Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:34])[NH:26][C@@H:27]([C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:34])[NH:26][C@H:27]([C@@H:29]1[CH2:33][CH2:32][N:31]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:30]1)[CH3:28])([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)n(N)c(=O)n1c23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1COc2c(N3CC[C@@H]([C@H](C)NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Yield: 73.7 %

Procedure:
A solution of 0.11 g (0.41 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.26 g (1.3 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and 10 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate/water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.14 g of the title compound. 1H NMR (400 MHz, CDCl3): 7.43 (d, 1H), 5.24 (bs, 2H), 4.82 (m, 1H), 4.56 (m, 1H), 4.33 (d, 1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.73 (m, 1H), 3.59 (m, 2H), 2.18 (m, 1H), 3.01 (m, 1H), 1.67 (m, 1H), 1.44 (s, 9H), 1.40 (m, 3H), 1.25 (m, 1H), 1.20 (d, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:28])([C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH2:17][OH:18].[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:28])([C:19]([F:26])([F:27])[C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH2:17][O:18][C:9]1[C:8]([F:13])=[C:7]([F:14])[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)c(F)c1F
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a mixture of 2,3,4,5,6-pentafluorobenzoic acid (1 g) and 2,2,3,3,4,4,5,5-octafluoropentanol (1.18 g) in N,N-dimethylformamide (5 ml) was added 62% sodium hydride (0.39 g) at room temperature. The mixture was stirred at the same temperature for 1 hour, and thereto was added a mixture of water and ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give 4-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-2,3,5,6-tetrafluorobenzoic acid (923.0 mg).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClS([N:32]=[C:33]=[O:34])(=O)=O.S(=O)(O)[O-].[Na+].[OH-].[Na+]>C1C=CC=CC=1.CCOCC.O>[CH2:12]([C@@:10]1([CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:32][C:33](=[O:34])[CH2:11]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=C(CCCCCCCCCCCCCCCC)COCc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCC[C@]1(COCc2ccccc2)CC(=O)N1
Reaction time: 8 h

Procedure:
To a solution of 3.0 g of 2-[(phenylmethoxy)methyl]-1-octadecene in 10 ml of benzene under argon is added 1.05 ml of chlorosulfonyl isocyanate. The mixture is stirred overnight and then poured into a solution of 22 g of sodium bisulfite, 100 ml of water, 5 ml of 10% sodium hydroxide and 100 ml of ether. This mixture is stirred for 2 hours, and the organic layer separated, dried and evaporated. The residue is purified by chromatography, to give 1.1 g of the desired compound as a colorless oil.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:25]([CH3:37])=[CH:26][C:27]([CH:33]4[CH2:36][CH2:35][CH2:34]4)=[C:28]([CH:32]=3)[C:29](Cl)=[O:30])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)#[N:9].[BrH:38]>ClCCl>[Br:38][CH2:2][C:29]([C:28]1[C:27]([CH:33]2[CH2:36][CH2:35][CH2:34]2)=[CH:26][C:25]([CH3:37])=[C:24]([CH:32]=1)[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)=[O:23])=[O:30]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(C2CCC2)c(C(=O)Cl)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: Br
Solvent: ClCCl
Product: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of TMSCHN2 (2 M in hexane) (0.476 mL, 2.00 equiv) in dichloromethane (10 mL) under nitrogen at 0° C. was added dropwise a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoyl chloride (compound 235.1, 200 mg, 0.480 mmol, 1.00 equiv) in dichloromethane (3 mL). The resulting mixture was stirred overnight at 25° C. HBr (40%) (0.154 mL, 1.50 equiv) was then added dropwise at 0° C. and the mixture was stirred for another 2 h at 0° C., then diluted with 50 mL of dichloromethane. The organic layer was washed with 2×20 mL of water and 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (0:1-1:50-1:5) as eluent to furnish 200 mg (88%) of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile as a yellow oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([Cl:19])[C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:20][C:11]1[C:12]([Cl:19])=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=1[Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 75 °C
Yield: 99 %

