Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of ethyl 2-(isonicotinamido)-4-methylthiazole-5-carboxylate (1.46 g, 5.0 mmol) and sodium hydroxide (0.40 g, 10.00 mmol) in methanol (100 mL) and water (25 mL) was stirred at ambient temperature overnight and then heated to reflux for 2 h. The mixture was concentrated and then neutralized with 5% hydrochloric acid solution to pH 5˜6. The precipitate obtained was collected by filtration and dried to give the title compound in 89% yield (1.17 g); 1H NMR (DMSO-d5, 300 MHz) δ 8.74 (d, J=6.0 Hz, 2H), 7.93 (d, J=6.0 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 264.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=2)[CH:20]=[CH:19]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:27]([C:24]4[CH:25]=[C:26]5[C:21]([CH:20]=[CH:19][NH:18]5)=[CH:22][CH:23]=4)=[O:28])=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc5cc[nH]c5c4)ccc32)cc1

Procedure:
Compound 557 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and indole-6-carboxylic acid. [M+H]+ calcd for C22H17N5O: 368.14; found: 367.90.
Reaction SMILES: N=C=N.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([NH:26][CH:27]2[CH2:31][CH2:30][O:29][NH:28]2)(=[O:25])=[O:24])[C:17]=1[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])=S.CS(Cl)(=O)=O.C(N(CC)CC)C>>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]=[C:13]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([NH:26][CH:27]2[CH2:31][CH2:30][O:29][NH:28]2)(=[O:25])=[O:24])[C:17]=1[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(NC(=S)Nc2cccc(Cl)c2Cl)ccc(Cl)c1S(=O)(=O)NC1CCON1
Agent: CS(=O)(=O)Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1c(N=C=Nc2cccc(Cl)c2Cl)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 105.5 %

Procedure:
Following the general procedure for carbodiimide formation outlined in example 1, N-(2,3-dichlorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]thiourea (547 mg, 0.897 mmol), methanesulfonyl chloride (0.14 mL, 1.79 mmol) and triethylamine (0.25 mL, 1.79 mmol) were reacted to form the desired product (547 mg, crude). 1H NMR (CDCl3) δ 0.36 (s, 6H), 1.03 (s, 9H), 1.68 (m, 2H), 1.9 (m, 2H), 3.53 (t, 2H), 4.0 (t, 2H), 7.11 (m, 2H), 7.14 (t, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 7.39 (d, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:6])[CH:4]=[CH2:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)(=O)C>O>[CH2:3]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)[CH:4]=[CH2:5]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 42.9 g of sodium hydroxide in 500 ml of water was made up under nitrogen and cooled to room temperature, 108 ml of allyl mercaptan were added and the mixture stirred under nitrogen for 30 minutes. 138.7 g of 4-acetoxyazetidin-2-one were added to the mixture over 10 minutes under nitrogen and the reaction mixture was stirred overnight. The reaction was checked for completion by T.L.C. (hexane-ethyl acetate) and extracted into dichloromethane (6×250 ml). The organic layer was washed with water (2×250 ml), dried over magnesium sulphate and evaporated in vacuo to dryness. Purification, over silica gel and elution with hexane-ethyl acetate afforded the above product as a yellow oil. (112.1 g, 73% of the theoretical yield). νmax=1769, 1778 (sh) cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([C:8](=[C:13]([OH:53])[C:14](=[O:52])[N:15]([CH:25]([CH3:51])[CH:26]([C:42]1[CH:47]=[CH:46][C:45]2[O:48][CH2:49][O:50][C:44]=2[CH:43]=1)[CH2:27][C:28]1[O:29][C:30]([C:33](=[O:41])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])(C)(C)[CH3:2].C1(/C=C/CNC(C)C(C2C=CC3OCOC=3C=2)CC2OC(C(=O)NC3C=CC=CC=3)=CC=2)C=CC=CC=1.Cl.NO.N1C=CC=CC=1>C(O)C>[CH2:1]([O:5][C:6]([C:8](=[C:13]([OH:53])[C:14](=[O:52])[N:15]([CH:25]([CH3:51])[CH:26]([C:42]1[CH:47]=[CH:46][C:45]2[O:48][CH2:49][O:50][C:44]=2[CH:43]=1)[CH2:27][C:28]1[O:29][C:30]([C:33](=[O:41])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH3:2]
Reactant: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2)N(C/C=C/c1ccccc1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(NC/C=C/c1ccccc1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(CC(=O)O)=C(O)C(=O)N(C/C=C/c1ccccc1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 33.7 %

