Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:41][C:42]1[C:50]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>ClCCl>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:44]([C:43]3[CH:47]=[CH:48][CH:49]=[C:50]([C:51]([F:52])([F:53])[F:54])[C:42]=3[Cl:41])=[O:45])[CH2:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: Clc1cnc2n1CCNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Cl)cnc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
3-Chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I20) (450 mg, 2.86 mmol) and diethylaminomethyl polystyrene (2855 mg, 9.14 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (763 mg, 3.14 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford 911 mg of material that was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford a crude product which was further purified by MDAP to afford desired product in 373 mg.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:16]([C:25]#[N:26])[CH:15]=1.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>C1COCC1>[C:25]([C:16]1[CH:15]=[C:14]([NH:13][C:1]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[S:2])[CH:19]=[CH:18][C:17]=1[N:20]=[CH:21][N:22]([CH3:23])[CH3:24])#[N:26]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(N)CO
Reactant: CN(C)C=Nc1ccc(N)cc1C#N
Solvent: C1CCOC1
Product: CN(C)C=Nc1ccc(NC(=S)NC(C)(C)CO)cc1C#N
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 34.2 %

Procedure:
To a cooled (−10° C.) solution of thiocarbonyldiimidazole (211 g, 1.178 mol) in THF (1.5 L) was added slowly via cannula a solution of N′-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine (201.6 g, 1.071 mol) in THF (1.5 L). After stirring at −10° C. for 25 minutes, a solution of 2-amino-2-methylpropan-1-ol (120 g, 1.4 mol) in THF (500 mL) was slowly added to the mixture. After warming to room temperature and stirring for 16 hours, the mixture was washed with saturated sodium chloride (2×2 L). The combined aqueous layers were extracted with MTBE (2 L) and ethyl acetate (4×1 L). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized with MTBE and ethyl acetate to provide the product (116.9 g, 34%) as yellow solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15](OS(C)(=O)=O)[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[F:31][C:30]([F:33])([F:32])[C:28]1[CH:29]=[C:24]([C:23]([N:9]2[C@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][N:12]3[CH2:14][C@H:15]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:16][CH2:17][C@@H:11]3[CH2:10]2)=[O:38])[CH:25]=[C:26]([C:34]([F:36])([F:35])[F:37])[CH:27]=1.[F:31][C:30]([F:33])([F:32])[C:28]1[CH:29]=[C:24]([C:23]([N:9]2[C@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][N:12]3[CH2:14][C@@H:15]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:16][CH2:17][C@@H:11]3[CH2:10]2)=[O:38])[CH:25]=[C:26]([C:34]([F:36])([F:35])[F:37])[CH:27]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccccc3)CN2C1
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@@H](N3CCOCC3)CN2C[C@H]1Cc1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](N3CCOCC3)CN2C[C@H]1Cc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of methanesulfonic acid (3R,7S,9aR)-3-benzyl-2-(3,5-bis(trifluoromethyl)benzoyl)-octahydropyrido[1,2-a]pyrazin-7-yl ester (1.97 g) and morpholine (0.44 mL) in acetonitrile (50 mL) was heated at 80° C. for 40 hours. After cooling to room temperature the mixture was concentrated in vacuo and the residue purified by flash-chromatography (SiO2, CH2Cl2/MeOH/NH4OH 980:18.75:1.25) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,9aR)-3-benzyl-7-morpholin-4-yl-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (0.97 g, Rf 0.24 (CH2Cl2/MeOH/NH4OH 96:3.75:0.25)) (compound 29) and 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,9aR)-3-benzyl-7-morpholin-4-yl-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (0.75 g, Rf 0.15 (CH2Cl2/MeOH/NH4OH 96:3.75:0.25)) (compound 30).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[CH3:29]N(C)C=O>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:29][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(Nn2cnnc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(CN(c2ccc(C(F)(F)F)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.23 Gram of 4-[(4-trifluoromethylphenyl)-amino]-4H-1,2,4-triazole was added little by little to an N,N-dimethylformamide suspension of 0.04 g of sodium hydride at room temperature. The mixture was stirred for 30 minutes at room temperature, and 0.15 g of 4-fluoronitrobenzene was added thereto and the mixture was stirred for 15 minutes at 100° C. The solvent was removed by distillation under reduced pressure and water was added to the residue, which was then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The crystals thus obtained were recrystallized from a mixed solvent of ethyl acetate/ether to give 280 mg of 4-[N-(4-nitrobenzyl)-N-(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[N:28]=[C:27]([NH:29][NH2:30])[C:26]([F:31])=[C:25]([N:32]2[CH2:35][C:34]([CH3:41])([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33]2)[N:24]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:29][NH:30][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:20]=[O:21])[C:26]([F:31])=[C:25]([N:32]2[CH2:33][C:34]([CH3:41])([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:35]2)[N:24]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: CC1(N2CCCC2)CN(c2nc(Cl)nc(NN)c2F)C1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC1(N2CCCC2)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (112 mg, 0.374 mmol), 2-chloro-5-fluoro-4-hydrazino-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]pyrimidine (assumed 112 mg of free base, 0.374 mmol), EDC (86 mg, 0.449 mmol), HOAt (56 mg, 0.411 mmol), and NMM (0.25 mL, 2.24 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was then purified via RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (145 mg, 66%). LCMS: (M+H)+: 582.5.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[NH:30][C:29]([C:31]5[CH:36]=[N:35][CH:34]=[CH:33][N:32]=5)=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].CO.[CH:45](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[NH:30][C:29]([C:31]6[CH:36]=[N:35][CH:34]=[CH:33][N:32]=6)=[N:28][N:27]=5)[CH2:22][CH2:21]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[CH:45]=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6cnccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5cnccn5)[nH]4)CC3)cc2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 10-3 (0.5 g, 0.9 mMol) in 16 mL of 3:1 toluene:methanol was added trimethyl orthoformate (0.3 g, 2.7 mMol) and p-toluenesulfonic acid monohydrate (0.017 g, 0.09 mMol). The reaction was heated to 100° C. in a microwave reactor for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The product was purified on a C18 reverse phase HPLC to give 10-4 as a solid. Mass (M+1) calculated: 565.2571 observed: 565.2523
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1>>[Cl:1][C:21]1[CH:22]=[C:23]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH:24]=[N:25][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10][C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: O=C1COc2ccccc2N1C1CCNCC1
Reactant: Cl
Reactant: CC(C)NC(=O)c1ccc(Cl)nc1
Product: CC(C)NC(=O)c1cnc(N2CCC(N3C(=O)COc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one hydrochloride (WO 9502405) (0.13 g) and the product from example 117 step (i) (0.13 g) according to the method of example 115 step (ii). Yield 0.04 g as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2cccc(C(=O)O)n2)c1
Yield: 95 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2-fluoro-5-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2-fluoro-5-methoxyphenyl)picolinic acid in 95% yield. LC/MS=248.2 (M+H), Rt=0.78 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][NH:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[N:11]([O-])=[O:12].[Na+]>CC(O)=O.O>[CH3:1][C:2]1([CH3:10])[CH2:6][N:5]([N:11]=[O:12])[CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=N[O-]
Reactant: CC1(C)CNC(C(=O)O)C1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(C(=O)O)N(N=O)C1
Reaction time: 3 h