Procedure:
Benzyl bromide (17.25 mL, 144 mmol) was added to a stirring solution of 2,6-dichloro-4-nitrophenol (5 g, 24 mmol) and potassium carbonate (13.3 g, 96 mmol) in acetone (30 mL). The mixture was heated to 75° C. for 12 h before being cooled to room temperature and poured into ice-water (100 mL). The mixture was extracted with chloroform (200 mL), washed with brine (100 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (9:1, hexane/dichloromethane) to afford 2-(benzyloxy)-1,3-dichloro-5-nitrobenzene as a white solid (99% yield).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[OH:8][CH2:9][CH2:10][S:11]([C:14]1[C:15](OCCC)=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([CH:20](O)[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[OH:24])[CH:19]=1)(=[O:13])=[O:12].[C:44]([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:5][CH2:3][CH2:2][CH3:44])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([C@H:20]2[CH2:21][CH2:22][C@H:23]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[O:24]2)[CH:19]=1)(=[O:13])=[O:12]
Reactant: CCCOc1c(OC)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCOc1c(OC)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Trifluoroacetic acid (10%, v/v) in chloroform (500 mL) was added to a stirred 0° C. solution of 1-(5-(2-hydroxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl) butan-1,4-diol (75 g, 0.142 mole) in chloroform (500 mL). The temperature was slowly raised to room temperature and the mixture stirred for 3-4 hours. Anhydrous Na2CO3 (80 g, 0.75 mole) was added to this solution, and the mixture was stirred vigorously for 30 minutes. The solid was filtered off, and the filtrate was evaporated to a residue, which was purified by flash column chromatography on SiO2 eluted with hexane-ethyl acetate (6:1, v/v) to afford the desired trans isomer which is more mobile than the cis isomer. The product was recrystallized from methylene chloride-hexane to give of pure trans-2-(5-(2-hydroxyethylsulphonyl)-4-n-propoxy-3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, m.p. 141°-142° C. NMR (CDCl3) δ: 1.03 (t, J=7.8 Hz, CH2CH2CH3), 1.85 (m, CH2CH2CH3), 2.01, 2.46 (m, H-3 and H-4), 3.64 (m, SO2CH2CH2OH) 3.84, 3.86, 3.88 (35, 4 OCH3), 4.89 (m, SO2CH2CH2OH), 4.07 (t, J=8 Hz, OCH2CH2CH3), 5.13 (m, H-2 and H-5) 6.62 (s, Ar-H H-2 and H-6), 7.32 (d, J=2 Hz, Ar-H H-6), 7.52 (d, J=2 Hz, Ar-H H-2).
Reaction SMILES: [Cl:1][CH:2]([Cl:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)=[O:4].[CH2:13](O)[CH2:14][CH2:15][OH:16].C[Si](C)(C)Cl>>[CH2:15]1[O:16][C:8]2([CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]([Cl:1])[Cl:12])[CH2:10][CH2:9]2)[O:11][CH:14]1[CH3:13]
Reactant: OCCCO
Reactant: O=C1CCN(C(=O)C(Cl)Cl)CC1
Agent: C[Si](C)(C)Cl
Product: CC1COC2(CCN(C(=O)C(Cl)Cl)CC2)O1
Yield: 66.3 %

Procedure:
A mixture of 19 g (0.09 mol) of N-dichloroacetylpiperid-4-one, 7.5 g (0.099 mol) of propane-1,3-diol and 22.4 g (0.21 mol) of trimethylchlorosilane was boiled under reflux for 12 hours, while stirring. Thereafter, the reaction mixture was concentrated under reduced pressure and the residue was then subjected to brief incipient distillation under greatly reduced pressure. The resulting brown oil, which slowly crystallized completely, was recrystallized from 200 ml of toluene. 16 g (66.6% of theory) of N-dichloroacetyl-piperid-4-one propylene ketal of melting point 115° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]([CH3:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=[O:51])=[CH:46][N:45]=2)[CH2:39][C@@H:38]1[CH3:53])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]([CH3:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50](=[O:51])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][C:10]([F:12])([F:11])[F:13])[CH:4]=3)=[CH:46][N:45]=2)[CH2:39][C@@H:38]1[CH3:53])=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)Nc2ccc(Br)c(OC(F)(F)F)c2)cn1
Temperature: 50 °C
Yield: 36.5 %

