Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.C1COCC1>[CH3:10][C:9]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1]
Reactant: COC(=O)C(N=[N+]=[N-])C(C)(C)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)C(C)(C)c1ccccc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of methyl 2-azido-3-methyl-3-phenylbutanoate (2.6 g, 11.2 mmol) and PPh3 (4.4 g, 16.7 mmol) in H2O (400 uL) and THF (100 mL) was stirred at 25° C. over 2 d then at 50° C. for 12 h. The solution was concentrated and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)) yielding the title compound (1.4 g, quant.): LCMS (ES) m/e 208 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[OH-].[Na+].O.Cl>CO>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([OH:42])=[O:8])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:21]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
30.0 g of the crystals obtained in Example 4 was dissolved in 600 ml of methanol, and after the addition of 65 ml of 10% sodium hydroxide, the mixture was stirred at a room temperature for 20 hours, and 1000 ml of water was added. The reaction mixture was adjusted to pH 4 with concentrated hydrochloric acid, and extracted twice with 800 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure to crystallize the title compound, which was then filtered and washed with hexane to obtain 25.2 g of colorless crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[CH:5]([OH:7])[CH3:6].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>CCOCC>[CH3:1][Si:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6]
Reactant: CC(O)/C=C/[Si](C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)/C=C/[Si](C)(C)C

Procedure:
Referring to Flowchart II, 3-butyn-2-ol (formula 21) is treated in step H with sodium hydride in ether at -20° C. and then with 2.0 n-butyllithium in hexane, followed by chlorotrimethylsilane, to produce (+)-4-trimethylsilyl-3-butyn-2-ol (formula 22), which is then reacted in step I with lithium aluminum hydride in ether at reflux for several hours, basified and distilled, to produce (±)-trans-4-(trimethylsilyl)-3-buten-2-ol (formula 23). The reaction in step J of (23) in ether with a mixture of sodium dichromate hydrate and sulfuric acid at <5° C. or below produces trans-4-(trimethylsilyl)-3-buten-2-one (formula 24), which upon distillation with selected solvents gives trans-4-(trimethylsilyl)-2-acetoxy-1,3-butadiene (formula 25).
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][C:7]=1[CH3:26])([OH:5])[CH3:4].C1C(=O)N([Cl:34])C(=O)C1>CN(C)C=O.CO>[Cl:34][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[C:7]([CH3:26])[CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-methylbenzamide (40 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.57 mL) to give a light yellow solution. NCS (14 mg, 0.10 mmol) was then added at room temperature. The mixture was heated mixture at 60° C.; after 3 hr, another 15 mg of NCS was added, and the reaction completed after 1 hr. The mixture was diluted with MeOH (1 ml) and then purified by preparatory HPLC (basic mode, 20-70% ACN in water). Product-containing fractions were combined, concentrated and freeze-dried to obtain the title compound as a tan colored solid (10 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.20 Hz, 3H) 1.48 (s, 3H) 2.58 (s, 3H) 3.58-3.64 (m, 2H) 4.19 (q, J=7.24 Hz, 2H) 4.77 (br. s., 1H) 4.92 (br. s., 1H) 7.55 (d, J=8.34 Hz, 1H) 7.68 (s, 1H) 7.76-7.88 (m, 2H) 8.36 (d, J=0.76 Hz, 1H) 8.59 (d, J=1.01 Hz, 1H) 10.58 (s, 1H); ESI-MS: m/z 388 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:39])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[N:34]([CH3:38])[N:35]=[C:36](I)[C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][CH2:42]OC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:39])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[N:34]([CH3:38])[N:35]=[C:36]([CH:41]=[CH2:42])[C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: Cn1nc(I)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: C=Cc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of {1-[4-(3-iodo-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (27 mg, 0.0417 mmol), tetrakis(triphenylphosphine)palladium(0) (4.8 mg, 0.004 mmol) and vinyltributylin (0.0183 mL, 0.063 mmol) in toluene (2 mL) was stirred at 90° C. under nitrogen. After 3 hours, reaction mixture cooled to RT and was subjected to flash chromatography (SiO2, gradient 20 to 40% EtOAc in cyclohexane) to afford the title compound (23.4 mg) as a yellow gum. LCMS (Method H): RT=4.67 min, [M+H]+=548.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[CH:28]=[CH2:29])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(Cl)Cl.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[C@@H:28]1[O:6][CH2:29]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]([C@H]1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
1.360 g (6.19 mmole) of 3-chloroperoxybenzoic acid of 80% purity) were added at 0° C. to a solution of 960 mg (3.44 mmole) of (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-penten-2-ol (which was synthesized following the procedure disclosed in Japanese Patent Provisional Publication No. Sho 60-36468) in 30 ml of methylene chloride. Five minutes after the addition, the reaction mixture was stirred, and this stirring was continued overnight at room temperature. The reaction mixture was then diluted with ethyl acetate, after which it was washed, in turn, with an aqueous solution of sodium sulfite, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride. After it had been dried, the mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:2 by volume mixture of ethyl actate and hexane as the eluent, to afford 320 mg of stereoisomer A of the title compound (having the lower polarity), melting at 160°-180° C. and 206 mg of the desired stereoisomer B of the title compound (having the higher polarity) as an oil.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[C:1]([OH:11])=[N:2][CH:3]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]ccc2ccncc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)c2cnccc12
Temperature: 85 °C
Yield: 87 %

