Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:11]([C:13]2[S:21][C:16]3=[N:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]=2[CH2:22][CH2:23][CH3:24])=[O:12])[CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl>>[ClH:2].[Cl:9][C:7]1[CH:6]=[C:5]([N:10]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:11]([C:13]2[S:21][C:16]3=[N:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]=2[CH2:22][CH2:23][CH3:24])=[O:12])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: CCCC1=C(C(=O)N(CCC(=O)OCC)c2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Agent: Cl
Product: CCCC1=C(C(=O)N(CCC(=O)O)c2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Temperature: 90 °C
Reaction time: 1 h
Yield: 161.9 %

Procedure:
To 54.8 mg of N-(3,5-dichlorophenyl)-N-(2-ethoxycarbonylethyl)-3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]-pyrimidine-2-carboxamide hydrochloride obtained in Example 57 was added 5 ml of concentrated hydrochloric acid, followed by stirring at 90° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. The residue was suspended in isopropanol and to the suspension was added diethylether. The formed powder was collected by filtration. This powder was recrystallized from a mixed solvent of methanol and diethylether to obtain 41.9 mg of the titled compound.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1([CH:18]2SCCCS2)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[OH2:24].B(F)(F)F>O1CCCC1.CCOCC>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1([CH:18]=[O:24])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: O
Reactant: CN1CCC(OCc2ccccc2F)(C2SCCCS2)CC1
Agent: Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC(C=O)(OCc2ccccc2F)CC1
Yield: 36.9 %

Procedure:
The compound 4-(2-fluorophenylmethoxy)-1-methyl-4-(1,3-dithian-2-yl)piperidine hydrochloride (5 g, 13.1 mmole) was suspended in tetrahydrofuran (50 ml), and water (5 ml) was added to completely dissolve the compound. Red mercuric oxide (8.6 g, 39.7 mmole) was added to the solution. After a complex was formed, BF3 etherate (32.3 ml, 39.7 mmole) was added dropwise to the stirred suspension under nitrogen and reaction was taken to completion as indicated by TLC. The reaction mixture was diluted with an equal volume of ether and filtered. The filtrate was treated with saturated potassium carbonate to form a precipitate. The mixture was extracted with ethyl acetate, and the ethyl acetate extracts were washed with saturated brine. The washed extract was dried over anhydrous potassium carbonate, filtered and taken to dryness. The residue was dissolved in ether from which the hydrochloride was precipitated. The resulting material was recrystallized from ethyl acetate/ethanol. After filtration, washing with ethyl acetate and ether, the product was air-dried to yield 1.3 g (4.5 mmole, 36.9%) of 4-(2-fluorophenylmethoxy)-1-methyl-4-oxomethyl piperidine hydrochloride. MS (MH+ =252), NMR (CDCl3) and IR (CHCl3) were consistent with the structure, mp=164°-167° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]#[C:15][C@:16]2([OH:24])[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:25]2[CH2:29][C@@H:28]([O:30][CH3:31])[C@H:27]([OH:32])[CH2:26]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[CH2:1]([C:8]1[C:13](/[CH:14]=[CH:15]/[C@:16]2([OH:24])[CH:21]3[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]3)[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:25]2[CH2:29][C@@H:28]([O:30][CH3:31])[C@H:27]([OH:32])[CH2:26]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CO[C@@H]1CN(c2ccc(/C=C/[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Yield: 60.8 %

Procedure:
270 mg of (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol (Example 10) was dissolved in 10 ml of ethyl ether. 300 mg of lithium aluminum hydride was added thereto, followed by heating under reflux for 6 hours. While stirring in an ice-bath, 0.3 ml of water, 0.3 ml of an aqueous 5N sodium hydroxide solution, 1 ml of water and 10 ml of tetrahydrofuran were added thereto. The mixture was filtered, and the filtrate was concentrated. The residue was then subjected to NH-silica gel column chromatography and eluted with 10% methanol/ethyl acetate, to give 165 mg of the target compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)Cl.ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:16]1[CH:7]2[CH:8]([C:9](=[O:13])[NH:10][C:11]3[CH:12]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=32)[CH2:14][CH2:15]1
Reactant: O=C1Nc2cc(CO)ccc2C2CCCC12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)NC(=O)C1CCCC21
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A solution of 187 mg (0.86 mmol) of 7-hydroxymethyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 20 ml of chloroform-dichloromethane-acetonitrile (2:1:1) is mixed with 151 mg (1.29 mmol) of N-methylmorpholin-N-oxide and 1.5 g of molecular sieve 4 Å. After 15 mg (0.043 mmol) of tetrapropylammonium perruthenate (TPAP) is added, the batch is stirred for 2.5 hours at room temperature, before another 10 mg (0.028 mmol) of TPAP is added. After 1.5 hours, silica gel is added to the reaction mixture, and the solvent is distilled off in a vacuum. Column chromatography with hexane-ethyl acetate yields 156 mg of product.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15]>>[OH:16][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C#CCCCCO
Reactant: O=Cc1ccccc1Br
Product: O=Cc1ccccc1C#CCCCCO
Yield: 59.4 %

