Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])C=C.CCCCCC.CCOCC>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]1([CH2:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH:12][CH2:14][Si:17]([CH:18]([CH3:20])[CH3:19])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=CCC(O)CCc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](CC=CCC(O)CCc1ccccc1)(C(C)C)C(C)C
Yield: 61.3 %

Procedure:
To a round-bottomed flask containing 1-phenyl-hex-5-en-3-ol (43 mg, 0.24 mmol, 1 eq)) in DCM (2 mL) was added allyltriisopropylsilane (0.173 mL, 0.72 mmol, 3 eq). Hoveyda-Grubbs' Catalyst (4 mg, 0.006 mmol, 0.025 eq) was subsequently added as a solid and the reaction was left to stir under an atmosphere of argon. After 6 days the reaction was concentrated under reduced pressure to a dark brown oil. Column chromatography (hexane:ether, 100:0, 90:10, 85:15) gave 1-phenyl-7-(triisopropylsilyl)hept-5-en-3-ol as a colourless oil (51 mg, 61% yield). For major isomer E: 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 21H, Si(i−Pr)3), 1.60-1.62 (d, 2H, CH2 Si(i−Pr)3, J=8 Hz), 1.72-1.85 (m, 2H, CH2CH2CHOH), 2.06-2.14 (m, 1H, CHOHCH2CH), 2.22-2.34 (m, 1H, CHOHCH2CH), 2.64-2.74 (m, 1H, PhCH2), 2.78-2.87 (m, 1H, PhCH2), 3.58-3.64 (m, 1H, CHOH), 5.24-5.34 (m, 1H, CH2CHCH), 5.58-5.66 (dt, 1H, CH2CHCH, J=16, 8 Hz), 7.17-7.23 (m, 4H, Ph), 7.27-7.31 (m, 1H, Ph); 13C NMR (100 MHz, CDCl3) δ 11.0 (Si(i−Pr)3), 15.6 (CH2 Si(i−Pr)3), 18.7 (Si(i−Pr)3), 32.1 (PhCH2), 38.4 (PhCH2CH2), 41.1 (CHOHCH2), 70.4 (CHOH), 123.9 (CH2CHCH), 125.7 (Ph), 128.3 (Ph), 128.4 (Ph), 131.9 (CH2CHCH), 142.2 (Ph). For minor isomer Z: 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 21H, Si(i−Pr)3), 1.60-1.62 (d, 2H, CH2 Si(i−Pr)3, J=8 Hz), 1.72-1.85 (m, 2H, CH2CH2CHOH), 2.06-2.14 (m, 1H, CHOHCH2CH), 2.22-2.34 (m, 1H, CHOHCH2CH), 2.64-2.74 (m, 1H, PhCH2), 2.78-2.87 (m, 1H, PhCH2), 3.65-3.71 (m, 1H, CHOH), 5.24-5.34 (m, 1H, CH2CHCH), 5.68-5.75 (dt, 1H, CH2CHCH, J=12, 8 Hz), 7.17-7.23 (m, 4H, Ph), 7.27-7.31 (m, 1H, Ph); 13C NMR (100 MHz, CDCl3) δ 11.0 (Si(i−Pr)3), 15.6 (CH2 Si(i−Pr)3), 18.7 (Si(i−Pr)3), 32.1 (PhCH2), 35.3 (CHOHCH2), 38.4 (PhCH2CH2), 70.9 (CHOH), 122.3 (CH2CHCH), 125.7 (Ph), 128.3 (Ph), 128.4 (Ph), 130.3 (CH2CHCH), 142.2 (Ph); IR (v, cm−1) 3362 (OH), 3026 (Ar—H), 1604 (C═C), 1496 (Ar), 1462 (Ar), 699 (Si—C); HRMS required for C22H38OSi: 346.2692, found 346.2683.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].CO>C(O)C.ClCCl.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Nc1cnccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in the mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. After the atmosphere was replaced with nitrogen, 0.10 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=2:1 (v/v)]to obtain 1.07 g of a light brown solid (yield: 88.7%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:42][O:43][C:44]([C:46]1[N:47]=[C:48]([NH:51][C:52](=[O:62])[C@@H:53]([NH2:61])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:49][CH:50]=1)=[O:45]>O1CCCC1>[CH3:42][O:43][C:44]([C:46]1[N:47]=[C:48]([NH:51][C:52](=[O:62])[C@@H:53]([NH:61][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:49][CH:50]=1)=[O:45]
Reactant: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2nc(C(=O)OC)cs2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(R)-tert-butoxycarbonylamino-{4-[2-(methoxy)-ethoxy]-phenyl}-acetic acid (0.6 g, 1.84 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.32 g, 1.84 mmol) and N-methylmorpholine (0.19 g, 1.84 mmol) in anhydrous tetrahydrofuran (20 mL) were stirred at room temperature for 4 hours. Then a solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (0.56 g, 1.84 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at room temperature for 20 hours. The mixture was filtered though a short pad of silica gel and the residual material eluted from the silica gel with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography over silica gel eluted with 1:1 ethyl acetate/hexanes to give 2-((S)-2-{2-tert-butoxycarbonylamino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a mixture of two epimers (R/S=85:15) (0.21 g,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:12])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(Br)cc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1cc(Br)cc(=O)n1C

