Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41]>C(Cl)CCl.CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Reactant: NOC1CCCCO1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1)NOC1CCCCO1

Procedure:
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound B2) (0.300 g), HOBtH2O (0.130 g), triethylamine (668 μl), DMF (20 ml), EDC?HCl (0.508 g), O-(tetrahydro-2H-pyran-yl)hydroxylamine (0.089 g). Reaction conditions: room temperature, 1 hour; room temperature, 18 hours.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CCCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37921.8 %

Procedure:
Phenylheptane (100 g, 0.57 mol) was dissolved in 900 mL of chloroform, and ferric chloride (1.41 g, 9 mmol) was added. The mixture was cooled to 0° C. and bromine (32 mL, 0.62 mmol) was added dropwise through an additional funnel. The reaction was kept in dark to prevent the bromination of the aliphatic side chain. After stirring at room temperature overnight, the reaction was quenched with 1N KOH. After extraction, the organic phase was washed with water and dried over MgSO4. The crude product was a brown oil and was purified by column chromatography on silica gel using heptane as an eluent to give 60 g of pure product as light yellow oil at 42% yield. 1H NMR (CDCl3) δ (ppm): 0.88 (t, J=6.9 Hz, 3H), 1.26-1.31 (m, 8H), 1.54-1.59 (m, 2H), 2.54 (t, J=7.8 Hz, 2H), 7.04 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H). FD-MS: m/z 255 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10]P(OCC)(=O)OCC)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].COC([O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)C>>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[OH:23])[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(C)Oc1ccccc1C=O
Reactant: CCOP(=O)(Cc1cc(C(C)(C)C)no1)OCC
Product: CC(C)(C)c1cc(C=Cc2ccccc2O)on1

Procedure:
Using the method described in Example I, 35 g (0.13 mole) of diethyl (3-tert.-butyl-isoxazol-5-yl)methanephosphonate and 23 g (0.13 mole) of o-(1-methoxy-ethoxy)-benzaldehyde are reacted and the product is recrystallized from toluene. 24.8 g (78% of theory) of colorless crystals, of melting point 152°-155° C., are obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH2:22][CH3:23]>CN(C)C=O>[CH3:13][O:12][C:6]1[CH:7]=[C:8]([CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[O:14][CH2:21][CH2:22][CH3:23])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
A mixture of 5-nitrovanillin (19.72 g, 100 mmol), potassium carbonate (35 g, 253.23 mmol) and propyl iodide (32.86 mL, 335.83 mmol) in 160 mL of N,N-dimethylformamide was stirred at 60° C. for 12 hours. The mixture was then cooled, quenched with water and extracted with methylene chloride. The organic layer was washed several times with water, dried over magnesium sulfate, filtered and evaporated in vacuo to an oil which was purified by flash chromatography on silica gel (230-400 mesh) using 2:1 hexane/ethyl acetate as eluent, to provide 3-methoxy-4-propoxy-5-nitrobenzaldehyde (13.54 g, 57%). 1H NMR (CDCl3): 1.00 (t, 3H), 1.85 (m, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.65 (s, 1H), 7.85 (s, 1H), 9.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.N1C=CC=CC=1>CS(C)=O.C(OCC)(=O)C>[OH2:13].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[N:24]=[N:25][C:26]([N:34]4[CH2:35][CH2:36][CH2:37][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[N:24]=[N:25][C:26]([N:34]4[CH2:35][CH2:36][CH2:37][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CN1CCCNCC1
Reactant: O=C(c1ccc(Cl)nn1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN1CCCN(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)nn2)CC1
Product: O
Temperature: 80 °C
Yield: 62.9 %

Procedure:
A mixture of 1-(6-chloronaphthalene-2-sulfonyl)-4-(6-chloropyridazin-3-ylcarbonyl)piperazine (0.2 g, 0.443 mmol), 1-methylhexahydro-1,4-diazepine (0.166 mL, 1.33 mmol) and pyridine (0.11 mL, 1.33 mmol) in DMSO (5 mL) was heated in a sealed tube at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate (200 mL), water (2×150 mL) and brine, and dried over sodium sulfate. After filtration and evaporation of the solvent, the residue was purified by flash chromatography over silica, eluting with 5–7% methanol/methylene chloride, to afford the title compound (0.1 g, 43%).
Reaction SMILES: I.CS[C:4](=[N:19][CH3:20])[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:21][NH2:22]>C(O)C>[CH3:20][NH:19][C:4]([NH:22][CH3:21])=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Reactant: CN
Agent: I
Solvent: CCO
Product: CNC(=Nc1cc(C)ccc1N1CCOCC1)NC
Reaction time: 504 h