Procedure:
37 mg of 3-(tert-butoxycarbonyl)-4-hydroxy-4-[N-[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-3-butenoic acid prepared by reactions similar to those in Example 1 using N-{(E)-3-phenyl-2-propenyl}-[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]amine instead of N-{(E)-3-phenyl-2-propenyl}-[(1R,2R)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]amine used as the starting material in Example 1 was dissolved in 10 ml of ethanol and refluxed together with 3.9 mg of hydroxylamine hydrochloride and 9.6 mg of pyridine under heating for 15 hours. The reaction solution was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was purified by silica gel thin layer chromatography [Kieselgel™60F254, Art™5744; chloroform/methanol=10/1] to give 12 mg (yield: 34%) of the title compound as a colorless foamy substance.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]2=[O:28])=[CH:18][CH:17]=1>C(O)CC(C)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:24][C:23]2=[O:28])=[CH:20][CH:21]=1
Reactant: COc1ccc(N2CCNCC2=O)cc1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Product: COc1ccc(N2CCN(c3nc4c(c(=O)[nH]3)CCCC4)CC2=O)cc1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(4-methoxyphenyl)piperazin-2-one (105 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up. The crude product obtained in this way is purified by column chromatography; yield: 8 mg (4%), crystals; HPLC method P; RT/min 2,87.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32]>CN(C)C1C=CN=CC=1.C(OCC)C>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:32]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Oc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenol (5.0 g, 39.0 mmol), a 1M solution of 1,3-dicyclohexylcarbodiimide in dichloromethane (39.0 mL, 39.0 mmol) and 4-dimethylaminopyridine (0.5 g, 3.9 mmol) were added to a solution of thiophene-2-carboxylic acid (5.0 g, 39.0 mmol) in diethyl ether (400 mL) at about 0° C. The reaction mixture was stirred overnight while being allowed to warm to room temperature. The precipitate was collected by filtration and was washed with diethyl ether. The combined filtrates were washed successively with water, 5% aqueous acetic acid, water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (5:1) as the mobile phase to provide phenyl thiophene-2-carboxylate. MS (DCI-NH3): m/z 222 (M+NH4)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:28]3[C@H:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32](=[O:38])[NH:31][C@H:30]([CH:39]4[CH2:47][C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH2:40]4)[C:29]3=[O:48])[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20]CC3C=CC=CC=3)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.B(Br)(Br)Br.Cl>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:28]3[C@H:33]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:32](=[O:38])[NH:31][C@H:30]([CH:39]4[CH2:47][C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH2:40]4)[C:29]3=[O:48])[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1OCc1ccccc1)c1ccc2sccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
(2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide (1.0 g) was dissolved in dichloromethane (5 ml) and to this was added dropwise a 1.0M solution of BBr3 in dichloromethane (2.0 ml). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid (30 ml) and dichloromethane (20 ml). The phases were separated and the organic phase was washed with 1N hydrochloric acid (30 ml) and brine (30 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by Biotage™ flash column chromatography, eluting with 3:2 ethyl acetate:cyclohexane. The required fractions were combined and evaporated in vacuo to give (2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (210 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(OCC2C=CC=CC=2)=O)=[CH:5][C:4]=1[F:22])#[N:2].C(Cl)Cl.[H][H]>C1COCC1.[Pd]>[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:22])[CH:5]=1
Reactant: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN)cc1F
Yield: 100 %

Procedure:
Into a 100 mL single neck flask were placed N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide (2 g, 6.7 mmol) in THF: MeOH (25:25 mL). The mixture was treated with a 10% palladium on carbon (0.5 g, 25 mol%) and stirred under the hydrogen balloon for 12 hour. The reaction mixture was filtered through a Celite® cake. The filtrate was concentrated under reduced vacuum to provide the intermediate title compound, 4-(2-aminoethyl)-2-fluorobenzenecarbonitrile, (1.1 g, 100%) as a white solid. Electron spray M.S. 165 (M*+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:36])[C:12]([CH:14]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:43]([OH:46])(=[S:45])[CH3:44]>>[CH2:8]([O:10][C:11](=[O:36])[CH:12]([CH2:13][S:45][C:43](=[O:46])[CH3:44])[CH:14]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 65 %