Procedure:
To a suspension of 37.5 g of the crude 4,4-dimethylpyrrolidine-2-carboxylic acid in 420 mL of AcOH was added a solution of 13.3 g (0.19 mol) of NaNO2 in 210 mL of water over 15 min at room temperature and stirred for 3 h. The solution was concentrated under reduced pressure. Acetone (250 mL) was added to the residue and the precipitate was filtered off, and the solution was concentrated under reduced pressure to dryness and crude 4,4-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid was obtained as brown oil.
Reaction SMILES: [C:1]([C@@H:5]([C@H:11]1[C@@H:14]([CH2:15][C:16](=[O:26])[C:17]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[N+]=[N-])[NH:13][C:12]1=[O:27])[CH2:6][O:7][SiH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:23]([O:22][C:20]([C@@H:17]1[C:16](=[O:26])[CH2:15][C@H:14]2[N:13]1[C:12](=[O:27])[C@H:11]2[C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][O:7][SiH:8]([CH3:10])[CH3:9])=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)C[C@H]1NC(=O)[C@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1C(=O)C[C@@H]2[C@H]([C@@H](CO[SiH](C)C)C(C)(C)C)C(=O)N12
Yield: 95.2 %

Procedure:
A solution of 3.96 g (10 mmol) of (3S,4R)-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-4-[3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one in 50 ml of anhydrous dichloromethane was heated to reflux for 30 minutes in the presence of 40 mg (1 mol-%) of rhodium(II) acetate. The reaction solution was filtered through a little kieselguhr and silica gel and evaporated in vacuo. 3.5 g (95%) of the title compound were obtained as a colorless oil, Rf: 0.46 (toluene:ethyl acetate 7:3).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[CH:33](OCC)=[O:34]>>[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:33]=[O:34])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(N)c2)C[C@H]1C
Reactant: CCOC=O
Product: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC=O)c2)C[C@H]1C
Yield: 51 %

