Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:37][CH3:36])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,4R)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.7 g, 5.48 mmol) in MeOH (containing 2% AcOH, 25 mL), methylamine (13.7 mL, 27.41 mmol, 2M in MeOH) is added. The solution is stirred at RT for 1 h under nitrogen atmosphere and cooled to 10° C., before the careful addition of NaBH4 (0.415 g, 10.96 mmol) (exothermic !!). The resulting mixture is allowed to reach RT and stirred for 1.5 h. The excess reducing agent is quenched with water, AcOEt is added and the reaction mixture is poured into an aqueous saturated solution of NaHCO3. The organic layer is separated and the aqueous layer extracted twice with AcOEt, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.05. MS (LC-MS) [M+H]+=508.1. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 4.53 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:23][NH:24][O:25][CH3:26].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([N:24]([O:25][CH3:26])[CH3:23])=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C(=O)O)cnc21
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C(=O)N(C)OC)cnc21
Reaction time: 1 h

Procedure:
4-Cyclohexylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.200 gm, 0.0006 mole) (example 5) and N,O-dimethylhydroxylamine hydrochloride (0.102 gm, 0.0010 mole) were taken in dimethylformamide. At 0° C., hydroxybenzotriazole (0.162 gm, 0.0012 mole) and N-methylmorpholine (0.30 ml, 0.0027 mole) were added and the reaction mixture was stirred for about 1 h. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.266 gm, 0.0012 mole) was added and the reaction mixture was stirred for about 14 h. Water was added and extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The compound was purified over preparative thin layer chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Brc1cccc(NC2CCOCC2)c1
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of 3-Bromo-phenylamine (0.54 ml, 5 mmol) and tetrahydro-4H-pyran-4-one (0.5 g, 5 mmol) in DCE (20 ml) was added sodium triacetoxyborohydride (1.48 g, 7 mmol) and acetic acid (0.3 g). The mixture was stirred for 18 h before being quenched with 1N NaOH (10 ml). The mixture was partitioned between Et2O and H2O, the aqueous layer further extracted with Et2O, the organics combined, dried (MgSO4), filtered and the solvent removed in vacuo to give a colourless liquid. Purification using silica column chromatography (0-80% EtOAc/hexane gradient) afforded the title compound as a white solid (0.81 g). MS: [M+H]+=256,258
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][C:5]([OH:15])=[C:4]([I:16])[CH:3]=1.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:26])=[O:25])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:17][C:18]1[C:19]([O:15][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:2]([Cl:1])=[CH:3][C:4]=2[I:16])=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:25])=[O:26])[CH:23]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(-c2ccccc2F)c(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccccc4F)c(Cl)cc3I)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Chloro-2′-fluoro-4-iodobiphenyl-3-ol (Preparation 94, 651 mg, 1.75 mmol) was added to a mixture of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 671 mg, 1.85 mmol) and potassium carbonate (967 mg, 7.00 mmol) in dimethylsulfoxide (17.5 mL) and the mixture stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.75 N aq. sodium hydroxide (30.0 mL) and ethyl acetate (30 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and evaporated. The residue was purified on silica, eluting with ethyl acetate:heptanes (3:7) to give the title compound as a mixture of regioisomers (930 mg, 67%). Further purification by preparative HPLC using acetonitrile/water as eluent (5/95-95/5, Phenomenex Luna C18 5 u 110 A 21.2×150 mm) gave the title compound (600 mg, 43%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:30])[C:23]2[C:18](=[CH:19][C:20]([C:25](=O)[CH3:26])=[C:21]([CH3:24])[CH:22]=2)[C:17]([CH3:29])([CH3:28])[CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:30])[C:23]2[C:18](=[CH:19][C:20]([C:25]#[CH:26])=[C:21]([CH3:24])[CH:22]=2)[C:17]([CH3:29])([CH3:28])[CH2:16][CH2:15]1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
