Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][N:25]([CH:34]=[O:35])[O:26]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].CO>[CH:1]1([CH2:6][C@H:7]([CH2:24][N:25]([CH:34]=[O:35])[OH:26])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccncn1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccncn1
Reaction time: 0.83 h
Yield: 93.1 %

Procedure:
A mixture of (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-4-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (76 mg, 0.159 mmol) and Pearlman's catalyst (22.30 mg, 0.032 mmol) in methanol (8.8 ml) was degassed and placed under 1 atm of H2 at ambient temperature. After 1 h 50 min, the reaction mixture was filtered and concentrated to give a residue which was purified by RP-HPLC to give (5S)-1-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-4-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (58 mg, 0.148 mmol, 93% yield). MS (ES+) m/z 389.2 (MH+). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.04-1.21 (m, 2H) 1.37-1.67 (m, 5H) 1.70-1.99 (m, 4H) 3.05-3.20 (m, 1H) 3.35 (d, J=11.87 Hz, 1H) 3.55 (dd, J=14.02, 4.67 Hz, 1H) 3.75-3.90 (m, 1H) 3.90-4.02 (m, 1H) 4.99 (dd, J=11.87, 5.81 Hz, 1H) 7.11 (s, 1H) 7.89 (s, 0.7H) 8.14 (d, J=5.31 Hz, 1H) 8.22 (s, 0.3H) 8.60 (d, J=5.81 Hz, 1H) 8.83 (s, 1H)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1N(C)N=NN=1.ClC1[C:38](=[O:39])C2C(=CC=CC=2)C(=O)C=1NC1C=CC(S(NC2C=C(C)C=CC=2)(=O)=O)=C(OC)C=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][CH2:38][OH:39]
Reactant: COc1cc(NC2=C(Cl)C(=O)c3ccccc3C2=O)ccc1S(=O)(=O)Nc1cccc(C)c1
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=S(=O)(Nc1cc(SCCO)c(O)c2ccccc12)c1cccs1

Procedure:
5.2.53 N-(4-hydroxy-3-(2-hydroxyethylthio)naphthalen-1-yl)thiophene-2-sulfonamide (14k) was prepared according to the procedure for 14d except using N-(3-(2-hydroxyethylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13k), which, after purification via flash chromatography (Hex/EtOAc), afforded the title compound 20.3 mg (53.1%) as a grey solid, m.p.: ° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29](=[O:41])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:37]3[CH:38]=[CH:39][C:34]([C:31]4([CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:41])[CH2:32][CH2:33]4)=[CH:35][CH:36]=3)[C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(I)cc2)CC1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C3(CC(=O)OC(C)(C)C)CC3)cc1)C2=O
Yield: 86 %

Procedure:
Part A. Following procedure similar to that of Part C in Example 220 but using 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester and [1-(4-iodo-phenyl)-cyclopropyl]-acetic acid tert-butyl ester as starting materials, 6-[4-(1-tert-butoxycarbonylmethyl-cyclopropyl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester was obtained (406.29 mg, yield: 86%). 1H NMR (CDCl3) δ 7.48 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H), 4.12 (m, 2H), 3.81 (s, 3H), 3.32 (t, J=6.6 Hz, 2H), 2.50 (s, 2H), 1.44 (t, J=7.1 Hz, 3H), 1.38 (s, 9H), 0.90 (s, 4H) ppm. LRMS (ESI) 546.2 (M+H).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].Cl.[NH2:19][C@H:20]([C:24]([NH:26][CH:27]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22].O>C(Cl)Cl>[O:11]([C:9]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([C:29]([NH:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(NC(=O)[C@@H](N)C(C)C)C(=O)NCc1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C)C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
0.55 g of N-methyhnorpholine, and subsequently 0.43 g of phenyl chloroformate were added to a suspension containing 0.95 g of L-valyl-N-(4-chlorobenzyl)-DL-alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.9 g of the desired product in the form of white powder (yield: 75%).
Reaction SMILES: [CH:1]1([CH:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]2[C:15](Cl)=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[N:12][N:11]2[CH:20]=1.CO>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15]([NH:6][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[N:12][N:11]2[CH:20]=1
Reactant: CC(N)C1CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Yield: 61.9 %