Procedure:
(±)-4-(α-(trans-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-aminobenzyl) -N,N-diethylbenzamide (0.42 g, 0.97 mmol) (Example 32, infra) was dissolved in 15 mL of ethyl formate and heated at reflux overnight under nitrogen. The reaction was concentrated to dryness and purified by chromatography on silica gel with ethanol (0-10%) in dichloromethane to give 0.23 g (51%) of (±)-trans-4-(α-(4-allyl-2,5-dimethyl-1 -piperazinyl)-3-formamidobenzyl)-N,N -diethylbenzamide. NMR (300 MHz, CDCl3): δ1.0 (m, 3H); 1.2 (d, m, 9H); 1.8-2.2 (m, 3H); 2.4-2.9 (m, 5H); 3.2-3.6 (m, 5H); 5.1-5.3 (m, 3H) 5.8 (m, 1H); 6.7-7.8 (m, 8H); 7.9-8.1 (m, 1H), 8.6-8.9 (m, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration with ethanolic hydrogen chloride. The solution was concentrated to dryness. The resulting foam was dissolved in a minimal amount of ethanol and precipitated with diethyl ether to give 0.96 g of the hydrated monohydrochloride salt as an off-white solid. Calc. for C28H38N4O2HCl 1.5 H2O: C, 63.92; H, 8.05; N, 10.65; Cl, 6.74. Found: C, 64.21; H, 7.96; N, 10.77; C! , 6.92.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C:3]([NH:6][C:7](=[O:36])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:23]=[C:22]([C@H:24]3[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([S:33][CH3:34])[O:25]3)[CH:21]=[CH:20][C:19]=2[CH3:35])=[CH:13][CH:12]=1)([CH3:5])[CH3:4].Cl.N[C:40](C)(C)[C:41]([N:43]1[CH2:48]CN(C)[CH2:45][CH2:44]1)=O>>[CH3:4][C:3]([NH:6][C:7](=[O:36])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[CH:23]=[C:22]([C@H:24]3[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([S:33][CH3:34])[O:25]3)[CH:21]=[CH:20][C:19]=2[CH3:35])=[CH:15][CH:16]=1)([CH3:5])[C:2]([N:1]1[CH2:45][CH2:44][N:43]([CH3:48])[CH2:41][CH2:40]1)=[O:37]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCC(=O)NC(C)(C)C(N)=O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CN1CCN(C(=O)C(C)(C)N)CC1
Agent: Cl
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCC(=O)NC(C)(C)C(=O)N4CCN(C)CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amide 11, using 2-amino-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one hydrochloride, to provide the product 12 as the bisformate salt. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.40 (s, 2 H), 7.11-7.21 (m, 3 H), 7.02-7.11 (m, 4 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1 H), 3.96 (s, 2 H), 3.74 (br. s., 4 H), 3.34-3.52 (m, 3 H), 2.67 (t, J=4.6 Hz, 4 H), 2.60 (t, J=7.6 Hz, 2 H), 2.47 (s, 3 H), 2.19 (t, J=7.6 Hz, 2 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 1.88 (quin, J=7.5 Hz, 2 H), 1.44 (s, 6 H). MS (ES+) [M+H]+=614.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[Br-:1].[O:22]([CH2:21][C:20]([NH:19][C@@H:18]1[C:17](=[O:30])[N:7]2[C:8]([C:9]([O:11][CH2:12][C:13]([Cl:15])([Cl:14])[Cl:16])=[O:10])=[C:3]([CH2:2][P+:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:4][S:5][C@H:6]12)=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 2,2,2-trichloroethyl 3-bromomethyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate (ca. 7 mmole) in ethyl acetate (25 ml) was stirred at 25° in the absence of light while a solution of triphenylphosphine (3.67g, 2 equiv.) in ethyl acetate (40 ml) was added over 10 minutes. The reaction mixture was stirred at 25° for 31/2 hours and the precipitated solid was filtered off washed with ethyl acetate and dried, (5.62 g), and redissolved in chloroform (40 ml). The filtered solution was diluted with a mixture of ether (20 ml) and light petroleum (b.p. 40° to 60°; 10 ml) and stirred for 30 minutes, and the precipitated solid was filtered off and dried to give the title phosphonium salt (5.47 g, 95%), m.p. 125 to 135°, [α]D23 +4.4° (C 1.06; (Me2SO), λmax. (EtOH) 268 nm (ε 9,250) and 275 nm (ε 8,850), νmax. (CHBr3) 3430 (NH), 1794 (azetidin-2-one), 1730 (CO2R), 1693 and 1520 (CONH) and 1442 cm-1 (P+-C6H5).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.ClC1C=C(O)C=CC=1.[C:20]1(=[O:25])[O:24][CH:22]([CH3:23])[CH2:21]1>>[O:11]([CH:21]([CH2:22][CH3:23])[C:20]([OH:25])=[O:24])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC1CC(=O)O1
Agent: Oc1cccc(Cl)c1
Product: CCC(Oc1ccccc1)C(=O)O
Yield: 13 %