Procedure:
Triethylamine (0.096 g, 0.95 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-acrylic acid ethyl ester (0.34 g, 0.86 mmol) in thioacetic acid (3.5 mL) at 0° C. under argon. The mixture was heated at 45° C. for 24 h. Ethyl acetate was added and the organic phase was washed with aqueous saturated sodium bicarbonate and brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (CH2Cl2/ethyl acetate, 1:0→100:5) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-4-phenyl-butyric acid ethyl ester (0.264 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[N:7]=1.[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=2)[N:7]=1
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1O
Product: CCCCCCCCCCOc1ccc(C#Cc2ccc(C(=O)OC)cc2)nc1CCC(=O)OC
Yield: 75.1 %

Procedure:
Under the conditions of example 1 D, 500 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 358 mg of 1-decyl bromide and worked up. 531 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethinyl]-3-decyloxy-2-pyridyl}-propionic acid methyl ester of melting point 88°-90° C. is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH2:16][CH3:17])[C:8](/[CH:18]=[C:19](\[CH3:23])/[C:20]([OH:22])=[O:21])=[CH:7][C:6]=1[O:24][CH3:25])(=[O:3])[CH3:2]>CC(C)=O>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH2:16][CH3:17])[C:8](/[CH:18]=[C:19](/[CH3:23])\[C:20]([OH:22])=[O:21])=[CH:7][C:6]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OC(C)=O)c12
Solvent: CC(C)=O
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OC(C)=O)c12
Yield: 36.5 %

Procedure:
7.4 g of (E)-3-(4-acetoxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 1.3 liters of acetone, and irradiated with light from a high pressure mercury lamp through a Pyrex filter at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (3% methanol/chloroform) to obtain 2.7 g of the titled compound as colorless crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10](OCC)=[O:11].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)CCC(C)(C)CCCCCBr
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CCCO)CCCCCBr
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 9-bromo-4,4-dimethylnonanoate (example 285, step g) (0.56 g) in dry ether (19 mL) under nitrogen at 0° C. was treated with diisobutylaluminium hydride (1M in toluene, 4.20 mL) and the reaction mixture was stirred at 0° C. for 1 hour 15 minutes. The reaction mixture was treated cautiously with aqueous potassium sodium tartrate solution and stirred for 1 hour. The phases were separated and the aqueous layer was extracted with ether (×2) then the combined organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the subtitled compound as a colourless oil. Yield 0.42 g.
Reaction SMILES: [NH3:1].Cl.[CH:3]([N:6]([CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:8][N:9]([C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1)[C:10](=O)[O:11]C1C=CC=CC=1)([CH3:5])[CH3:4]>O1CCCC1>[CH:3]([N:6]([CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:8][N:9]([C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1)[C:10]([NH2:1])=[O:11])([CH3:5])[CH3:4]
Reactant: N
Reactant: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(N)=O)n1

Procedure:
Concentrated ammonia (10 ml) is added to a solution of phenyl N-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyrimidinyl)carbamate hydrochloride (7.33 g., 0.018 mole) in 50 ml of tetrahydrofuran and the mixture is allowed to stand for twenty-four hours. It is concentrated, water and chloroform are added to the residue, the chloroform is separated and concentrated. Crystallization of the residue from hexane yields N-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyrimidinyl)urea melting at 134°-136° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][N:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2.C(N(CC)CC)C>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][N:20]=1)[CH2:17][N:16]([C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:8])[CH2:15][CH2:14]2
Reactant: O=C(Cl)c1cccnc1
Reactant: Clc1cc2c(cn1)CNCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCc2cc(Cl)ncc2C1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A solution of nicotinoyl chloride (0.084 g, 0.593 mmol) in anhydrous THF (1.2 mL) was treated with 6-chloro-1,2,3,4-tetrahydro-2,7-naphthyridine (0.100 g, 0.593 mmol) and triethylamine (0.12 mL, 1.19 mmol). and subsequently allowed to stir at room temperature. After 4 hours the reaction was quenched with deionized H2O (10 mL). Following dilution with EtOAc (10 mL) the reaction mixture was washed twice with brine and once with saturated Na2HCO3(aq). The combined aqueous layers were then washed once with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and then concentrated in vacuo. Purification over silica using a Methanol/CHCl3 gradient afforded the desired product, in 73.3% yield (0.119356 g, 0.435 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([NH+](CCCC)CCCC)CCC.[NH:41]([CH2:45][CH2:46][N:47]1[C:51]([SH:52])=[N:50][N:49]=[N:48]1)[C:42]([NH2:44])=[NH:43]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:52][C:51]4[N:47]([CH2:46][CH2:45][NH:41][C:42]([NH2:44])=[NH:43])[N:48]=[N:49][N:50]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: N=C(N)NCCn1nnnc1S
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Agent: CCCC[NH+](CCCC)CCCC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=N)N)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 45 %