Procedure:
To a stirred solution of 2H-[2,7]naphthyridin-1-one (300 mg, 2.05 mmol) (Baldwin, J. J.; Mensler, K.; Ponticello, G. S, J. Org. Chem. 1978, 43(25), 4878-80.) in 98% sulfuric acid (2 ml), 60% nitric acid (0.30 ml) was added dropwise and the mixture was warmed to 85° C. during 3 h. Addition, of ice-cold water and basification to pH 7, gave a precipitate which was filtered and washed with ethyl ether to yield the title product as a yellow solid (87%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4].Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[C:3]([C:5]1[CH:20]=[C:19]([CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1)#[N:4]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1F
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from sodium hydride, 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-fluorobenzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[CH:18]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])[CH3:19]
Reactant: CC(C)[Si](OC(=O)N1CCN(c2ccc(Br)cc2)CC1)(C(C)C)C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of triisopropylsilyl 4-(4-bromophenyl)-1-piperazinecarboxylate (4.5 g, 10.2 mmoles) in toluene (17 mL) and tetrahydrofuran (17 mL) was degassed by bubbling nitrogen at room temperature via a fritted gas dispenser for 10 minutes and then cooled to −78° C. for the addition of butyllithium (4.9 mL as a 2.5 M solution in hexanes, 12.3 mmoles). The solution turned yellow and after 30 minutes, triisopropylborate (3 mL, 13.3 mmoles) was added and the solution was warmed to 0° C. over 2.5 h prior to quenching with sat. aq. ammonium chloride (22 mL). To the flask was added 0.825 mL of phosphoric acid (14.8 M, 12.3 mmoles). The solution was stirred for 30 minutes. The phases were separated and the organic phase was dried over sodium sulfate. Right after filtering off the drying agent, the organic phase was washed with wet tetrahydrofuran (approx 2% water). The solution was concentrated to approx 15 mL. While concentrating, three 0.5 mL-portions of water were added to prevent boroxine formation. At this point, hexane was added and the resulting precipitate was filtered to yield 4-(4-{[(triisopropylsilyl)oxy]carbonyl}-1-piperazinyl)phenylboronic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][C:21]=1[CH3:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.P(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:21]([CH3:28])[CH:22]=1
Reactant: Cc1cc(CO)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of [4-[(tert-butyl(diphenyl)silyl)oxymethyl]-3-methyl-phenyl]methanol (0.3 g, 0.76 mmol) in DCM (30 mL) is added phosphorus tribromide (0.072 mL, 0.76 mmol) at 0° C. and the reaction mixture is stirred for 1 hour. The reaction mixture is diluted with dichloromethane (50 mL), washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate, and concentrated under vacuum to give the title compound as a light yellow liquid (0.3 g, crude). ESI/MS m/z 438.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([NH2:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:5][CH:6]([NH:13][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)Cl
Reactant: CCCCCCC(C)N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCC(C)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of acetyl chloride (7.11 mL, 100 mmol) was added dropwise to an ice water-cooled solution of 1-methylheptyl amine (8.30 g, 64 mmol) and triethylamine (20.91 mL, 150 mmol) in TF (100 mL). The resulting mixture was stirred at RT for 1 h, then was diluted with ethyl acetate and washed twice with 10% HCl, twice with sat aq NaHCO3, and then twice with brine. The organic solution was dried (MgSO4), and concentrated to afford 8.13 g N-(1-methylhept-1-yl)acetamide, a 73% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:4][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.4 %

Procedure:
To a solution of 7.18 g (71 mmol) of 4-hydroxypiperidine in 100 ml dimethylformamide are added first 19.6 g (142 mmol) of powdered potassium carbonate and then 19.8 9 (71 mmol) of tritylchloride. The mixture is stirred for 22 hours at ambient temperature, diluted with ethyl acetate to twice the volume, washed with water and saturated saline solution, dried with magnesium sulphate and concentrated by evaporation. The residue is recrystallised from ethyl acetate/petroleum ether (1:4, v:v). 17.65 g (72.4% of theory) of 4-hydroxy-N-tritylpiperidine are obtained as colourless crystals, melting point 157-158° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].CCO>C(CC(C)(C)C)(C)C>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CCCCN
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Solvent: CC(C)CC(C)(C)C
Product: CCCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 130 °C