Procedure:
4-bromo-1,6-dimethylpyridin-2(1H)-one was prepared by methylation of 4-bromo-6-methylpyridin-2(1H)-one with methyl iodide using K2CO3 following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.[CH2:12]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][NH2:18])[CH2:13][CH2:14][CH3:15].CC(N)=NCC1C=CC=C(CN)C=1.Cl.Cl>CCCCCCC>[CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([NH:18][CH2:17][CH:16]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:6]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CCCCCCC(CN)CCCC
Agent: CC(N)=NCc1cccc(CN)c1
Agent: Cl
Solvent: CCCCCCC
Product: CCCCCCC(CCCC)CNC(=O)CC(C)CC(C)(C)C
Yield: 76.6 %

Procedure:
29.2 g of 3,5,5-trimethylhexanoic acid and 34.2 g of 2-butyloctylamine were mixed together in an open Pyrex container and placed in a microwave oven (Menumaster™3100 i; frequency 2450, power at a setting of 30%: 1400 W). After 6 irradiations of about 5 minutes (for each irradiation), the reaction mixture was dissolved in heptane and then purified on silica. 46 g (77%) of the desired amide were obtained.
Reaction SMILES: C(O[C:4](OCC)(OCC)[CH2:5][CH3:6])C.Cl.N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[NH:31][CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[CH:28][CH:27]=[CH:26][CH:25]=2>C1(C)C=CC=CC=1>[CH2:5]([C:6]1[N:31]([CH2:32][C:33]2([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=1)[CH3:4]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1

Procedure:
Triethylorthopropionate (2.4 mL, 12.0 mmol) and pyridine hydrochloride (60 mg, 0.5 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux for 2.5 hours and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the filtered to provide 4-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.263 mmol) of (3S)-6-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoic acid (Bioorg. Med. Chem. Lett. (1998) 8:1477-1482) and 0.108 g (0.342 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.066 g (0.342 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1>>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[N:8]=3)=[O:14])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: O=C(O)c1ccn(-c2ccncc2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2ccncc2)n1
Yield: 73.7 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (47.5 mg, 0.251 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (70 mg, 0.251 mmol). The precipitate that formed during the reaction was filtered out of the reaction mixture was washed with 2×5 ml of water and dried with vacuum at 40° C. Yield 73.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 4.31-4.42 (m, 2H), 4.43-4.54 (m, 1H), 6.90 (d, 1H), 7.01 (dd, 1H), 7.79-8.01 (m, 5H), 8.39 (d, 1H), 8.66-8.73 (m, 2H), 8.77 (d, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]([C:17]([F:20])([F:19])[F:18])=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5].[CH3:22][Li].Cl>C(OCC)C>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][C:10]2=[C:6]([C:4](=[O:5])[CH3:22])[S:7][C:8]([C:17]([F:20])([F:19])[F:18])=[C:9]2[CH2:14]1
Reactant: CON(C)C(=O)c1sc(C(F)(F)F)c2c1CCC(C)(C)C2
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1sc(C(F)(F)F)c2c1CCC(C)(C)C2
Reaction time: 0.25 h

