Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCCC(O)c1ccccc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a mixture of 792 mg of 4-hydroxycoumarin and 809 mg of 1-phenyl- 1 -butanol of Preparation 12 in 25 mL of dioxane under an argon atmosphere is added 2.6 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed under reduced pressure and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether, acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 183 mg of the title product as white crystals.
Reaction SMILES: CN1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=O.ClC(OCC(C)C)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)=[O:16]
Reactant: O=C(O)c1ccccn1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccccn1
Temperature: -15 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
N-Methylmorpholine (3.7 ml) is added to a solution of picolinic acid (2.05 g, 16.65 mmol) in anhydrous dichloromethane (50 mL) and cooled to −15° C. Isobutyl chloroformate (2.2 ml, 16.75 mmol) is added thereto, and the mixture is stirred for 15 hr, after which N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.71 mmol) is added. After 15 min, the cooling bath is removed and stirring is continued at room temperature for 4 hr. The reaction mixture is added to water (50 ml) and extracted with dichloromethane. The organic phases are washed with water and brine and dried over Na2SO4. The residue is chromatographed on silica gel to afford N-methoxy-N-methylpyridine-2-carboxamide as a colorless oil (2.2 g; 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:47])=[O:46].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:46])=[O:47])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12)c1ccc(C(=O)O)cc1
Reactant: CC(=O)OCCCS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)cc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a mixture of 4-[(1S)-1-({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (250 mg) and DMF (5 mL) was added 1,1′-carbonyldiimidazole (187 mgl) at room temperature, followed by stirring for 5 minutes, and then 3-(aminosulfonyl)propylacetate (209 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (173 μL) were added in this order, followed by stirring for 3 days. The reaction mixture was ice-cooled, and 10% aqueous citric acid (30 mL) was added thereto, followed by stirring for 30 minutes. The precipitated solid was collected by filtration and washed with cold ethanol (4 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (210 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[NH:14][C:13]3[CH:19]=[CH:20][C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:12]=3[S:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][N:14]1[C:13]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][C:12]=2[S:11][C@@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C@@H:16]([OH:17])[C:15]1=[O:18]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1F
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F

Procedure:
Following a procedure similar to that described in Example 11(d), 400 mg of (2S, 3S)-2-(3-fluoro-4-methoxyphenyl)-2,3-dihydro-3-hydroxy- 8-phenoxy-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) aboVe] were alkylated with 2-dimethylaminoethyl chloride hydrochloride to afford 500 mg of the title compound as a syrup.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylxanthine (2.882 g) was suspended in N,N-dimethylformamide (40 ml), and potassium carbonate (3 g) and benzyl bromide (2.5 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The deposited crystals were collected by filtration and washed with ethyl acetate to give 3.18 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[Si:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[Br:9][C:4]1[CH:3]=[C:2]([Si:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
Into a solution of 1,3,5-tribromobenzene (9.0 g, 28.6 mmol) in diethyl ether (200 mL) was added n-butyllithium solution in hexane (2.5 M, 12 mL, 30.6 mmol) dropwise at −78° C. The reaction was stirred at this temperature for 30 minutes before a solution of chlorotriphenylsilane (9.27 g, 31.4 mmol) in diethyl ether (90 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature and continue to stir overnight, and finally refluxed for 2 hours. After cooling to room temperature, the solid was filtered off. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3,5-dibromophenyl)triphenylsilane (4.0 g, 28%) as a white solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.[H-].[Na+].[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>C1COCC1>[Cl:20][CH2:21][CH2:22][NH:23][C:24]([NH:17][C@@H:14]1[CH2:15][CH2:16][O:12][CH2:13]1)=[O:25]
Reactant: O=C=NCCCl
Reactant: N[C@@H]1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCCl)N[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
A 0° C. suspension of (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (1.00 g, 3.86 mmol) in THF (40 mL) was treated with NaH (60% in mineral oil, 0.170 g, 4.24 mmol), stirred at 0° C. for 1.5 h, treated with 2-chloroethyl isocyanate (0.362 mL, 4.24 mmol) and stirred at RT overnight as the cooling bath expired. The mixture was treated with satd. NH4Cl and water, extracted with EtOAc (2×) and the combined organics were washed with brine (2×), dried over Na2SO4 and concentrated to dryness. The residue was treated with 1:1 EtOAc/Hex and the resulting solid collected via filtration to afford (R)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (522 mg, 70%). MS (ESI) m/z: 193.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13].[NH2:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13]
Reactant: COc1cc(Cl)nc(N)n1
