Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH:39]1([OH:43])[CH2:42][CH2:41][CH2:40]1>C(N(CC)CC)C>[CH:39]1([O:43][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:22])[CH2:42][CH2:41][CH2:40]1
Reactant: OC1CCC1
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Solvent: CCN(CC)CC
Product: O=C(OC1CCC1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 18 %

Procedure:
(R)-1-(4-Fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride (0.12 g), triethylamine (0.11 g) and cyclobutanol (0.24 g) were heated in a microwave apparatus at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with ethyl acetate in dichloromethane (1:4 to 2:3 by volume) followed by preparative reverse-phase HPLC eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 4:1 by volume) to give the title compound as a white solid (0.023 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.78 (dd, 1H), 7.47-7.35 (m, 3H), 7.19-7.11 (m, 2H), 6.62 (d, 1H), 6.40 (d, 1H), 4.95 (t, 1H), 4.38 (dd, 1H), 3.81 (t, 5H), 3.66 (t, 4H), 3.29 (d, 1H), 2.99-2.90 (m, 1H), 2.57 (d, 1H), 2.48-2.28 (m, 5H), 2.16-2.05 (m, 2H), 1.87-1.77 (m, 1H),1.66-1.52 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenylamine hydrochloride (76 mg, 0.209 mmol), triethylamine (29 uL, 0.209 mmol) and methanesulfonyl chloride (19.3 uL, 0.249 mmol) in dry pyridine (3 mL) was stirred at ice bath temperature for 1 hr and then at RT for 2 hrs. The reaction mixture was evaporated, re-evaporated from toluene, dissolved in EtOAc, washed with H2O, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography with a 0-25% gradient of ethyl acetate in hexanes and lyophilized to yield 48 mg of N-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide as a white amorphous powder. LC-MS (ES) calculated for C20H16F3NO3S, 407.41; found m/z 406 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:38]1[CH:43]=CC=[CH:40][CH:39]=1)C>>[CH2:33]([N:3]([C:1]1[CH:40]=[CH:39][CH:38]=[CH:43][CH:2]=1)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:34]
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCNc1ccccc1
Product: CCN(C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 44 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (500 mg) obtained in Example 6 (4) and N-ethylaniline (141 mg). This was purified by silica gel column chromatography to give the title compound (242 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[CH2:28]([NH:35][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CNCc2ccccc2)CC1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (52 mg, 0.143 mmol) was dissolved in THF (2 mL) and benzylamine (0.025 mL, 0.285 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (18 mg, 0.285 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 23 mg, 0.050 mmol, 40%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37-7.23, 7.14, 7.12-7.02, 6.89, 6.59, 5.46, 4.62, 4.09, 3.76, 2.75, 2.44, 1.98-0.49
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2=[N:4][C:5]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1nc(C(F)(F)F)ccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2ccc(C(F)(F)F)nc2n1C
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of N2-methyl-6-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-ethylsulfanylbenzoic acid (1.01 g), WSC (1.06 g), and pyridine (5 ml) was stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, a mixture of tripotassium phosphate (2.65 g) and 1-propanol (10 ml) was added, and stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.98 g of 2-(2-ethylsulfanylphenyl)-3-methyl-5-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 151).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[OH:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[C:6]([C:27]4[CH:26]=[CH:25][C:24]([OH:23])=[N:29][CH:28]=4)[CH:7]=[CH:2][CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(O)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (124 mg, 0.557 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-ol. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.0 (d, 1H), 7.8 (d, 1H), 7.68 (m, 2H), 7.6 (s, 1H), 7.4 (dd, 1H), 7.36 (s, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.62 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.56 (m, 1H), 3.18 (m, 4H), 3.02 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC(C)C)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.94 (s, 1H) 8.61 (d, J=5 Hz, 1H) 7.78 (d, J=8.8, 1H) 7.61 (d, J=8 Hz, 1H) 7.50 (dd, J=11 Hz, 2 Hz, 2H) 7.27 (d, J=2.4 Hz, 1H) 7.07 (s, 1H) 6.96 (d, J=4 Hz, 1H) 6.75 (d, J=8.8 Hz, 2H) 4.47 (m, 1H) 2.63 (s, 3H) 1.27 (s, 6H). MS (ES) m/z=445.0 (M++1).
Reaction SMILES: [N+:1]([C:4]1[C:47]([F:48])=[C:46]([F:49])[C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[C:6]([F:50])[C:5]=1[OH:51])([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:47]([F:48])=[C:46]([F:49])[C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[C:6]([F:50])[C:5]=1[OH:51]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4c(F)c(O)c([N+](=O)[O-])c(F)c4F)c(F)c3F)c(F)c2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1c(O)c(F)c(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)c(F)c1F
Reaction time: 72 h
Yield: 93 %

Procedure:
50 g of 4-(4-nitro-3-hydroxy-2,5,6-trifluoro-phenoxy)-4'-(4-benzyloxycarbonylphenoxy)octafluoro-biphenyl prepared as described in Example 5 (0.069 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:11])[CH3:8]>O.CO>[CH2:7]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:2])=[O:11])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CSCCNC(=O)OCC
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CS(=O)CCNC(=O)OCC
Yield: 78.8 %