Procedure:
To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (190 mg, 0.74 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.73 mmol; in N,N-dimethylacetamide (3 mL) was added a solution of (2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester TFA (330 mg, 0.74 mmol; Preparation 26) and HCTU (401 mg, 0.97 mmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated by rotary evaporation, extracted with ethyl acetate/sat. sodium carbonate, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% ethyl acetate:hexanes) to provide the title compound (155 mg, yield 36%). (m/z): [M+H]+ calcd for C24H28BrF3N4O4 573.12, 575.12. found 575.5.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:8][C:9]1[C:10]([CH3:19])=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:9]1[C:10]([CH3:19])=[C:11]([S:15]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1csc(N)n1
Product: Cc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
The title compound was prepared from 2-amino-4-methylthiazole (285 mg) and 3-chloro-2-methylbenzenesulfonyl chloride (619 mg) according to METHOD A. This afforded 167 mg (22%) of a yellow solid after purification: 1H NMR (DMSO-4) δ 2.1 (s, 3H), 2.6 (s, 3H), 6.35 (s, 1H), 7.35 (t, 1H), 7.65 (d, 1H), 7.85 (d, 1H), 12.7 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].C=[O:12].N>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:12])#[N:2]
Reactant: N#Cc1cccc(CN)c1
Reactant: C=O
Agent: N
Solvent: CC(=O)O
Product: N#Cc1cccc(C=O)c1
Yield: 54 %

Procedure:
13.2 g of m-cyanobenzylamine, 51 g of a 35% aqueous formalin solution, 24 g of a 28% aqueous ammonia solution and 50 ml of acetic acid were mixed and reacted at 100° C. for 3 hours while stirring. The reaction solution was concentrated to dry in an evaporator and thereto 100 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 7 g (yield: 54%) of m-cyanobenzaldehyde. The purity was 99% or more.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([F:11])([F:10])[O:9][C:5]=2[CH:4]=1.[C-:14]#[N:15].[Na+].O.CC(OC)(C)C>CS(C)=O>[F:10][C:8]1([F:11])[O:7][C:6]2[CH:12]=[CH:13][C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]=2[O:9]1
Reactant: [C-]#N
Reactant: FC1(F)Oc2ccc(CCl)cc2O1
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 35 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40° C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (95%) that is used directly in the next step. 1H NMR (500 MHz, DMSO) δ 7.44 (br s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.22 (dd, J=8.2, 1.8 Hz, 1H), 4.07 (s, 2H).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[C:37]([O:39][CH3:40])[CH:38]=1)[N:35]=[C:34]([CH:41]=O)[CH:33]=[CH:32]2>C(Cl)Cl>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18]/[N:19]=[CH:41]/[C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[C:37]([O:39][CH3:40])[CH:38]=[C:29]([F:28])[CH:30]=4)[N:35]=3)=[CH:16][CH:17]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cc(F)cc2ccc(C=O)nc12
Solvent: ClCCl
Product: COc1cc(F)cc2ccc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.00 g, 2.57 mmol) in DCM (15 mL) was added 6-fluoro-8-methoxyquinoline-2-carbaldehyde (0.5269 g, 2.568 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and the residue purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column volumes) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-methoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.132 g, 1.963 mmol, 76.45% yield).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.[C:36]([OH:39])(=[O:38])[CH3:37].[H][H]>CO.[Pd]>[C:13]([OH:15])(=[O:14])[CH3:12].[C:36]([OH:39])(=[O:38])[CH3:37].[C:13]([OH:15])(=[O:14])[CH3:12].[NH2:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC1CCN(c2ccncc2)CC1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the product of step (iii) (1.34 g) and acetic acid (0.48 ml) in methanol under argon was added 10% Pd on C.(100 mg). The mixture was covered with a blanket. of hydrogen and stirred at room temperature for 4 hr. The catalyst was then removed by filtration through a pad of kieselguhr and the pH of the filtrate was adjusted to 4 by addition of acetic acid. To this mixture, under argon, was then added a further quantity of 10% Pd on C (100 mg), it was covered again with hydrogen and stirred at room temperature for 3 days. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. Toluene (100 ml) was then added to the residue and the solvents were again removed in vacuo to give tert. butyl (S)-2-amino-5-[1-(4-pyridyl)piperidin-4-yl]aminopentanoate, triacetate salt (1.68 g) as a yellow gum: NMR (d6-DMSO+CD3CO2D) δ 1.49 (9H, s), 1.70 (6H, m), 2.23 (2H, m), 3.03 (2H, m), 3.25 (2H, m), 3.50 (1H, m), 3.96 (1H, m), 4.30 (2H, m), 7.18 (2H, d), 8.20 (2H, d); m/Z 349 (M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.Cl.C(O[C:17](=O)[C@H:18](C)[NH2:19])C>N1C=CC=CC=1>[CH3:17][C@@H:18]1[NH:19][C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]1=[O:12]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H]1NC(=O)c2ccccc2NC1=O
Yield: 48.5 %

