Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH:23]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:26]([CH:23]3[CH2:25][CH2:24]3)(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 94.4 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.03 mmol) and cyclopropanesulfonyl chloride (465 mg, 3.32 mmol) the title compound of Step A was obtained (1.24 g, 94.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.29-7.36 (m, 2H), 7.01 (d, J=5.3 Hz, 1H), 6.91-6.93 (br, 1H), 3.29-3.40 (m, 1H), 2.46-2.53 (m, 1H), 1.44 (d, J=7.0 Hz, 6H), 1.12-1.18 (m, 2H), 0.93-1.01 (m, 2H). MS (ES+): 435 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[CH3:11][C:12](OC(C)=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCCCCN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCNCCCCCCCCN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ten mmole of 1,8 diaminooctane is dissolved in 50 ml of pyridine. Five mmole of Ac2O is added to the solution dropwise at 10° C. The organic solvent is then evaporated. Using column chromatography, N-monoacetoamide-1,8-diaminooctane subsequently is separated out. The N-monoacetoamide-1,8-diaminooctane is dissolved in 25 ml 1,2-dichloroethane. To this solution, 6 mmole of LiAlH4 is added. The solution is then stirred under nitrogen gas at room temperature for 1 day. Subsequently, the solution is diluted with 100 ml of ethyl acetate. The resulting solution is washed with 20 ml of saturated sodium chloride solution. The solution is dried over MgSO4 and evaporated to produce a residue of N-monoethyl-1,8-diaminooctane. The obtained N-monoethyl-1,8-diaminooctane is dissolved in 80 ml of 1,2-dichloroethane containing about 15 mmole of 2-methyl-5-nitro-imidazolyl-1-yl-acetaldehyde. This reaction mixture is stirred for 30 minutes and then acidified with 15 mmole of acetic acid. Eighteen mmole of sodium triacetoxyborohydride is added as a reducing agent and the solution is stirred for 48 hours at room temperature. The resulting mixture is diluted with 80 ml of ethyl acetate, and the mixture solution is washed with 100 ml of saturated aqueous NaHCO3 and 50 ml of water. The organic layer is dried over anhydrous MGSO4, and the solvent is evaporated to leave residual oil which solidified at 4° C. for 2 days. The obtained solid is recrystallized from ethyl acetate/hexane to give N, N, N'-tri[2'-(2-methyl-5-nitro-1-imidazolyl) ethyl]-N'-ethyl-1,8-octanediamine.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([Br:16])[C:8]=1[CH:9]=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>CO>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][N:27]=[CH:9][C:8]2[C:7]([Br:6])=[CH:14][C:13]([CH3:15])=[CH:12][C:11]=2[Br:16])=[CH:22][CH:21]=1
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(NN=Cc2c(Br)cc(C)cc2Br)cc1