To a stirred solution of 794.2 mg (7.8486 mmol) diisopropylamine in 7 ml dry tetrahydrofuran under argon at -78° C. was added dropwise 4.9 ml of 1.6M (7.84 mmol) n-butyllithium in hexane. This solution was stirred at -78° C. for 1.25 hours and then treated via a double ended needle with a solution of 1.9 g (7.7749 mmol) of 1,1,4,4,7-pentamethyl-6-acetyl-1,2,3,4-tetrahydronapthalene in 4 ml dry tetrahydrofuran. After stirring at -78° C. for 1 hour, the mixture was treated with 1.3134 g (7.6117 mmol) of diethyl chlorophosphate. The cooling bath was removed and mixture stirred at room temperature for 3 hours. This material was then transferred using a double ended needle into a solution of lithium diisopropylamide [prepared as above using 1.5884 g (15.6972 mmol) of diisopropylamine and 10 ml of 1.6M (16 mmol) n-butyllithium in hexane] in 15 ml dry tetrahydrofuran at -78° C. The cooling bath was removed and mixture stirred at room temperature for 15 hours, then quenched with 50 ml water, and acidified to pH 1 with 3N hydrogen chloride. The mixture was extracted with 3×75 ml petroleum ether and the organic extracts were combined, washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 3% ethyl acetate in hexane) followed by kugelrohr distillation (50° C., 0.05 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ1.28 (12H, s), 1.67 (4H, s), 1.42 (3H, s), 3.20 (1H, s), 7.15 (1H, s), 7.44 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:29][CH2:28][C@@H:27]([N:30]=[N+]=[N-])[CH2:26][C@@H:25]2[OH:33])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.N>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:29][CH2:28][C@@H:27]([NH2:30])[CH2:26][C@@H:25]2[OH:33])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:35][CH:34]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC[C@H]2OC[C@@H](N=[N+]=[N-])C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@@H](N)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
6.5 g (13.7 mmole) of 6-O-DMT-1,5-anhydro-2-azido-2,3-dideoxy-D-mannitol (5) were dissolved in 70 ml of pyridine and 50 ml of 32% aqueous ammonia, then 6.1 g (23.3 mmole) of triphenylphosphane are added. The reaction mixture was stirred for 18 h at r.t. Thereafter the reaction mixture was evaporated. The residue was dissolved in 400 ml of ethyl acetate und washed twice with 200 ml of 5% sodium hydrogencarbonate solution. Organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in 10 ml of ethyl acetate and purified by flash-chromatography over silica gel (ethyl acetate/methanol/1% triethylamine gradient). Product fractions were combined, evaporated and dried at high vacuum to yield 5.7 g (93%) of a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:68][N:69]([CH3:76])[CH:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1>CCOC(C)=O.CN(C=O)C.C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13]([N:73]1[CH2:74][CH2:75][CH:70]([N:69]([CH3:76])[CH3:68])[CH2:71][CH2:72]1)=[O:14])[CH3:2]
Reactant: CN(C)C1CCNCC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N(C)C)CC2)cc1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid, 280 mg (0.87 mmol) TBTU, 0.17 mL (0.97 mmol) ethyldiisopropylamine and 45 mL THF was stirred for 1 h at RT, then combined with 130 mg (1.01 mmol) dimethyl-piperidin-4-yl-amine and 5 mL DMF and stirred overnight. The reaction mixture was diluted by the addition of 30 mL EtOAc, extracted with 30 mL of a 15% K2CO3 solution and the organic phase was dried. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: [OH-].[K+].CN1CCCC1=O.[OH:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH2:13]Br.C(O)(=O)C.[SH:26][CH2:27][CH:28]([CH2:30][OH:31])[OH:29]>O>[OH:29][CH:28]([CH2:30][OH:31])[CH2:27][S:26][CH2:13][C:12]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:11]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)c(CBr)c1