Reactant: COCCOc1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Product: COCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A mixture consisting of 5.15 g of 2-methoxyethoxy-phenylsulfonyl isocyanate, 3.2 g of 2-amino-4-chloro-6-methoxy-pyrimidine and 70 ml of absolute dioxane is stirred for 3 hours at a temperature of 60°-70° C. The reaction mixture is cooled to a temperature of 20° C., treated with activated carbon, filtrated and evaporated to 1/4 of the original volume. After addition of 50 ml ether to the residue, 5.6 g of N-(2-methoxyethoxy-phenylsulfonyl)-N'-(4-chloro-6-methoxy-pyrimidin-2-yl)urea are obtained in the form of crystals having a melting point of 166°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[NH2:16].CS([C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1)=O.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[NH:16][C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1
Reactant: COc1cc(N2CCN(C)CC2)ncc1N
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)ncc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 85 °C
Yield: 76.9 %

Procedure:
4-Methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a; 1.22 g, 5.49 mmol), tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52; 1.40 g, 3.50 mmol) were treated with tert-butanol (20 mL) and DIEA (1.53 mL, 8.74 mmol) and heated to 85° C. overnight (20 h) in a 250 mL round-bottomed flask with a reflux condenser. The reaction mixture was concentrated on the rotovap and the crude solid was suspended in Et2O and filtered affording the crude tert-butyl (3-(24(4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8b; 1.50 g, 2.69 mmol, 77% yield) as a brownish-yellow amorphous solid. m/z (ESI, +ve ion) 559.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (1H, br. s.), 8.65 (1H, br. s.), 8.54 (1H, s), 7.86 (1H, d, J=9.4 Hz), 7.82 (1H, s), 7.43 (1H, d, J=8.0 Hz), 7.37 (2H, br. s.), 6.81 (1H, br. s.), 6.38 (1H, d, J=9.4 Hz), 6.29 (1H, br. s.), 3.73 (3H, s), 3.45 (4H, br. s.), 2.40 (4H, br. s.), 2.24 (3H, s), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH3:3].[Cl:14][S:15](O)(=[O:17])=[O:16].S(Cl)(Cl)=O>C(Cl)Cl>[Cl:14][S:15]([C:11]1[CH:12]=[CH:13][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:17])=[O:16]
Reactant: CCCOc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A solution of 2-n-propoxybenzoic acid (20 g, 111 mmol) in DCM (40 ml) was added dropwise over 30 min to a mixture of chlorosulphonic acid (30 ml, 440 mmol) and thionyl chloride (8.1 ml, 110 mmol) at −10° C. whilst keeping the temperature below 0° C. The mixture was slowly warmed to 20° C. and stirred for 18 h. The reaction mixture was cautiously poured onto crushed ice (260 g), keeping the temperature below 0° C. The ice slurry was stirred for 20 min and then the precipitated white solid was filtered, washed with H2O (20 ml), dissolved in DCM (200 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a yellow solid (31.2 g, 103 mmol, 92%); mp 121-124° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:21][CH:20]2[O:22][CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)[C:6]#[N:7].Br[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([O:28][C:27](=[O:33])[NH:26][CH2:25][CH2:24][N:18]1[CH2:19][CH:20]2[O:22][CH:16]([CH2:15][N:14]([CH2:13][CH2:12][O:11][C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[F:2])[CH2:21]2)[CH2:17]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A suspension of intermediate 3-fluoro-4-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile hydrochloride (5 g, 0.0137 mol, from step (vii) above), and tert-butyl 2-bromoethylcarbamate (3.98 g, 0.0178 mol , see WO 01/28992) and potassium carbonate (7.57 g, 0.0548 mol) in dry acetonitrile (100 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 5% methanol in dichloromethane as eluent to give the sub-title compound (4.6 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.O.O.[SH2:13].[Na].Cl>CCO.O>[S:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[SH:13])[CH:8]=[CH:9]1
Reactant: S
Reactant: Clc1ccnc2ccsc12
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Sc1ccnc2ccsc12
Temperature: 90 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
7-chlorothieno[3,2-b]pyridine (1.0 g, 5.9 mmol) in EtOH (15 mL) was treated with sodium hydrogen sulfide dihydrate (3.26 g, 35.4 mmol). The solution was heated at 90° C. overnight. An additional amount of sodium hydrogen sulfide dihydrate (3.26 g, 35.4 mmol) was added and the reaction stirred an additional 20 hours at reflux. The solution was cooled to ambient temperature and diluted with water (100 mL) to dissolve the solids. The solution was cooled to 0° C. and concentrated hydrochloric acid solution was added slowly to adjust the pH to 1. The solution was then filtered and the solid was dried under high vacuum to provide thieno[3,2-b]pyridine-7-thiol (0.73 g, 74% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH:10]([CH2:13][OH:14])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:14][CH2:13][CH:10]2[CH2:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[O:11]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc2c1OC(CO)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc([N+](=O)[O-])c3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
To a solution of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol (3.14 g, 16.09 mol) in dichloromethane (100 mL) was added diisopropylethyl amine (4.16 g, 32.18 mmol), N,N-dimethylaminopyridine (0.39 g, 3.2 mmol), and p-toluenesulfonyl chloride (4.6 g, 24.13 mmol) the reaction was allowed to stir at room temperature for 12 h. The reaction was diluted with dichloromethane (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, dichloromethane: hexanes 3:10) afforded 5.2 g (94%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as off-white solid. mp 129-131° C.