Procedure:
To a solution of 559 mg of tributylammonium 7β-[2 -(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3 -hydroxymethyl-3-cephem-4-carboxylate and 374 mg of 1-(2-guanidinoethyl)-5-mercapto-1H-tetrazole in 10 ml of DMF was added 500 mg of ethyl o-phenylenephosphate under stirring at -20° C. The reaction mixture was stirred at -20° C. to 0° C. for 90 minutes and subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with a (5:1) mixture of acetonitrile and water. The eluate was concentrated under reduced pressure, and the concentrate was subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 10% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 245 mg of the title compound as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:13]([OH:16])[CH:14]=O.[C:24]([NH:28][C:29]([C@@H:31]1[CH2:40][C@H:39]2[C@H:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:33][NH:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>C(O)(=O)C>[C:24]([NH:28][C:29]([C@@H:31]1[CH2:40][C@H:39]2[C@H:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:33][N:32]1[CH2:14][C@@H:13]([OH:16])[C@@H:12]([N:3]1[C:2](=[O:1])[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]2[C:4]1=[O:11])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
309 mg of (2S,3S)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyraldehyde and 238 mg of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide are dissolved in 5 ml of acetic acid and treated portionwise with 120 mg of sodium cyanoborohydride. After completion of the reaction the mixture is concentrated to dryness, treated with 10 ml of water and extracted with methylene chloride. The extracts are dried and filtered, the filtrate is concentrated and the residue is purified on silica gel with methylene chloride/methanol (95:5). N-tert.Butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide is obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:29])=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([NH:35][CH3:36])=[CH:33][CH:32]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.CCCCCC>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([N:35]([CH3:36])[C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:29])=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[N:8]=2)=[CH:33][CH:32]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: Cc1nn2ccccc2c1-c1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nn2ccccc2c1-c1nc(N(C)c2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 112 °C
Yield: 75.2 %

Procedure:
The mixture of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine (0.0700 g, 0.142 mmol), p-Chloro-N-methylaniline (33.5 mg, 0.236 mmol), Tris(dibenzylideneacetone)dipalladium(0) (4.4 mg, 0.0048 mmol.), racemic 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (8.8 mg, 0.014 mmol) and Sodium tert-butoxide (22.7 mg, 0.236 mmol) in dry Toluene (2.0 mL, 19 mmol) was degassed by vacuum and backfilling with N2 for 5 times, sonicated under N2 for 1 min to dissolve all material, degassed for 5 more times. The resulted brown solution was heated under N2 in a capped vial to 112° C. for 18 hours. The mixture was partitioned in EtOAc (80 mL) and water (30 mL). The EtOAc layer was washed with water, brine, dried over Na2SO4, filtered, rotavaped to give a crude product. Chromatograph in a 24 g ISCO column using EtOAc/hexane (0/100 to 40/60) afforded a solid product (0.059 g, 75% yield). LCMS: (FA) ES+ 552, 554. 1H NMR (400 MHz, d1-chloroform) δ 8.43 (d, J=6.53 Hz, 1H), 8.32 (d, J=9.04 Hz, 1H), 8.13 (s, 1H), 7.29-7.33 (m, 1H), 7.10-7.12 (d, J=9.04 Hz, 2H), 6.84-6.88 (m, 1H), 6.82-6.84 (d, J=9.04 Hz, 2H), 5.39 (s, 2H), 3.55 (t, J=7.78 Hz, 2H), 3.51 (s, 3H), 2.78 (s, 3H), 0.90 (t, J=7.78 Hz, 2H), 0.00 (s, 9H).