Procedure:
Using the procedure of example 5 and starting with 11.1 g (60 mmol) of 2-bromobenzaldehyde and 7.62 g (77 mol) of 5-hexyn-1-ol, 2-(6-hydroxy-1-hexynyl)benzaldehyde was obtained in 59.4% yield, as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:4][N:3]=1.O[Li].O>C1COCC1.CO.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3cnn(C)c3)cnc2N)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(-c2cc(-c3cnn(C)c3)cnc2N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of methyl 4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-methylbenzoate (1.20 g, 3.72 mmol) in THF/MeOH/H2O (1:1:1, 36 mL) was added LiOH—H2O (0.234 g, 5.58 mmol). The solution was stirred at room temperature overnight. The pH was adjusted to 3-5, optimally 4. All the organic solvents were removed by reduced pressure. EtOAc was added to triturate out all the impurities. Water was added and the mixture was stirred for 30 min. Solid was filtered and washed well with 50% of ether and water. The solid was then azotropied on rotovap with toluene to provide about 800 mg of desired acid in 69.7% yield. LCMS (m/z): 309.2 (MH+), 0.50 min.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 100 °C

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (1410 mg (3.77 mmol), diethyl malonate (2.00 mL (13.2 mmol), palladium (II) acetate (42.3 mg, 0.188 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (148 mg, 0.377 mmol) and potassium phosphate (2.80 g, 13.2 mmol) in 6.0 ml of 1,4-Dioxane was degassed and heated for 24 hours at 100° C. The mixture was concentrated in vacuum and the residue purified on 24 g silica column eluting with 1% of MeOH in EtOAc to give diethyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)malonate. Yield 974 mg. M/z 454.3, calc. 453.20
Reaction SMILES: FC(F)(F)C1CC(N)(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.[F:25][C:26]([F:50])([F:49])[C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].S.[Na]>>[F:25][C:26]([F:49])([F:50])[C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=1[C:45]([F:46])([F:47])[F:48]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Agent: NC1(C(=O)O)C=CC(c2ccccc2C(F)(F)F)=C(C(F)(F)F)C1
Agent: S
Agent: [Na]
Product: Nc1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1

Procedure:
This example illustrates the preparation of poly-2,2'(bis-trifluoromethyl)-4,4'-biphenylene carboxamide, i.e., a polymer having the following recurring structural units: ##STR51## The polymer was prepared by polymerization (as described hereinafter) of the monomer 2,2'-bis(trifluoromethyl)-4-amino-4-biphenylcarboxylic acid having the structure ##STR52## This monomer was prepared from 2,2'-bis(trifluoromethyl)-4,4'-dinitro-biphenyl by partial reduction using sodium hydrogen sulfide to provide 2,2'-bis(trifluoromethyl)-4-nitro-4'-amino-biphenyl; diazotization of the resulting compound followed by reaction with sodium triiodide to provide 2,2'-bis(trisfluoromethyl)-4-nitro-4'-iodo-biphenyl; a Rosenmund-von Braun reaction using cuprous cyanide in N-methyl-2-pyrrolidone to provide 2,2'-bis(trifluoromethyl)-4-nitro-4'-cyano-biphenyl; hydrolysis using 63% sulfuric acid to provide 2,2'-bis(trifluoromethyl)-4-nitro-4'-biphenyl carboxylic acid; and catalytic reduction using palladium on carbon to provide the aforesaid monomer 2,2'-bis(trifluoromethyl)-4-amino-4'-biphenyl carboxylic acid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19]>>[ClH:19].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(OCCN2CCCC2)cc1
Yield: 96 %