Reaction SMILES: [F-:1].[Cs+].[Cl:3][C:4](=[CH2:12])[CH2:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9]>>[Cl:3][C:4](=[CH2:12])[CH2:5][O:6][C:7](=[O:11])[C:8]([F:1])=[O:9]
Reactant: [F-]
Reactant: C=C(Cl)COC(=O)C(=O)Cl
Agent: [Cs+]
Product: C=C(Cl)COC(=O)C(=O)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
Under dry N2 in flame dried glass apparatus, cesium fluoride (167 g, 1.1 mol) was placed in a 1 liter single neck flask and placed under high vacuum and gently heated with a flame until the solid became free flowing, then cooled to room temperature. Acetonitrile, distilled from CaH2 (183 ml) was added and the mixture cooled to -20° C. internal temperature. 2-Chloroallyl oxalochloride (183 g, 1.0 mol) was added dropwise over a 30 minute period and the mixture slowly warmed to room temperature, stirred at that temperature for 16 hours, and byproduct cesium chloride recovered by filtration with acetonitrile wash. The filtrate and wash were combined and stripped, and the residue distilled at reduced temperature to yield 129 g (77%) of the desired product, b.p. 62°-64° C./22 mm.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1[CH2:11][CH2:10][CH2:9][S:8]C1.ICCC>O1CCCC1>[CH2:2]([CH:1]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: C1CSCSC1
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCC1SCCCS1
Reaction time: 2.5 h

Procedure:
n-Butyl lithium (2.5M, 56.32 ml, 141 mmol) was added dropwise to a 500 ml tetrahydrofuran solution of 1,3-dithiane (15.42 g, 128 mmol) at -20°. After stirring for 2.5 hours at -20°, the solution was cooled to -78° and 1-iodopropane (12.5 ml, 128 mmol) was added to it in one portion. The reaction mixture was left for gradual warming (-78° to 0° C.) and overnight stirring (19 hours). Tetrahydrofuran was removed on the rotary evaporator, residue taken in ether (250 ml) and washed with water (200 ml). The aqueous layer was reextracted with ether (250 ml). Combined ethereal extracts were washed sequentially once with water, once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a yellow oil which on distillation under vacuum yielded 19.310 g of the title A compound.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Br[CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]=1[CH3:39].[Cl-].[NH4+]>CCOCC.CCCCCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH:8]([CH:28]=[CH:29][CH:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[C:31]3[CH3:39])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: CC1=C(CCBr)c2ccccc2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2ccccc2C1C=CC1c2cc(C(C)(C)C)ccc2-c2ccc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
To a 100 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel, 2,7-di-t-butylfluorene (1.18 g, 4.22 mmol) and dehydrated ether (30 ml) were introduced. To the flask was dropwise added a hexane solution of n-butyllithium (1.67 mol/l, 2.8 ml, 4.64 mmol) at 0° C. over a period of 1 hour, followed by stirring at room temperature for 7 hours. The reaction liquid became red orange transparent. Then, the liquid was cooled to −78° C. (a yellow orange slurry), to which a solution of 3-(2-bromoethyl)-2-methylindene (1 g, 4.22 mmol) in dehydrated ether (10 ml) was dropwise added over a period of 30 minutes. Then, the temperature of the system was allowed to spontaneously rise to room temperature, followed by stirring for 15 hours. The reaction mixture gradually became a yellow slurry. The resulting yellow slurry was poured into 200 ml of a saturated ammonium chloride aqueous solution to separate an ether phase. The aqueous phase was extracted with ether (100 ml×2), and a combined organic phase was dried over anhydrous magnesium sulfate, Then, the solvent was distilled off, and the resulting white yellow powder was reslurried with hexane (100 ml) and filtrated to obtain 1.70 g (yield: 93%) of an aimed product of a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (165) (7.5 mg, 0.03 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (12 μl, 3 eq) followed by addition of DIEA (26 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (150 μl) at r.t. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (166) (8.3 mg, yield: 75.3%, purity>95%) as off-white solid.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[NH:3][CH:2]=1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[NH:3][CH:2]=[N:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1cnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3cnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (3H-imidazol-4-yl)-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.52 min, [M+1]+ 449. Potency class A.