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (6 g) and 33% methylamine in absolute ethanol solution (250 ml) was kept at room temperature for 21 days to yield 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine as an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g) to give 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine fumarate (1.2 g) as a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether (m.p. 201°-202° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(OCl)(C)(C)C.[CH3:16][S:17][CH2:18][C:19](OCC)=[O:20].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:16][S:17][CH:18]1[C:9]2[C:2](=[CH:3][CH:4]=[C:5]([C:6]#[N:7])[CH:8]=2)[NH:1][C:19]1=[O:20]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CSC1C(=O)Nc2ccc(C#N)cc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-amino-benzonitrile (84.64 mmoles) in DCM (200 ml) under a nitrogen atmosphere, at −78° C., there is added, dropwise, tBuOCl (84.64 mmoles) dissolved in 20 ml of DCM and then, after 10 minutes, ethyl (methylsulphanyl)acetate (84.64 mmoles) dissolved in 20 ml of DCM is added dropwise to the reaction mixture. After stirring for one hour at −78° C., triethylamine (0.152 mol) is added dropwise. The reaction mixture is stirred at ambient temperature for one hour. Water is added and the phases are then separated. The organic phase is washed with water and then with saturated aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The residue is taken up in ethyl ether and aq. 2M HCl solution is added. After stirring overnight, the yellow precipitate is filtered off and dried in vacuo to yield the title product, which is used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:16]=[N:17][CH:18]=1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cncc(Cl)c1
Product: O=Cc1cc(F)c(Oc2cncc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4,5-trifluorobenzaldehyde and 5-chloropyridin-3-ol.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=O)([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C[O:30][C:31](=[O:33])[CH3:32].[Li+].[OH-].O>C1COCC1.CO>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=[CH:32][C:31]([OH:33])=[O:30])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: COC(C)=O
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=O)(CCC3)C4)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCCC(C=CC(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde (355 mg) was taken in THF (25 ml). Triphenyl-□□-phosphanylidene)-acetic acid methyl ester (614 mg) was added and refluxed overnight. Next day another 460 mg of Triphenyl-□□-phosphanylidene)-acetic acid methyl ester was added and refluxed for 24 hrs. Cooled to RT LiOH (210 mg), water (2 ml), MeOH (5 ml) were added and stirred at rt overnight. Solvent was removed under reduced pressure. Diluted with water (25 ml), extracted with ethyl acetate (3×25 ml). Aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (3×50 ml), dried over Na2SO4 and concentrated. Yield 254 mg. Mass (ES+ 429).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH:25]([OH:28])[CH2:26]O.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CCC>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:28][CH:25]([CH2:24][O:23][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)[CH2:26][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: OCC(O)COc1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: c1ccccc1
Solvent: O
Product: Clc1ccc(C2(CBr)OCC(COc3ccc4ccccc4c3)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 13.1 parts of 3-(2-naphtalenyloxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 180 parts of benzene and 80 parts of butanol is stirred and refluxed for 12 hours with water-separator. The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from 2-propanol, yielding A 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[(2-naphthalenyloxy)methyl]-1,3-dioxo-lane; mp. 117.6° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:13])[C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
A solution of 2,3,4,5-tetrafluorobenzoic acid (4.68 g, 24.1 mmol) in dichloromethane (50 mL) at 0° C. is treated with oxalyl chloride (11.5 mL, 132 mmol) followed by N,N-dimethylformamide (4 drops). The mixture is stirred at 0° C. for 5 minutes and then at room temperature for 1.5 hours. The mixture is concentrated to dryness and subsequently co-evaporated from benzene. The resulting acid chloride is diluted with dichloromethane (50 mL), cooled to 0° C., and anhydrous ethanol (15.0 mL, 256 mmol) is added dropwise. The resulting solution is stirred at room temperature for 4.5 hours, then poured into saturated NaHCO3 and extracted with chloroform. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (5.37 g). 1H NMR (CDCl3): δ 7.67-7.55 (m, 1H), 4.42 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.IC1C=CC(O)=CC=1.[Cl:30][C:31]1[C:32]([F:40])=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C[Si](C)(C)[C:43]#[C:44][C:45]1([CH3:49])[CH2:48][O:47][CH2:46]1>>[Cl:30][C:31]1[C:32]([F:40])=[C:33]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:43]#[C:44][C:45]5([CH3:49])[CH2:48][O:47][CH2:46]5)[CH:3]=4)[O:8][C:9]3=[CH:10][CH:11]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: Oc1ccc(I)cc1
Product: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccc(Cl)c4F)ccc2O3)COC1