Procedure:
Methyl 4-[2-(1-pyrrolidinyl)ethoxy]benzoate (5.3 g, 21.2 mol) in 1 N aqueous HCl (50 mL) was heated at reflux for 18 h. The reaction mixture was washed with ethyl acetate (2×20 mL). The aqueous solvent was removed under reduced pressure to give the desired acid as a white solid (5.55 g, 96%) after drying under vacuum at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:10]=1.N#N.Br[C:43]1[C:44]([NH2:49])=[N:45][N:46]([CH3:48])[CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCO.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:49][C:44]1[C:43]([C:22]2[CH:21]=[CH:20][C:19]3[N:15]([C:13]4[CH:12]=[C:11]([NH:33][S:34]([CH:37]5[CH2:39][CH2:38]5)(=[O:35])=[O:36])[CH:10]=[C:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[CH:14]=4)[CH:16]=[N:17][C:18]=3[CH:23]=2)=[CH:47][N:46]([CH3:48])[N:45]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: CC1(C)OB(c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)c(N)n1
Temperature: 90 °C
Yield: 27 %

Procedure:
A solution of N-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (100 mg, 0.181 mmol) in THF/EtOH/Water (5:5:2) was degassed by N2 bubbling for 5 min. 4-Bromo-1-methyl-1H-pyrazol-3-amine (35 mg, 0.19 mmol, 1.1 eq.) was added and the mixture was degassed for another 5 min. Bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.009 mmol, 0.05 eq.) and cesium carbonate (170 mg, 0.54 mmol, 3.0 eq.) were added sequentially and the mixture was further degassed for 5 min and heated at 90° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the crude residue which was purified by preparative HPLC to give the product in 27% yield (25 mg). 1H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 8.79 (s, 1H), 7.95-7.92 (m, 2H), 7.77-7.07 (m, 2H), 7.59 (s, 2H), 7.53-7.47 (m, 3H), 7.29 (m, 1H), 3.75 (s, 3H), 2.91 (m, 1H), 1.5-1.49 (d, 2H), 1.30-1.26 (t, 2H), 1.03-1.01 (t, 2H); LC-MS (ESI): Calculated mass: 520.5; Observed mass: 521.0 [M+H]+ (rt: 0.676 min).
Reaction SMILES: [C:1]1([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([NH:30][C:31]5[NH:32][CH2:33][CH2:34][CH2:35][N:36]=5)=[O:29])[CH2:24][CH2:23]4)[C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([NH:30][C:31]5[NH:32][CH2:33][CH2:34][CH2:35][N:36]=5)=[O:29])[CH2:24][CH2:23]4)[C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)NC4=NCCCN4)CC3)cccc21
Agent: Cl
Product: O=C(O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)NC4=NCCCN4)CC3)cccc21

Procedure:
A solution of methyl 3-phenyl-3-(4-{4-[(1,4,5,6-tetrahydro-2-pyrimidinylamino)carbonyl]-1-piperidinyl}-1H-benzimidazol-1-yl)propanoate (17 mg, 24 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 48 hours. The solution was evaporated in vacuo, and the residue purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.5 min, MH+ 475].
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].Br[C:26]1[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[N:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[F:24][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:26]2[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6]
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[C@@H](COC(F)F)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(C(=O)Nc2ccn(C)n2)c1

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazol-3-yl)benzamide (100 mg, 0.29 mmol), 5-bromo-2-methylsulfonyl-pyridine (CAS no. 98626-95-0) (77 mg, 0.32 mmol), cesium carbonate (191 mg, 0.59 mmol) and bromotris(triphenylphosphine)copper(I) (55 mg, 0.06 mmol) in DMA (5 mL) was stirred in a microwave reactor at 160° C. for 6 hours. Ethyl acetate (50 mL) was added and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The residue was chromatographed on silica, eluting with 10-80% ethyl acetate in isohexane to give the desired compound (31 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[C:12]([F:27])=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Cl.O1CCOCC1>>[F:27][C:12]1[C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=3[O:10][CH:9]=2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][NH:16]2
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc(-c1coc3ccnc(N)c13)c2F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccc2occ(-c3ccc4c(c3F)CCN4)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (205 mg, 0.555 mmol) and HCl, 4.0 M in dioxane (2775 μl, 11.10 mmol) was stirred at room temperature under Nitrogen for 16 hr. The reaction mixture was then concentrated in vacuo to give 3-(4-fluoro-2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (226 mg, 0.555 mmol, 100% yield) as an off-white solid. LC/MS (ES) m/z=270 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.ClC(N(C)C)=C(C)C.[NH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].N1C=CC=CC=1>C(Cl)Cl.O>[C:30]([C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[NH:27][C:16]([C:13]1[CH:12]=[CH:11][C:10]2[CH:9]=[C:8]3[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]3[C:15]=2[CH:14]=1)=[O:18])(=[O:31])[NH2:32]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CC(C)=C(Cl)N(C)C
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccccc1NC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 5 h
Yield: 26.9 %