Procedure:
1-Cyclopropylethanamine (93 mg, 1.09 mmol) and 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 100 mg, 0.36 mmol) in NMP (0.5 mL) were heated in the CEM microwave at 120° C. for 10 min. The reaction was allowed to cool to room temperature before the addition of MeOH. The resulting precipitate was then filtered and air dried to afford the title compound (72 mg, 61%). HPLC (condition G): retention time=3.87 min. LCMS (condition B): m/z 323.0, 325.0. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.99 Hz), 8.40-8.49 (2 H, m), 8.32-8.40 (1 H, m), 8.28 (1 H, s), 7.76 (1 H, td, J=6.59, 1.25 Hz), 7.68 (1 H, d, J=1.94 Hz), 4.12 (1 H, quin, J=6.45 Hz), 1.52 (3 H, d, J=6.38 Hz), 1.14-1.29 (1 H, m), 0.58-0.75 (2 H, m), 0.35-0.51 (2 H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25](O)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:3])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(CC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of oxalyl chloride (1.25 g, 0.17 mL, 2.6 mmol) in dichloromethane (5 mL) was cooled to -78°60 C. in a flame dried flask under a nitrogen atmosphere with stirring. A solution of dimethylsulfoxide (0.41 g, 0.37 mL, 5.2 mmol) in dichloromethane (5 mL) was added dropwise; then the reaction mixture was stirred for 15 minutes. A solution of 1-benzyl-4-(2'-(4''-fluorophenyl)hydroxyethyl)piperidine (0.6 g, 2 mmol) in dichloromethane was added dropwise, then the reaction mixture was stirred at -65° to -60° C. for 15 minutes. The mixture was then cooled to -78° C. and triethylamine (0.73 g, 1.0 mL, 7.2 mmol) was added in one portion. The reaction mixture was stirred while being warmed gradually to ambient temperature. After 3 hours, the reaction mixture was poured onto water (100 mL), mixed and extracted three times with ether. The combined organic layers were dried over magnesium sulfate filtered and concentrated in vacuo. Column chromatography (ethyl acetate) gave an oil (588 mg, Rf=0.2):1H-NMR:7.4-6.9(m,9H), 4.65(s,2H), 4.5(s,2H), 3.0-2.9(m,2H), 2.5-2.35(m,1H), 2.1-1.6(m,8H); HR-MS:Calcd for C20H22FNO:311.1700; Found:311.1693.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(=O)C>[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2cccc3c2ccc2nc(C)[nH]c(=O)c23)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc2ccc3c(S(=O)(=O)Nc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cccc3c2c(=O)[nH]1

Procedure:
A solution of diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamate (0.16 g, 0.3 mmoles) in 0.1N NaOH (10 ml) was stirred at room temperature under a nitrogen atmosphere for 48 hrs, after which time the solution was acidified (pH 3.5) with acetic acid. The precipitate was collected, washed with water and dried to give N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamic acid as an off-white solid. (0.12 g, 86%) 1H NMR(DMSO-d6, 200 MHz) δ: 1.72-2.08(m, 2H, glu-CH2); 2.26(t, J=Hz, 2H, glu-CH2); 2.43(s, 3H, CH3); 4.18-4.35(m, 1H, glu-CH); 7.07(d, J=8.4 Hz, 2H, Ar); 7.63(d, J=8.3 Hz, 2H, Ar); 7.82(t, J=7.3 Hz, 1H, Ar); 7.84(d, J=8.9 Hz, 1H, Ar); 8.32(m, 2H, glu-NH+Ar); 9.07(d, J=9.3 Hz, 1H, Ar); 10.16(d, J=8.8 Hz, 1H, Ar); 12.71(br s, 1H, NH). Anal. Calculated for C25H22N4O8S.7/4H2O: C, 52.67; H, 4.55; N, 9.83. Found: C, 52.52; H, 4.36; N, 9.70.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:17])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[OH-].[K+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:17])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCC#CCC(O)c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCC#CCC(O)c1ccco1
Temperature: 0 °C
Yield: 98.7 %