Procedure:
Sodium bicarbonate (0.84 g, 10 mmol) was added to a solution of 2,6-dibromo-4-methylbenzaldehyde (2.62 g, 9.43 mmol) and [4-(methyloxy)phenyl]hydrazine hydrochloride (1.65 g, 9.45 mmol) in methanol (60 mL) and the mixture heated under reflux for 15 min. The mixture was then cooled and evaporated to give the crude title compound which was used without purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl.O>[CH3:9][S:10]([O:1][CH:2]1[CH:3]([C:7]#[N:8])[CH2:4][S:5][CH2:6]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1CSCC1O
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CSCC1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxytetrahydrothiophene-3-carbonitrile (1.0 g, 7.7 mmol) in DCM (15 mL) was stirred at 0° C. TEA (4.3 mL, 31 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (1.77 g, 15.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes then warmed to ambient temperature and stirred for an additional 30 minutes. The mixture was carefully diluted with water and extracted with DCM (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH/DCM) to afford the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([N:24]=[N+:25]=[N-:26])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCCC(O)(c2ccccc2)C1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
g (3.212 mmol) 3-Hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester was dissolved in a cold mixture (10° C.) of trifluoroacetic acid (12.3 ml) and water (2.0 ml). The solution was cooled to 0° C. and 1.46 g (22.48 mmol) sodium azide were added portionwise. The temperature rose to 10° C. The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was cooled in an ice bath and basified by dropwise addition of a 25% ammonium hydroxide solution (13.0 ml) maintaining the temperature below 20° C. The mixture was diluted with water (45 ml) and extracted 3 times with dichloromethane. The combined extracts were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3ccccn3)cc2)CC1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 261. Starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributylstannyl)-pyridine (12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[Cl:16]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:16])[CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1cccc(Cl)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(Cl)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-chlorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.[Cl-].[Na+].O>[F:19][CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Trimethylsilyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (13.2 g, 48.6 mmol) was dissolved in acetonitrile (250 mL). 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (19.0 g, 53.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Brine was added to the reaction mixture and the aqueous phase extracted ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 100 g, 0% to 100% EtOAc in heptane). The title compound was obtained as white solid (5.66 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([C:35]2[C:36]([CH3:43])=[C:37]([CH:41]=O)[NH:38][C:39]=2[CH3:40])=[O:34])[CH2:25][CH2:24]1>N1CCCCC1.C(O)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([C:35]2[C:36]([CH3:43])=[C:37](/[CH:41]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:38][C:39]=2[CH3:40])=[O:34])[CH2:24][CH2:25]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(F)cccc3F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-difluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (280 mg, 0.87 mmol), 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (250 mg, 0.86 mmol) and piperidine (2 drops) in ethanol (2 mL) was stirred at rt for 4 days. The reaction was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C>[CH:27]1([N:13]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2C1CCCC1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.42 mmol) was dissolved in DMF (3 mL) and K2CO3 (220 mg, 1.6 mmol) and cyclopentyl bromide (49.5 μL, 0.46 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 330.2, found 330.2.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][N:18]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[NH:21][CH2:20][C:19]1=[O:27]>N1C=CC=CC=1.[Cu-]=O>[O:26]=[S:22]1(=[O:25])[CH2:23][CH2:24][N:18]([CH3:17])[C:19](=[O:27])[CH2:20][N:21]1[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CN1CCS(=O)(=O)NCC1=O
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: COC(=O)c1nc(N2CC(=O)N(C)CCS2(=O)=O)c2cccnc2c1O
Temperature: 115 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 5-bromo-8-hydroxy[1,6]naphthyridine-7-carboxylate (0.28 g, 1.0 mmol), 5-methyl-1,2,5-thiadiazepan-4-one 1,1-dioxide from step 2 (0.178 g, 1.0 mmol) and copper (I) oxide (0.143 g, 1.0 mmol) in pyridine (5 mL) was heated in an oil bath at 115° C. overnight. The resultant mixture was filtered, and the filtrate concentrated under vacuum. The residue was treated with a mixture of chloroform (50 mL) and ethylenediamine tetraacetic acid, disodium salt (5 g) in water (30 mL) and stirred vigorously at room temp in the presence of air for 5 hours. The slurry was filtered through a pad of Celite. The organic extract was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with methanol (25 mL) and the resultant suspension stirred at room temperature overnight. The solid was filtered, washed with cold (0° C.) methanol, and dried under vacuum to provide methyl 5-(1,1-dioxido-5-methyl-4-oxo-1,2,5-thiadiazepan-2-yl)-8-hydroxy[1,6]-naphthyridine-7-carboxylate as light brown solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:22]=[C:21]([CH3:20])[CH:26]=[C:25]([CH3:27])[CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: Cc1cc(C)cc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)c1

Procedure:
The product of Example 86A and 2-(3,5-dimethylphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.74 (m, 1H), 7.59-7.69 (m, 4H), 6.98-6.99 (bs, 2H), 6.90-6.91 (bs, 1H), 3.60 (s, 2H), 2.26 (s, 6H); MS (ESI−) M/Z 416 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:55])[C@@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([O:24][C:25](=[O:55])[C@@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.0.093 g, 0.4 mmol), (2S)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]amino}butanedioic acid dibenzyl ester (0.4 mmol) and glacial acetic acid (0.022 g, 0.4 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.025 g, 0.4 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give the product (0.074 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH:5]=[C:6](Br)Br)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].P(O)(O)([O-])=O.[Na+]>O1CCCC1.C1CCCCC1>[CH3:1][C:2]1([CH3:16])[C@@H:4]([C:5]#[C:6][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)Oc2ccccc2)C1(C)C
Temperature: -65 °C