Procedure:
There was dissolved 149.7 g (0.7 mol) of sodium metaperiodate in 1400 ml of water, and thereto was added dropwise a solution of 164.5 g (0.7 mol) of ethyl 2-[2-(ethoxycarbonylamino)ethylthio]acetate in 125 ml of methanol under cooling with ice. After dropping the mixture was stirred for, hours under cooling with ice. The precipitate was removed by filtration and washed with water and with chloroform, successively. The filtrate was extracted with chloroform and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give 138.6 g of white solid. The solid was recrystallized from ethanol-n-hexane (1:4) to give 113.5 g of the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]#[CH:9].[C:11]([O:15][C:16]([NH:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([C:35]2[N:36]=[CH:37][NH:38][CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([C:35]2[N:36]=[CH:37][N:38]([CH2:9][C:8]#[CH:7])[CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C#CCBr
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1cnc(C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)(C(=O)OC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
322 mg (0.99 mmol) of cesium carbonate and sowie 20 μl (0.27 mmol, 80% pure in toluene) of propargyl bromide were successively added to a solution of 100 mg (0.25 mmol) of dimethyl 2-(6-tert-butoxycarbonylaminopyridin-3-ylmethyl)-2-(1H-imidazol-4-yl)malonate (example 12d) in 2 ml of DMF. The mixture was stirred at RT for 3 h and then poured into water and extracted with EA. Purification by chromatography on silica afforded 27 mg of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:17])=[C:10]([C:14]([NH2:16])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][F:30].Cl>CN(C=O)C>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH2:28][CH2:29][F:30])=[C:10]([C:14]([NH2:16])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1Cc2cc(O)c(C(N)=O)cc2C1
Reactant: FCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OCCF)c(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(Dipropylamino)-2,3-dihydro-6-hydroxy-1H-indene-5-carboxamide (87, 0.14 g, 0.5 mmol), potassium carbonate (0.2 g, 1.5 mmol), 1-bromo-2-fluoroethane (0.19 g, 1.5 mmol) in DMF (10 mL) was stirred at room temperature for 5 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Chromatographic purification yielded a pale yellow solid which was converted into the HCl salt and crystallized from EtOAc/MeOH to give the title compound 88 as an off-white solid (m.p. 232-233° C.).
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])=[O:13].[OH-].[Na+]>O>[CH:11]1([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[O:13])[CH2:9][CH2:10]1
Reactant: O=C(CCCCl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
The 13.8% toluene solution of 4-chloro-2'-nitrobutyrophenone obtained in Example 6 is treated, with stirring, first with 90 mL water and second with 50% NaOH (48 g, 0.6 mole NaOH). The resultant reaction mixture is allowed to exotherm, then is heated at 85°-90° C. for 2-3 hours, cooled to room temperature and allowed to settle. The phases are separated and the organic phase is washed with water. The aqueous phases are combined and washed with toluene. The organic phases are combined and concentrated in vacuo to give the title product as a toluene solution, 235 g, 23.6% title product by LC analysis (91% yield from furanone). The product solution is used as is in Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1C=C(O[C:21](OC2N=CC=CC=2)=[S:22])N=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]=[C:21]=[S:22])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: COC(=O)c1cc(N=C=S)ccc1OC
Reaction time: 0.5 h

Procedure:
According to the method of Tet. Let., 26, 1661 (1985), combine methyl 2-methoxy-5-aminobenzoate (0.5 g, 2.76 mmol) and di-2-pyridyl thionocarbonate (0.64 g, 2.76 mmol) in dichloromethane (10 mL). After 30 minutes, dilute the reaction mixture with dichloromethane and extract five times with water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give methyl 2-methoxy-5-thioisocyanatobenzoate: Rf=0.51 (silica gel, dichloromethane).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 140 °C
Yield: 47.7 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine (100 mg, 0.24 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (94 mg, 0.37 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol) and Cs2CO3 (159 mg, 0.48 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) to afford 212 as a cream solid (58 mg, 48%). LCMS (Method G): RT 9.83 min, [M+H]+ 507.3. 1H NMR (CDCl3, 400 MHz): δ 8.39-8.36 (m, 1 H); 7.45-7.42 (m, 1 H); 7.32-7.24 (m, 2 H); 4.40 (m, 4 H); 4.01 (s, 2 H); 3.89 (m, 4 H); 3.70 (m, 6 H); 3.18-3.08 (m, 3 H); 2.92 (s, 3H) and 2.36 (m, 4 H)
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:68])/[C:30](=[N:56]\[O:57][C:58]([C:61]([O:63]C(C)(C)C)=[O:62])([CH3:60])[CH3:59])/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)[C:26](=[O:69])[N:17]2[C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])[CH3:9]>C1(OC)C=CC=CC=1>[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:68])/[C:30](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:56]\[O:57][C:58]([C:61]([OH:63])=[O:62])([CH3:60])[CH3:59])[C:26](=[O:69])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Trifluoroacetic acid (18 ml) was added to a solution of the product of Stage (a) (2.4 g) in anisole (18 ml) at 0°. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The pH of the aqueous extracts was adjusted to 6, and the solution washed with ethyl acetate. The aqueous phase was acidified to pH 1.5 under ethyl acetate, saturated with sodium chloride, and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated. The residue was dissolved in warm 50% aqueous formic acid (20 ml) and allowed to stand for 2 hours. The mixture was diluted with water (50 ml). and filtered. The filtrate was concentrated. The residue was taken up in water (50 ml), refiltered, and lyophilized to give the title compound (920 mg), λmax (pH 6 buffer) 236 nm (E1 cm1% 250), λinf 255 nm (E1 cm1% 235), 296 nm (E1 cm1% 103); [α]D20 +20.0° (c 1.0, DMSO).
Reaction SMILES: O[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4]1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+]>C(O)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:4]2)[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: OCn1nc(-c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(-c2nn(CN3CCOCC3)c3ccccc23)cc1

Procedure:
1-Hydroxymethyl-3-phenylindazole (2 g), morpholine (0.84 g) and 5% aqueous sodium hydroxide solution (1 ml) were dissolved in ethanol (30 ml), and the mixture was heated under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting oily residue was treated with ether-hydrochloric acid to obtain 1-morpholinomethyl-3-phenylindazole having a melting point between 166°-167° C (decomposition) after recrystallization from ethanol-ether.