Procedure:
To a stirred solution of 4.73 g of methyl 8-(2-furyl)-8-hydroxy-5-octynoate in 60 ml of methanol was added 4 ml of 1 N potassium hydroxide. This mixture was stirred at reflux for one hour, then cooled and concentrated. The residue was partitioned between water and ether. The aqueous layer was separated, cooled to 0° C. and acidified with 1 N hydrochloric acid, then saturated with sodium chloride and extracted with ether. The ether extract was washed with brine, dried and concentrated, giving 4.39 g of the desired compound as an oil; PMR δ 4.85 (1H, t, CHOH).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccnc3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3cccnc3)nc2c1C#N
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (123 μl, 0.970 mmol) and triethylamine (135 μl, 0.970 mmol) were added to a dimethyl sulfoxide (6 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(pyridin-3-yl)-1,3-benzoxazole-4-carbonitrile (I-209) (213 mg, 0.647 mmol), followed by stirring in an oil bath at 95° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml), then washed with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the residue was purified by silica gel column chromatography (eluent, chloroform/methanol=10:1), and the eluate was recrystallized from isopropanol to obtain the entitled compound (190 mg, 69.4%) as a yellow crystal.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:46][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and cyclohexylamine by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:20])[C:15]([O:17][CH2:18][CH3:19])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:20][C:14]1[C:15]([O:17][CH2:18][CH3:19])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.010 g, 0.026 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred overnight at 20 C. The product mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4 and concentrated to give 0.007 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.29 (s, 1H), 6.63 (s, 1H), 4.07 (q, J=6 Hz, 2H), 3.03 (m, 3H), 2.91 (m, 3H), 2.73 (m, 1H), 2.26 (bs, 1H), 1.46 (t, J=6 Hz, 3H), 1.32 (d, J=7 Hz, 3H). MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: NN.Cl.[NH2:4][CH:5]1[C:16](=[O:17])[N:7]2[C:8]([C:13]([O-:15])=[O:14])=[C:9]([CH3:12])[CH2:10][S:11][C@H:6]12.CC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O>O1CCCC1.O>[NH2:4][CH:5]1[C:16](=[O:17])[N:7]2[C:8]([C:13]([OH:15])=[O:14])=[C:9]([CH3:12])[CH2:10][S:11][C@H:6]12
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.12 h

Procedure:
To a suspension of 7-phthalisoimido-3-methyl-3-cephem-4-carboxylate (172 mg., 0.5 mmol.) in tetrahydrofuran (7 ml.) at 0° was added anhydrous hydrazine (.032 ml., 1 mmol.). After 7 min., 1N HCl (2.5 ml.) and water (2.5 ml.) were added. The mixture was heated on a stream bath for 10 min. after which it was cooled and evaporated in vacuo to a volume of ca. 5 ml. The aqueous solution was filtered, and the pH of the filtrate was adjusted to 3.7 with 5% sodium bicarbonate solution. After 15 min. the solution was filtered giving 73 mg. (68%) of 7-amino-3-methyl-3-cephem-4-carboxylate. Spectral data as well as tlc data showed the product to be identical with an authentic sample of 7-ADCA.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[C:32]([CH:39]=O)=[CH:31]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:39][C:32]4[C:33]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:30][CH:31]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3N)ccc2C(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 7-[(2-amino-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.0 g, 2.5 mmol), 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (730 mg, 5.0 mmol), and p-toluenesulfonic acid monohydrate (48 mg, 0.25 mmol) in 50 mL of anhydrous toluene was stirred at reflux for 1 h. After being cooled to RT, the mixture was diluted with 2 mL of MeOH and NaBH4 (475 mg, 12.5 mmol) was added, and the mixture was stirred at RT for 30 min. The reaction was quenched with MeOH, and the volatiles were removed under reduced pressure. The residue was taken up in water, AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, and condensed. The residue was purified by flash column chromatography to give 4,4-dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. MS (ES+): 527.2 (M+H)+. Calc'd for C30H34N6O3 526.27.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH2:25][CH2:24][C:11]2[N:12]([CH2:20][C:21](O)=[O:22])[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9]1>C1COCC1>[CH3:7][N:8]1[CH2:25][CH2:24][C:11]2[N:12]([CH2:20][CH2:21][OH:22])[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CCO)CCN(C)C1
Temperature: 0 °C