Reactant: OCC(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(CSCC(O)CO)c1

Procedure:
13.2 g of potassium hydroxide pellets (85 %) are heated to 45° C. in 27 g of thioglycerol. 10 ml of N-methylpyrrolidone are added followed portionwise over 30 minutes by 0.1 mole (23.2 g) of 2-hydroxy-5-nitrobenzyl bromide. The temperature of 67°-70° C. which is obtained is maintained for 30 minutes after the end of addition. The reaction mixture is diluted with 300 g of iced water. After neutralizing with acetic acid, the expected product precipitates. After filtering off, followed by drying at 45° C. under vacuum the product obtained is recrystallized from isopropyl acetate. It melts at 130° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[NH2:10]C1C=C(O)C=CC=1F>>[NH2:10][C:7]1[CH:6]=[C:5]([OH:8])[C:4]([F:9])=[CH:3][CH:2]=1
Reactant: Nc1cc(O)ccc1F
Reactant: Oc1ccc(Br)cc1F
Product: Nc1ccc(F)c(O)c1
Yield: 86 %

Procedure:
This compound was prepared from 4-bromo-2-fluorophenol (3.0 g, 15.71 mmol) in the manner described for 3-amino-4-fluorophenol, affording 1.79 g (86%) of 3-amino-6-fluorophenol. 1H-NMR (DMSO-d6) δ 10.42 (s, 1H), 9.69 (br s, 2H), 7.22 (dd, J=8.4, 6.6 Hz, 1H), 6.93 (dd, J=5.7, 2.1 Hz, 1H), 6.74 to 6.99 (m, 1H).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.CCCCC.[CH3:23][S:24]SC>O1CCCC1>[CH3:23][S:24][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CSSC
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CSc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of potassium hydride in mineral oil (35 wt. %, 3.04 g, 26.52 mmol) in tetrahydrofuran (53 mL) was cooled to 0° C. then was treated with a solution of 6-bromo-1H-indole (5.20 g, 26.52 mmol) in tetrahydrofuran (53 mL). The reaction was stirred at 0° C. for 30 min. At this time, the reaction was cooled to −78° C. and was treated with a 1.7M solution of tert-butyllithium in pentane (31.2 mL, 53.04 mmol). The reaction mixture was stirred at −78° C. for 20 min. At this time, the reaction was added to a solution of methyl disulfide (4.78 mL, 53.04 mmol) in tetrahydrofuran (15 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 18 h. The reaction was then quenched by the addition of a saturated aqueous ammonium chloride solution (300 mL) and was extracted with ethyl acetate (1×500 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded 6-methylsulfanyl-1H-indole (2.3 g, 53%) as an off-white solid: mp 88-90° C.; EI-HRMS m/e calcd for C9H9NS (M+) 163.0456, found 163.0457.
Reaction SMILES: [CH2:1]([CH2:5][CH:6]=O)[CH2:2][CH:3]=O.S(=O)(=O)(O)O.[CH2:13]([O:15][P:16]([CH2:21][N:22]1[C:31]2[CH:30]=[C:29]([NH2:32])[C:28]3[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=3[C:26]=2[NH:25][C:24](=[O:37])[C:23]1=[O:38])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14].[BH4-].[Na+].B([O-])[O-].[Na+].[Na+]>O1CCCC1.O1CCCC1.CO>[CH2:13]([O:15][P:16]([CH2:21][N:22]1[C:31]2[CH:30]=[C:29]([N:32]3[CH2:6][CH2:5][CH2:1][CH2:2][CH2:3]3)[C:28]3[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=3[C:26]=2[NH:25][C:24](=[O:37])[C:23]1=[O:38])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2c3ccccc3c(N)cc21)OCC
Reactant: O=CCCCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2c3ccccc3c(N3CCCCC3)cc21)OCC

Procedure:
A mixture of 100 microliters of aqueous glutaric dialdehyde (content about 25%), 300 microliters of diluted sulfuric acid and 1 ml of tetrahydrofuran/methanol 1:1 is added with stirring at ice bath temperature to 37 mg of (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-4-yl)-methanephosphonic acid diethyl ester in 2 ml of tetrahydrofuran z.A., to which 13 mg of sodium borohydride was added. Then, another 10 mg of sodium boronate is added and worked up for 1 more hour. The mixture is neutralized and extracted with ethyl acetate. After chromatography with a little silica gel, 16 mg of product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:35][C:34]([F:37])([F:36])[CH2:33][CH2:32][C@@H:31]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:35][C:34]([F:37])([F:36])[CH2:33][CH2:32][C@@H:31]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl
