:29])[N:16]2[C:17]([C:25]([OH:27])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]12>>[CH3:1][CH:2]([S:6]([C:8]1[S:12][CH:11]=[N:10][N:9]=1)=[O:7])[C:3]([NH:13][CH:14]1[C:28](=[O:29])[N:16]2[C:17]([C:25]([OH:27])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]12)=[O:5]
Reactant: CC(C(=O)O)S(=O)c1nncs1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)S(=O)c1nncs1

Procedure:
412 mg. of 2-methyl-1,3,4-thiadiazol-5-ylsulfinylacetic acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 124 mg. of 7-(2-methyl-1,3,4-thiadiazol-5-ylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N:36]2[CH2:47][CH2:46][C:39]3([C:43](=[O:44])[N:42]([CH3:45])[CH2:41][CH2:40]3)[CH2:38][CH2:37]2)[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([N:36]2[CH2:37][CH2:38][C:39]3([C:43](=[O:44])[N:42]([CH3:45])[CH2:41][CH2:40]3)[CH2:46][CH2:47]2)=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CN1CCC2(CCN(c3cc(C#N)cc(N)c3Cl)CC2)C1=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5(CCN(C)C5=O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (167 mg, 0.471 mmol), 3-amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonitrile (150 mg, 0.471 mmol), palladium(II) acetate (28.0 mg, 0.125 mmol), XANTPHOS (27.2 mg, 0.047 mmol), DPPF (26.1 mg, 0.047 mmol) and cesium carbonate (399 mg, 1.223 mmol) in dioxane (5 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 3 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 10% to 100% EtOAc in Hexane) to give (+/−)-2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (137 mg) as a light yellow solid.