Procedure:
A solution of 5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (14 g, 44 mmol) in diethyl ether (400 mL) is treated at it with methyl lithium (80 mL, 1.6 M in diethyl ether). Upon complete addition, the mixture is stirred at it for 15 min before it is poured onto water/ice and neutralized with aq. HCl. The ether phase is separated and the aq. phase is extracted two more times with diethyl ether (2×100 mL). The organic extracts are washed with brine, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane containing 20-30% of DCM to give 1-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (9.1 g) as a yellow oil; LC-MS: tR=1.11 min, [M+1+CH3CN]=318.34; 1H NMR (CDCl3): δ 3.04 (t, J=7.0 Hz, 2H), 2.57 (d, J=1.2 Hz, 2H), 2.53 (s, 3H), 1.58 (t, J=7.0 Hz, 2H), 0.99 (s, 6H).
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)=[CH:12][CH:11]=1>C(O)C.CN(C)C=O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)=[CH:12][CH:11]=1)=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: BrCc1ccc(-c2noc3ccccc23)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=Cc1ccc(-c2noc3ccccc23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
115.8 g of 2-nitropropane are introduced at about 30° C. into a solution of 23.13 g of sodium in 2,700 ml of anhydrous ethanol. The mixture is stirred for a further one hour and a solution of 288.1 g of 3-(p-bromomethyl-phenyl)-1,2-benzisoxazole in 350 ml of dimethylformamide is now added. Subsequently, the reaction mixture is warmed to 50° C., then stirred for 20 hours without external warming and finally cooled to -10° C. The product which has precipitated is filtered off with suction, washed with cold methanol and dried. This gives 107.4 g (48.1% of theory) of 3-(p-formylphenyl)-1,2-benzisoxazole in the form of a pale yellow powder with a melting point of 117° to 117.5° C. After recrystallising twice from ligroin, small, virtually colourless, glossy needles are obtained which melt at 117° to 117.5° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[S:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:22]2[C:26]3[C:27]4[C:32]([CH2:33][C:25]=3[C:24]([C:42]3[S:46]C(CN)=[CH:44][CH:43]=3)=[N:23]2)=[CH:31][C:30]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:29][CH:28]=4)=[CH:17][CH:16]=1.N[C:58]1[CH:59]=[C:60]([CH3:65])[CH:61]=CC=1N>C(#N)C.N1C=CC=CC=1>[NH2:10][C:11]1[CH:58]=[CH:59][C:60]([CH3:65])=[CH:61][C:12]=1[NH:8][C:1]([NH:3][CH2:7][C:6]1[S:46][C:42]([C:24]2[C:25]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH2:34][N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)[CH:31]=4)[C:26]=3[N:22]([CH:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[N:23]=2)=[CH:43][CH:44]=1)=[S:2]
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CN)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Reactant: Cc1ccc(N)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CNC(=S)Nc4cc(C)ccc4N)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1,1′-thiocarbonyldiimidazole (26 mg, 0.13 mmol) in acetonitrile (1 mL) and pyridine (1 mL) was cooled to about −20 C and a solution of Example 395 (60 mg, 0.09 mmol) in acetonitrile (1 mL) and pyridine (1 mL) was added dropwise. The reaction mixture was stirred for about 2.5 hours while being allowed to warm to room temperature, then 3,4-diaminotoluene (25 mg, 0.2 mmol) was added and the solution was stirred at about 35 C for about 2 days. The mixture was evaporated to dryness and the residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide Example 605. MS (ESI): m/z 771 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=[O:28].[CH2:37]([NH:41][CH3:42])[CH2:38][CH2:39][CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH2:37]([N:41]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][CH2:25][C:3]2[CH:4]=[CH:5][C:6]([C:8]([N:10]3[CH2:19][C:18]4[CH:17]=[N:16][N:15]([CH3:20])[C:14]=4[NH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:34][CH2:33]1)[CH3:42])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCNC
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCN(C)CC1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde from Example E58.1 (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of butyl-methyl-amine (0.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium tri-acetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+:[M+H]+=557.6
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13][C:14]2[C:19]([C:20]3[CH:25]=[C:24]([NH:26][CH3:27])[N:23]=[CH:22][N:21]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:8]1[C:9]2[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([NH:13][C:14]3[C:19]([C:20]4[CH:25]=[C:24]([NH:26][CH3:27])[N:23]=[CH:22][N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)[C:4]=2[CH:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(=O)[nH]ccc23)ncn1
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Cl)nccc23)ncn1
Temperature: 120 °C