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA5 above, but using (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (prepared using the same procedures as described in Method CC6 but using 4-iodophenol) 3-chloro-2-fluorophenylboronic acid and trimethyl((3-methyloxetan-3-yl)ethynyl)silane. MS m/z=476.1 [M+H]+. Calculated for C26H19ClFN3O3: 475.11. 1H NMR (400 MHz, DMSO-d6) δ=8.45 (br. s., 1 H), 7.67 (br. s., 2 H), 7.65-7.60 (m, 2H), 7.58-7.50 (m, 1 H), 7.47-7.39 (m, 1 H), 7.38-7.31 (m, 1 H), 4.78 (d, J=5.5 Hz, 4 H), 4.46 (d, J=5.6 Hz, 2 H), 1.66 (s, 3 H)
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:27][C@H:24]1[CH2:23][CH2:22][C@H:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:26][CH2:25]1)(=[O:33])=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@H](O)CC4)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 μL, 0.52 mmol). The resulting solution was then cooled to 0° C. and methanesulfonyl chloride (34 μL, 0.45 mmol) was added. The reaction was held for 2 hours, at which point tlc and LCMS indicated complete reaction. The reaction was partitioned between water and DCM, the phases were separated and the aqueous phase was extracted with additional solvent. The combined organic phase was washed with water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude product which was used without further purification (173 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=492.1 (M+H).
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[S:17][C:18]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[C:30]2[C:22]([CH2:21][C:18]3[S:17][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)=[N:20][CH:19]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ncc(Cc2c[nH]c3ncc(Cl)cc23)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(CNc2ncc(Cc3c[nH]c4ncc(Cl)cc34)s2)cc1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To the solution of crude [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (628, 0.186 mmol theory) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (1 mL) and the reaction was allowed to stir overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate and then washed with saturated aqueous potassium carbonate making sure basicity was reached. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by silica gel chromatography (0-10% methanol/ethyl acetate). The solvent was removed in vacuo and the material was triturated with dichloromethane to give the desired compound as an off-white solid (20 mg, 29% over 2 steps) consistent with compound structure by 1H-NMR and MS(ESI): [M+H+]+=372.9.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])(=O)[CH3:2].Cl.[NH2:36][OH:37]>C(O)C.C(OC(C)C)(C)C>[OH:37][N:36]=[C:1]([CH3:2])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34]
Reactant: CC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CC(CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)=NO
Temperature: 25 °C
Reaction time: 40 h
Yield: 42.3 %

Procedure:
A mixture of (3RS)-1-acetylmethyl-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1, 4-benzodiazepine-2-one (0.42 g), hydroxylamine hydrochloride (62.5 mg) in ethanol (20 ml) was stirred at room temperature for 40 hours. The mixture was evaporated to dryness and the residue was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (40:1). The fractions containing the objective product were combined and evaporated to give a pale green oil, which was pulverized in diisopropyl ether to afford (3RS)-1-(2-hydroxyiminopropyl)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1, 4-benzodiazepine-2-one (177 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 7.43 mmol) in THF (50 ml) was added BH3.DMS (452 ul, 7.43 mmol). The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concntrated in vacuo and quenced by the addition of H2O (100 ml). The mixture was extracted with CHCl3 (2×200 ml), dried over MgSO4, and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (1.76 g, 72%) as a colorless oil. 1H-NMR (CDCl3) δ1.45 (s, 9 H), 2.28-2.36 (m, 2 H), 3.58-4.99 (series of m, 8 H), 6.74-6.90 (m, 3 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:21][CH2:22][CH2:23][CH2:24]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:21][CH2:22][CH2:23][CH2:24][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran being stirred, 126 ml of a 1.6 M solution of n-butyl lithium in hexane wasadded at -5° to 0° C., followed by stirring for 30 minutes. After the reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise to the mixture and stirred for 1 hour. 41.8 g of 1,3-dibromopropane was added dropwise to the reaction mixture. After stirring at -78° C. for 1 hour and then at room temperature (15° to 20° C.) for 2 hours, the reaction mixture was added to an aqueous solution of ammonium chloride and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off, and the residue was distilled under reduced pressure, to yield 40.3 g of the title compound in the form of a colorless oily substance.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.CN(C=O)C.Br[CH2:24][C:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH:26]=1>O>[OH:34][C:31]([C@H:28]1[CH2:29][CH2:30][C:25]([CH2:24][N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])=[CH:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(O)[C@@H]1CC=C(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)[C@@H]1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of 2.2 g (16 mmol) K2CO3, 1.2 g (8.4 mmol) phthalimide, and 40 ml DMF was stirred at room temperature for 0.5 hours. Thereafter, 1.7 g (7.4 mmol) (S)-2-(4-bromomethyl-cyclohex-3-enyl)-propan-2-ol (Bull, et. al. Aust. J. Chem., 46 1869, 1993) was added and the resulting mixture was stirred at room temperature for 72 h. Water was added and the mixture was then extracted with ethyl acetate. The ethyl acetate extracts were combined; washed with water and brine; dried (MgSO4); and filtered and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate/hexanes yielded 0.62 g (28%) of the desired product.