Procedure:
To a suspension of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 100 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) is added 1-chloro-N,N,2-trimethylpropenylamine (0.20 mL, 1.43 mmol). The reaction mixture is stirred for 5 h. 2-Aminobenzamide (200 mg, 1.47 mmol) and pyridine (0.12 mL, 1.48 mmol) are added and the reaction mixture is stirred for another 16 h at room temperature. Water (55 mL) is added and the resulting white solid is collected by filtration and purified by flash column chromatography using methanol in CH2Cl2 to afford the title compound (40 mg, 27%). LCMS (ESMS): m/z 363.61 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[CH2:25](I)[CH:26]([CH3:28])[CH3:27].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:11]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2cccc(O)c2)c(F)c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2cccc(OCC(C)C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Ethyl 3-{3,5-difluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (200 mg, 0.59 mmol) was dissolved in DMF (10 mL), isobutyl iodide (339 μL, 3.0 mmol) and sodium hydride (47 mg, 1.2 mmol) were added thereto, and then the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (186 mg, yield 80%) as an oily matter.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([CH3:12])([CH3:11])[CH2:4][CH2:3]1.[C:14](Cl)(=[O:16])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.Cl>C1C=CC=CC=1.O>[C:14]([C:8]1[S:7][C:6]2[C:5]([CH3:12])([CH3:11])[CH2:4][CH2:3][C:2]([CH3:13])([CH3:1])[C:10]=2[CH:9]=1)(=[O:16])[CH3:15]
Reactant: CC1(C)CCC(C)(C)c2sccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)c1cc2c(s1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
18.2 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene and 7.4 g of acetyl chloride are dissolved in 200 ml of benzene and the solution is cooled to 0° C. At this temperature there are slowly added dropwise thereto 24.4 g of tin tetrachloride. After stirring at room temperature for 2.5 hours, the mixture is again cooled to 0° C. and a mixture of 9.3 ml of concentrated hydrochloric acid and 36.4 ml of water is added dropwise thereto. The mixture is extracted with ether, the organic phase is washed once with water, dried, evaporated and distilled in a high vacuum. There are obtained 21.7 g of 2-acetyl-4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene as a colorless liquid, b.p. 108°-115° C./0.05 mm, which can be crystallized from hexane, m.p. 53°-55° C.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:4].C([O-])(=O)C.[Na+].[BH4-].[Na+].[C:35](O)(=O)[CH2:36][CH3:37]>>[CH2:3]([N:5]([CH2:35][CH2:36][CH3:37])[CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:4]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Reactant: CCC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Product: CCCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Yield: 38.6 %

Procedure:
Prepared by the method described in Example 73 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrochloride (6.7 g, 0.016 moles), sodium acetate (2.6 g, 0.032 moles), sodium borohydride (3.3 g, 0.087 moles), and propionic acid (29.8 g, 0.40 moles) instead of acetic acid. Several recrystallizations from diisopropyl ether yielded the product as the free base (2.4 g), mp 93°-96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][C:7]=1[Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)OC(C)(C)C)c1ccc(N)c(Br)c1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 2-(4-aminophenyl)propanoate (5.00 g, 22.6 mmol) in DMF (15 mL) was added a solution of N-bromosuccinimide (4.22 g, 23.7 mmol) in DMF (15 ML) at room temperature which was maintained by water bath. The mixture was stirred overnight, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, then brine, dried over sodium sulfate, and filtered. After concentration, the residue was purified by flash chromatography (9:1 hexanes/ethyl acetate) to give tert-butyl 2-(4-amino-3-bromophenyl)propanoate (6.00 g, 85%) as a brown oil: 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J=1.6 Hz, 1H), 7.04 (dd, J=8.1, 1.7 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 4.01 (br s, 2H), 3.46 (q, J=7.1 Hz, 1H), 1.39 (m, 12H).