Procedure:
By the two-step method of Preparations G1/G2 and G3/G4, 3-methyl-4-nitrophenol and 3-chlorophenol were reacted with beta-butyrolactone and the intermediate phenoxybutyric acid derivative cyclized to form, respectively, 2,7-dimethyl-6-nitrochroman-4-one [overall yield 13.0%; m.p. 110°-113° C.;
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:16])=[O:15].[CH2:17]([OH:19])[CH3:18].[OH-].[Na+]>O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:18][C:17](=[O:19])[CH:5]=[CH:6][C:7]2[CH:10]=[CH:16][C:14]([O:15][CH:2]([F:12])[F:1])=[CH:13][CH:8]=2)=[CH:6][CH:5]=1
Reactant: CCO
Reactant: CC(C)=O
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C=Cc1ccc(OC(F)F)cc1)C=Cc1ccc(OC(F)F)cc1
Yield: 97.2 %

Procedure:
A mixture of p-difluoromethoxybenzaldehyde (10.7 g; 0.0622 mole), acetone (2.2 ml; 0.0296 mole, ethanol (103 ml) and water (10 ml) is added dropwise, rapidly, and with stirring to an aqueous sodium hydroxide solution (25.5 ml; 10%). The reaction mixture exotherms to 30° C. and a precipitate forms. The precipitate is filtered, washed and dried to afford 9.0 g (97.2%) of title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3](/[CH:11]=[CH:12]/[C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:19])[CH3:20])[N:17]=2)[CH:4]=1
Reactant: CC(C)c1csc(/C=C/c2cc([N+](=O)[O-])ccc2Cl)n1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1csc(/C=C/c2cc(N)ccc2Cl)n1
Temperature: 0 °C

Procedure:
A solution composed of 3.0 g of (E)-2-[2-(2-chloro-5-nitrophenyl)ethenyl]-4-(1-methylethyl)thiazole, 8.0 g of tin(II) chloride dihydrate and 100 ml of ethyl alcohol was heated to reflux for 1 hr. The reaction mixture was then condensed to half of its original volume, diluted with ice water, basified with 3N sodium hydroxide and extracted with methylene chloride. The combined extracts were washed with water and brine, dried (MgSO4)and condensed in vacuo to yield (E)-2-[2-(5-amino-2-chlorophenyl)ethenyl]-4-(1-methylethyl)thiazole; m.p. 82°-85° C. from hexane.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>C(O)C.[C].[Pd]>[CH:1]1([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OC2C=CCCC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1ccc(OC2CCCCC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
1-{1-[4-(2-Cyclohexenyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (200 mg) is dissolved in ethanol (5 ml) and thereto is added 10% palladium-carbon (50 mg). The mixture is stirred at room temperature under atmospheric pressure under hydrogen atmosphere. After the completion of the reaction, the catalyst is removed by filtration. The resulting filtrate is concentrated and purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-[1-(4-cyclohexyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (174 mg).
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[N-]=[C:8]=[O:9].[N-]=C=[O:12].C1(CC2C=CC=CC=2)C=CC=CC=1>>[C:8]([OH:9])(=[O:12])[CH:5]=[CH2:6].[NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: [N-]=C=O
Agent: CCOC(N)=O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=CC(=O)O

Procedure:
A urethane acrylate oligomer was prepared in the same manner as in Synthesis Example 1, with the exception that a urethane prepolymer obtained by adjusting the proportions of polyol, chain extender and diphenylmethane diisocyanate so that the ratio of HS/SS was about 1/1.32 was used.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1.S(Cl)([Cl:24])=O>C(O)C>[ClH:24].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:2][CH3:4])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nccc2ccc(C(=O)O)cc12
Reactant: O=C(O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2ccnc(N)c2c1
Product: Cl

Procedure:
To a suspension of 1-aminoisoquinoline-7-carboxylic acid TFA salt (6 g, 20 mmol) in anhydrous ethanol (150 mL) was added thionyl chloride (7.7 mL, 10 eq.) slowly at 0° C. and the reaction mixture was then refluxed for 5 hours. The volatiles were removed under vacuo and the resultant solid treated with diethyl ether and filtered to give the title compound as a brown solid.