Procedure:
Following the method of Example 5 isatoic anhydride (61.3 mmol) was allowed to react with L-alanine ethyl ester HCl (73.6 mmol) in pyridine (200 mL) to give 29.7 mmol of (3S)-3-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione as a light, brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Cl:10][C:11]1[S:15][C:14]([C:16](OCC)=[O:17])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[Cl:10][C:11]1[S:15][C:14]([C:16](=[O:17])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CSc1nccc(C)n1
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2ccc(Cl)s2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
To a solution of 4-methyl-2-(methylsulfanyl)pyrimidine (1 eq, 235 mmol) and ethyl 5-chlorothiophene-2-carboxylate (1.11 eq, 261 mmol) in anhydrous THF (400 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1M solution in hexanes, 1.6 eq, 376 mmol). The resulting mixture was stirred for 3 h at 0° C. and then stirred at room temperature overnight. A solution of HCl 1M (750 mL) was then added till pH=1. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was diluted with diisopropylether and the resulting precipitate was filtered and to afford 29.5 g (43% yield) of 1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.COCCN(S(F)(F)[F:32])CCOC.C(=O)(O)[O-].[Na+]>O>[CH:1]([N:14]1[CH2:17][CH:16]([F:32])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 250 mL, round bottom flask was charged with 3.0 g (12.5 mmol) of 1-benzhydryl-3-hydroxyazetidine and 80 mL of dichloromethane. To the stirring solution at −78° C. was added 4.6 mL (25 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 3 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise (with caution) to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with 80 mL of dichloromethane. The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution, water and saturated aqueous brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography using a Biotage® system (gradient, hexane to 80% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]=[CH:7]2.CC[N:17](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([NH2:17])=[O:14])=[CH:5][N:6]=[CH:7]2
Reactant: O=C(O)c1cncc2cccc(Cl)c12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cncc2cccc(Cl)c12
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A 100 mL RBF was charged with 5-chloroisoquinolin-4-carboxylic acid (1 equiv) in dry THF (20 mL), DIPEA (3 equiv), EDC.HCl (1.5 equiv), HOBT (1.5 equiv) under inert atmosphere and the mixture was stirred for 15 mins. To this, corresponding amine (1.2 equiv) was added dropwise and the reaction mixture was stirred overnight. After completion, it was diluted with EtOAc and water. The organic layer was then separated, dried and concentrated under reduced pressure to give the crude product that was purified by column chromatography using 100-200 silica gel (80% Ethyl acetate in Hexanes) to furnish the desired amide derivative in 70-84% yield.
Reaction SMILES: [CH:1]1[C:6]([O-:7])=[CH:5][CH:4]=[C:3]([S:8]([O-:11])(=[O:10])=[O:9])[CH:2]=1.[Na+:12].[Na+].[Cl:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](Cl)=[O:17]>>[Cl:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]([O:7][C:6]1[CH:1]=[CH:2][C:3]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:5]=1)=[O:17].[Na+:12]
Reactant: CCCCCCCC(Cl)C(=O)Cl
Reactant: O=S(=O)([O-])c1ccc([O-])cc1
Agent: [Na+]
Product: CCCCCCCC(Cl)C(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.08 h
Yield: 68 %

Procedure:
Anhydrous disodium p-phenolsulfonate (28.5 g; 0.130 mole) and 30.3 g (0.1436 mole) of 2-chlorononanoyl chloride were combined in a 500 ml round-bottomed flask. The flask was then immersed in an oil bath which had been preheated to 110° C. Within five minutes an exothermic reacting occurred which caused the entire mixture to congeal. After cooling, the mixture was triturated three times with 150-200 ml portions of ether and the product was vacuum dried. Elemental and nmr analyses of the resulting tan powder, 46.2 g, indicated that it was composed of 11.5% NaCl, 17.7% disodium p-phenolsulfonate, and 70.8% of sodium p-(2-chlorononanoyloxy)benzene sulfonate. This represents a 68% yield of the desired product.