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), n-butan-1-amine (0.50 ml, 5.1 mmol) and EtOH (1.0 ml) was heated under microwave radiation at 130° C. for 30 min. MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 123 (8), 86 (bp), 77 (9), 72 (10).
Reaction SMILES: [C:1]12[C:9](=[O:10])[O:8][C:6](=[O:7])[C:2]=1[CH2:3][CH2:4][CH2:5]2.Cl.[CH3:12][O:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1.CCN(CC)CC>C1COCC1>[C:6]([C:2]1[CH2:3][CH2:4][CH2:5][C:1]=1[C:9]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([O:13][CH3:12])=[O:20])=[O:10])([OH:8])=[O:7]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1C(=O)C1=C(C(=O)O)CCC1
Temperature: 10 °C

Procedure:
2.76 (20 mmol) of 1-cyclopentene-1,2-dicarboxylic anhydride was dissolved in 50 ml of THF at 25° C. under a nitrogen atmosphere. The solution was cooled to 10° C. and 3.31 g (20 mmol) of L-proline methyl ester HCl was added, followed by 2.78 ml (20 mmol) Et3N, which produced a slight exothermic reaction. The mixture was heated at reflux for 12 hours, cooled and the solvent removed under reduced pressure. The residue was dissolved in methylene chloride and the solution was washed with 1N hydrochloric acid and brine. The organic phase was then dried over magnesium sulfate and evaporated in vacuo to afford the title compound which crystallized from methylene chloride/ether as an off-white solid (4.20 g; 79%). TLC (90:10/CH2Cl2 :MeOH): Rf =0.35. 1 H NMR δ: 8.15-8.42(bs,1H); 4.35-4.60(m,1H); 3.38-3.76(m,5H); 2.48-2.98(m,4H); 1.70-2.32(m,6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=O)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:30].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:30])=[O:27])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 76.7 %

Procedure:
A 10-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate (0.036 g, 0.09 mmol) and ammonium chloride (0.015 g, 0.27 mmol). To this was added methanol (2 mL) followed by NH3 (4 mL, 7N in methanol, 27.6 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 48 hr. After this time, the crude reaction solution concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamide (0.026 g, 79%) as a white solid. MW=376.88. 1H NMR (CDCl3, 500 MHz) δ 7.93-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.39-7.30 (m, 2H), 7.26-7.14 (m, 5H), 5.55-5.25 (m, 2H), 3.97 (s, 2H), 3.56 (s, 2H), 3.08 (t, J=8.0 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.14 (quin, J=7.5 Hz, 2H). MS: APCI+, m/z 377 [M+H]+. Treatment of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamide with 1.25M HCl in methanol afforded the title compound (0.037 g, 99%) as a white solid. MW=413.34. M.p. 178-180° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.11-8.07 (m, 1H), 8.00-7.93 (m, 1H), 7.81 (s, 1H), 7.57-7.47 (m, 2H), 7.43 (br s, 1H), 7.25-7.34 (m, 4H), 6.84 (br s, 1H), 4.60 (br s, 1H), 4.00 (s, 2H), 3.31 (s, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.07 (quin, J=7.5 Hz, 2H); APCI MS m/z 377 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[CH:26][C:25]=3[O:31][CH3:32])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Product: COc1ccc(F)cc1-c1c(F)ccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 71.1 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 5-fluoro-2-methoxy-phenyl boronic acid (191 mg) were reacted to afford the title compound (141 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, 1H), 8.53 (m, 1H), 7.74 (m, 1H), 7.28 (m, 1H), 7.17 (m, 2H), 4.49 (m, 1H), 3.64 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=385 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[C:13]1=[O:16])[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(-c3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Yield: 72 %

Procedure:
A solution of 13.2 g of 6-phenyl-1-indanone, 11 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110ml of 2,2-dimethoxy-propane was boiled under reflux for 48 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 12.0 g (72%) of (RS)-2-(2-buten-1-yl)-6-phenyl-1-indanone was obtained as a light yellow solid which was used without further purification in the next reaction.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8].[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21]O)=[CH:18][CH:17]=1)[CH3:14]>Cl.O.C(=O)([O-])[O-].[K+].[K+]>[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:1][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: CNC(=C[N+](=O)[O-])NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 168 h

Procedure:
N-(2-Mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg) in concentrated hydrochloric acid (2 ml) was added dropwise to 5-(dimethylamino)methyl-2-furanmethanol (428 mg) at 0°. After standing at 0° for 7 days the reaction was diluted with water (3 ml), excess potassium carbonate was added and the solid extracted with ethyl acetate (50 ml).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].[CH3:23]I>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:18][CH2:19][O:20][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1c(Br)cnn1CC1(OCCO)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 180B (2.2 g) in N,N-dimethylformamide (20 mL) was added sodium hydride (0.38 g). After stirring for 30 minutes, methyl iodide (0.60 mL) was added. The reaction mixture was stirred for 2 hours at room temperature, diluted with ether (100 mL) and washed with water (2×75 mL) and brine (75 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 25% ethyl acetate/hexanes provided the title compound.