Procedure:
A solution of 25 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropane-carboxylate in 250 ml of tetrahydrofuran was admixed with 48 ml of a 20% solution of butyllithium in cyclohexane with stirring at -65° C. and the mixture was stirred for one hour at -65° C. 9.6 ml of phenyl chloroformate were added to mixture which was then stirred at -65° C. for one hour. The temperature was allowed to return to room temperature while the stirring was maintained and the mixture was poured into a saturated aqueous solution of monosodium phosphate. The mixture was extracted with ether and the ether phase was washed with water and dried. The 24.6 g of oil residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 14.4 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-phenoxy-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(O)(=O)C(O)=O.[C:12]1(C)[CH:17]=CC=[CH:14][CH:13]=1>>[CH:1](=[O:5])[C:2]1[C:3](=[CH:17][CH:12]=[CH:13][CH:14]=1)[OH:4]
Reactant: OCCCO
Reactant: Cc1ccccc1
Agent: O=C(O)C(=O)O
Product: O=Cc1ccccc1O

Procedure:
1,3-propanediol (228 g, 3.0 mol), and oxalic acid (4.5 g, 0.05 mol) were added to 400 mL toluene and heated to reflux for 8 hours in an apparatus equipped with a condenser and a Dean-Stark trap. After cooling, the solution was washed with NaHCO3 and distilled water, and the solution was dried over MgSO4. The product precipitated when the solvent was being evaporated. The solid was collected and dissolved in hot hexane. The solution was filtered through Celite® (a filter aid manufactured by Johns Manville Corp.), and the product was crystallized to give 108 g of an off-white solid.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CO[Na].[CH3:33][O:34][CH:35]([O:39][CH3:40])N(C)C>CO>[CH3:33][O:34][CH:35]([O:39][CH3:40])[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][C:16]2[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:15]=2)[CH2:29][CH2:28]1
Reactant: COC(OC)N(C)C
Reactant: C1CCNC(CCC2CCNCC2)=NC1
Agent: CO[Na]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCC(CCC2=NCCCCN2)CC1
Temperature: 90 °C

Procedure:
The dihydrochloride salt of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (1.6 g, 5.8 mM) in methanol (12 ml) which contained MeONa (12 mM) and dimethylformamide dimethyl acetal (20 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give the 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl] 1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.1 g, 5 mM) and diisopropylethylamine (0.96 ml) in 20 ml dry CHCl3 was added the solution (CHCl3 8 ml: MeOH 1 ml) of the above piperidine-carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and then at room temperature for 3 hrs. The solvent was then removed, and water added (30 ml). The aqueous solution, washed with ethylacetate, was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to yield [2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.85 g, 38% yield)
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([F:23])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mmol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([SH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[K+].Cl>C1COCC1>[CH:11]1([S:17][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: SC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: c1nc(SC2CCCCC2)c2cc[nH]c2n1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a solution of 100 mg (0.651 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine dissolved in 3.0 mL of THF was added 0.10 mL (0.818 mmol) of cyclohexylmercaptan and 100 mg (0.847 mmol) of 95% potassium tert-butoxide and the resulting mixture heated at reflux for 3.5 hr. After cooling to room temperature, the reaction mixture was acidified to pH 1 with 2 N HCl and concentrated in vacuo. The residue was then partitioned between ethylacetate and 1 N HCl. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The cude product was purified by silica-gel chromatography (1:3 ethylacetate/hexanes) providing 34 mg (22%) of the title compound as a white solid. Mp 162-163° C. 1H NMR (400 MHz) d: 1.22-1.36 (m, 1H), 1.45-1.64 (m, 5H), 1.75-1.79 (m, 2H), 2.12-2.14 (m, 2H), 4.18-4.20 (m, 1H), 6.50 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.5 Hz), 8.61 (s, 1H), 10.0 (br s, 1H). LRMS: 234 (M+1).