Procedure:
6-Methyl-5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-ylamino)isoquinolin-1(2H)-one (195 mg, 0.54 mmol) was suspended in POCl3 (10 mL) and heated at 120° C. for 3 h. POCl3 was removed in vacuo and the residue was washed with toluene three times. The residue was added to water and the resulting solid collected by filtration, washing with saturated aqueous sodium bicarbonate and water. The resulting title compound was dried in vacuo. MS (M+H)+ 377.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:23]3[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][N:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: COc1cc2c(=S)cc[nH]c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3ncc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1

Procedure:
7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.8 g), 2-bromo-5-nitro-1,3-thiazole (10.4 g), potassium carbonate (10.3 g) and dimethylformamide (150 ml) were stirred together at room temperature for 50 minutes. After adding 800 ml of water to the reaction solution, the precipitated solid was filtered out and washed with ethyl acetate to obtain 13.4 g of a light ochre powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[C:4]([CH3:12])=[N:3]1.[N+](=[CH:15]C(OCC)=O)=[N-]>>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH2:15][C:5]=2[C:4]([CH3:12])=[N:3]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1nn(C)c2c1C(=O)CCC2
Product: Cc1nn(C)c2c1CC(=O)CCC2

Procedure:
1,5,6,7-Tetrahydro-1,3-dimethyl-4H-indazol-4-one is reacted with ethyl diazoacetate according to the procedure described in Example 3 to give 4,6,7,8-tetrahydro-1,3-dimethyl-5(1H)-cycloheptapyrazolone. This is reacted with N,N-dimethylformamide dimethyl acetal according to the procedure described in the first paragraph of Example 6 to give 4-(dimethylaminomethylene)-4,6,7,8-tetrahydro-1,3-dimethyl-5(1H)-cycloheptapyrazolone. The dimethylaminomethylene compound is then reacted with hydrazine according to the procedure described in Example 7 to give 4,5,6,7-tetrahydro-1,3-dimethyl-3H-cyclohepta[1,2-c:4,3-c']dipyrazole.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][CH2:11][N:12]([CH3:24])[CH2:13][CH2:14][O:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([Cl:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[Cl-:32].[CH:1]1([C:7]([O:9][CH2:10][CH2:11][N+:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:13][CH2:14][O:15][C:16]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[CH3:24])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(CCOC(=O)C1CCCCC1)CCOC(=O)C1CCCCC1
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: C[N+](CCOC(=O)C1CCCCC1)(CCOC(=O)C1CCCCC1)Cc1ccccc1
Product: [Cl-]

Procedure:
A solution of 28.5 g (0.084 mol) of N,N-bis(2-cyclohexanoyloxyethyl)methylamine (prepared as described in Example 22), 10.63 g (0.084 mol) of benzyl chloride and 200 ml of acetonitrile was heated at reflux for 2.5 hours and concentrated to an oil. Ether was added to the oil which induced crystallization. The white solid was collected, washed two times with ether and recrystallized from 2-butanone. The yield of product was 8.3 g; mp=143.5°-4.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:45]/[O:46]C(=O)C)/[C:22]([NH:24][C@@H:25]2[C:43](=[O:44])[N:27]3[C:28]([C:40]([OH:42])=[O:41])=[C:29]([S:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH2:30][S:31][C@H:26]23)=[O:23])[N:20]=1.[Cl-].[NH4+].Cl>O.CO>[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:45]/[OH:46])/[C:22]([NH:24][C@@H:25]2[C:43](=[O:44])[N:27]3[C:28]([C:40]([OH:42])=[O:41])=[C:29]([S:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH2:30][S:31][C@H:26]23)=[O:23])[N:20]=1
Reactant: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cccnc3)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cccnc4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.9 %

Procedure:
A solution of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(3-pyridyl)methylthio]-3-cephem-4-carboxylic acid bis(trifluoroacetic acid) salt (3.85 g, 5.05 m mol) and ammonium chloride (810 mg, 15.2 m mol) in a mixture of water (116 ml) and methanol (11.6 ml) was stirred at room temperature for 2.5 hours with keeping pH 8. The reaction mixture was adjusted to pH 6 by addition of 1N HCl. Methanol in the mixture was removed by evaporation in vacuo. The aqueous solution was adjusted to pH 5 and chromatographed on HP-20 (100 ml) and eluted with 5-10% aqueous isopropanol. The eluent was lyophilized. To the crude product was added water and acetonitrile. The precipitates were collected by filtration, washed with water and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(3-pyridyl)methyl-thio]-3-cephem-4-carboxylic acid (445 mg, 0.903 m mol).