Yield: 81.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (291 mg, 0.442 mmol) prepared in Example 134a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (183 mg, 81%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][C:16]=4[O:26][CH2:27][CH:28]=[CH2:29])=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:30])[CH2:3]1>C(O)C.[Pd]>[CH3:31][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:17][C:16]=4[O:26][CH2:27][CH2:28][CH3:29])=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:30])[CH2:3]1
Reactant: C=CCOc1cc(N(CC)CC)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3
Agent: [Pd]
Solvent: CCO
Product: CCCOc1cc(N(CC)CC)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3

Procedure:
2 g. 8,8-Dimethyl-2-(4-diethylamino-2-allyloxyphenyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolin-6one were hydrogenated in ethanol in the presence of palladium/charcoal. After completion of the take up of hydrogen, the catalyst was filtered off, the filtration was evaporated and the residue recrystallized from isopropanol to give 1.8 g. of the title compound; m.p. 147°-148° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=O)[N:6]=1.O.P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:36](=[O:37])[N:28]2[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]12>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([NH:25][CH:26]2[C:36](=[O:37])[N:28]3[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:10])[N:6]=1
Reactant: CCCCCCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 24.3 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 3 g.), water (0.15 g.), phosphoryl chloride (3.8 g.), trimethylsilyacetamide (10.7 g.), N,N-dimethylformamide (1.0 g.), tetrahydrofuran (50 ml.) and 7-amino-3-cephem-4-carboxylic acid (2.0 g.) were treated in a similar manner to that of Example 18 to give 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[C:5]2[O:10][CH2:9][CH:8]=[CH:7][C:6]2=[C:11]([C:13](OC)=[O:14])[CH:12]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].N1CCOCC1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:13]=[O:14])[C:6]2[CH:7]=[CH:8][CH2:9][O:10][C:5]=2[C:4]=1[O:17][CH3:18]
Reactant: COC(=O)c1cc(OC)c(OC)c2c1C=CCO2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1cc(C=O)c2c(c1OC)OCC=C2
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Methyl 7,8-dimethoxy-2H-1-benzopyran-5-carboxylate (390 g, 1.56 mol) in toluene (1.6 L) was cooled to -15° and a solution of sodium bis(2-methoxyethoxy)aluminum hydride (908 mL, 3.5M in toluene, 3.18 mol) and morpholine (277 g, 3.18 mol) in toluene (900 mL) was added over a 45 min period. After stirring for an additional 30 min, 2N sodium hydroxide solution (2.85 L) was added. The organic layer was separated, washed with 0.8N hydrochloric acid (3×1 L), 5% sodium bicarbonate (500 mL) and water (1 L), dried (MgSO4) and concentrated to give 7,8-Dimethoxy-5-formyl-2H-1-benzopyran (344 g, 86%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[NH:5][C:6]([N:8]([CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH3:9])=[O:7].Cl>O1CCOCC1.O>[CH3:9][N:8]([CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[C:6]([NH:5][C@H:4]([C:3]([OH:24])=[O:2])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)N(C)CC(O)CO
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)N(C)CC(O)CO)C(=O)O)cc1

Procedure:
The resultant compound from Example 129 (114 mg, 0.355 mmol) in dioxane (4 m) and water (2 ml) at 0° C. was treated with LiOH monohydrate (42.0 mg, 1 mmol). After 90 min 2 M HCl (0.6 ml, 2.3 mmol) was added and the mixture was evaporated to a foam which was used without further purification; DCI-MS: (M+H)+ =327.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:24])[CH2:22][CH3:23])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)cc1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once, saturated sodium bicarbonate solution 50 ml, and a saturated salt solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 4 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 251.6 mg.