Procedure:
Lithium Aluminum Hydride (0.088 g, 2.3 mmol) was charged in dry THF (5 mL) and the contents cooled to 0° C. 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.2 g, 0.77 mmol) was then added to it portion wise. The reaction mixture was refluxed overnight. The reaction mixture was cooled to 0° C. and quenched with aqueous sodium sulfate. The solid formed was filtered through Celite, washed with THF, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to give 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanol. 10 mg of it was taken in dry THF (2 mL), oxalic acid (5 mg) was added to it. The solvent was evaporated under reduced pressure to afford 0.1 g of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanol as oxalate salt. 1H NMR (DMSO) 7.4 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.4 (bs, 1H), 4.2 (s, 2H), 3.7 (bs, 2H), 3.2 (bs, 2H), 2.9 (s, 3H), 2.6-2.4 (m, 4H), 2.3 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5](C)([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][C:9]=1[CH2:29][CH2:30][CH3:31])C)C.[OH-].[Na+]>CO>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][C:4]([OH:33])=[O:3])=[C:9]([CH2:29][CH2:30][CH3:31])[CH:10]=1
Reactant: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OC(C)(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OCC(=O)O
Temperature: 55 °C

Procedure:
A solution of 2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy}propionic acid ethyl ester (0.21 g, 0.5 mmol) in MeOH (10 mL) was treated with 2.5N aqueous NaOH (1.2 mL). The solution was heated at 55° C. for 1.5 h, cooled to ambient temperature, and concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and water (30 mL) and acidified to pH=1 with 5N aqueous HCl. The organic layer was washed with brine (40 mL), dried (Na2SO4), and concentrated to a white solid (0.17 g, 86%). 1H. NMR (400 MHz, CDCl3) δ 7.97 (dd, J=7.4, 2.4 Hz, 2H), 7.44-7.41 (m, 3H), 6.72 (d, J=2.9 Hz, 1H), 6.68-6.59 (m, 2H), 4.59 (s, 2H), 4.14 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.61 (q, J=7.7 Hz, 2H), 0.94 (t, J=7.6 Hz, 3H); MS (ES) m/e 396 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3](O)=O.C(N(CC)CC)C.C(O)C.[NH2:16][C:17]1[N:18]=[N:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=1>O>[Cl:1][C:2]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[N:19][N:18]2[CH:3]=1
Reactant: CC(C)c1ccc(N)nn1
Reactant: O=C(O)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc2nc(Cl)cn2n1
Temperature: 25 °C

Procedure:
Chloroacetic acid (0.32 g, 3.3 mmol), triethylamine (0.33 g, 3.3 mmol), ethanol (5.0 ml) and water (5.0 ml) were mixed and 3-amino-6-isopropylpyridazine (0.45 g, 3.28 mmol) was added thereto with stirring at room temperature, and after the mixture was heated at 80 to 90° C. for 5 hours under stirring, the reaction solution was concentrated to dryness. The resulting solids and phosphorus oxychloride (5.0 ml) were stirred at 150° C. for 12 hours in a sealed tube reactor. The reaction solution was left and cooled to room temperature and poured into water (50.0 ml) of 40 to 50° C., to decompose an excess of phosphorus oxychloride. The reaction solution was adjusted to pH 7 with 20% aqueous sodium hydroxide solution and extracted 3 times with ethyl acetate, and the extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2), to give the title compound as pale yellow crystals. The yield was 0.15 g (23.4%).