Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[C:33]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:32]=2[O:31][CH2:30][CH2:29]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:38][C:35]4[CH:36]=[CH:37][C:32]5[O:31][CH2:30][CH2:29][N:28]([CH3:27])[C:33]=5[CH:34]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOc2ccc(N)cc21
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Product: CN1CCOc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc21
Yield: 33 %

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzene sulfonamide and 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine to give N-tert-butyl-3-[2-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a light tan foam (45.5 mg, 33% yield). LCMS (E/I+) 493 (M+H). 1H NMR (CDCl3; 400 MHz) δ 8.71 (s, 1H), 8.59 (s, 1H), 8.43 (d, 1H, J=8.0 Hz), 7.83 (d, 1H, J=8 Hz), 7.54 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=4.8 Hz), 6.88 (m, 2H), 6.82 (m, 2H), 6.66 (s, 1H), 4.64 (s, 1H), 4.3 (t, 2H, J=4.4 Hz), 3.29 (t, 2H, J=4.4 Hz), 2.76 (s, 3H), 1.21 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=2)=[N:17][N:16]=[N:15]1.C([O-])(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:26][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Yield: 37.5 %

Procedure:
To 50 mL of tetrahydrofuran were added 2,4-dichloroquinazoline (0.30 g). N-[[-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl amine hydrochloride (0.434 g) and 2.0 g of sodium acetate. The resulting suspension was stirred at room temperature for 53 hours at which time all the THF was removed by evaporation. The residue was purified by silica gel chromatography to yield 0.234 g of the desired product. (38%). The product was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ 9.30 (t, J=5.9 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.79 (m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (m, 2H), 7.32 (m, 3H), 7.18 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 4.72 (d, J=5.8 Hz, 2H); negative FAB MS m/e 412 (M-Na)
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C.Cl[Si](C)(C)C>CN(C=O)C.CO>[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-])OC
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a solution of 2,3-dinitrotoluene (3.02 g, 16.6 mmol) in 25 mL of DMF was added dimethylformamide dimethylacetal (6.0 mL, 5.4 g, 45 mmol), and the solution was brought to 140° C. and stirred for 16 hours. The solvent was removed under reduced pressure to afford a dark red solid mass. This crude enamine was dissolved in 40 mL of MeOH and 4.0 mL of chlorotrimethylsilane (3.4 g, 31.7 mmol) was added. The solution was brought to reflux and stirred for 16 hours at reflux. The solvent was removed under reduced pressure and the crude material chromatographed directly to afford the 1-(2,2-dimethoxy-ethyl)-2,3-dinitro-benzene (1.85 g, 44%). 1H NMR (CDCl3) δ 2.96 (2H, d, J=5.2 Hz), 3.35 (6H, s), 4.49 (1H, t, J=5.2 Hz), 7.60 (apparent t, 1H, J=8.0 Hz), 7.76 (d, 1H, J=6.5 Hz), 8.05 (dd, 1H, J=1.3, 8.0).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:29]([OH:31])=[O:30])[CH2:10]1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34]([CH2:33][O:30][C:29]([C@H:18]1[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([C:22](=[O:28])[CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C@H:11]([CH2:10][C@H:9]([OH:8])[CH2:26][CH2:25]1)[CH2:12][CH2:13]3)=[O:31])=[O:35])[CH3:38]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mmole) was added to a solution of 3α-hydroxy-5α-androstan-11-one 17β-carboxylic acid (1.025g.,) in warm acetone (50 ml.) followed by ethyl bromoacetate (6 mmole) and the reaction mixture stood at room temperature overnight. The reaction was completed by refluxing for 1 hr., evaporating to dryness and partitioning the residue between water and ether. The ethereal solution was washed with water, dried, and evaporated to give a residue (1.61g.) which was purified by preparative t.l.c. to afford the pure title compound; [α]D + 76°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][CH:30]=O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:30]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: COc1cccc(CC=O)c1
Product: COc1cccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Methoxy-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 394.0; HRMS: calcd for C23H16F3NO2+H+, 396.12059; found (ESI, [M+H]+), 396.1196.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:7]1([C:5]2[N:6]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nc(-c2ccccc2)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-phenyl-1,3-thiazole (1.16 g, 5.92 mmol), 1-(tert-butoxycarbonyl)-piperazine (3.30 g, 17.8 mmol), potassium carbonate (817 mg, 5.92 mmol) and N,N-dimethylformamide (20 ml) was stirred at 120° C. for 2 hours, poured to water, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 1.43 g (70.1%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Fc1ccc(-c2cc(CCl)ccn2)cc1F
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccc(F)c(F)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,4-difluorophenyl)pyridine (240 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:24])([F:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15](OC)=[O:16])[CH:9]=[CH:10][CH:11]=1>CO>[F:4][C:5]([F:24])([F:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:2][NH2:3])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 52 %

Procedure:
Hydrazine hydrate (14 ml) is added dropwise to a solution of methyl 2-[(3-trifluoromethylphenyl)amino]-benzoate (1.463 g, 4.95 mmol) in 70 ml of methanol. The reaction solution is heated at 60° C. under an inert atmosphere for two hours and then concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (1:1), providing 763.0 mg (52%) of a white solid, mp 134°-135° C.
Reaction SMILES: [NH:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCOCC.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+]>[CH2:14]([O:21][C:22]([N:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 94 ml of 2-N NaOH was dissolved 25 g of L-thioproline, and 20 ml of ether was added to the solution under agitation and ice-cooling. To this solution under agitation were added dropwise 38 ml of benzyloxycarbonyl chloride and 70 ml of 4-N NaOH at the same time in 30 minutes. The mixture was stirred for 2 hours at room temperature, washed with 100 ml of ether and treated with 6-N HCl to adjust pH to 2. The mixture was extracted with 200 ml and 100 ml of ethyl acetate and the ethyl acetate phase was washed 50 ml of water, dried over MgSO4 and filtered. The filtrate was concentrated until dryness under reduced pressure whereby an oily substance was obtained.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:19]1[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=[CH:17][C:18]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 202.1 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (86.9 g, 0.298 mol) was added in about 5 g portions to a solution of p-nitrocumene (X) (100 g, 0.581 mol, GC purity 96%) and sulphuric acid (178 g, 1.743 mol, 98% strength) over a period of 5 hours. The mixture was then warmed to room temperature and stirred for another 1 hour. The reaction mixture was poured onto 200 g of ice water and admixed with sodium bisulphite (15.1 g, 0.06 mol) and toluene (300 g). The phases were then separated. The organic phase was washed with 5% strength aqueous sodium hydroxide and the toluene was distilled off under reduced pressure. 2-Bromo-1-isopropyl-4-nitrobenzene (147 g, 93.6 GC-% by area, 97% of theory) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[F-].[Cs+]>C(#N)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 81.7 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (3.70 g, 24.3 mmol), 1-chloro-4-nitrobenzene (3.84 g, 24.3 mmol) and cesium fluoride (7.40 g, 48.7 mmol) in 150 mL of 2:1 acetonitrile-water was degassed under vacuum for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (844.0 mg, 0.73 mmol) was added and the reaction refluxed for 3 h. The solvent was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic phase was separated, dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue on silica gel using 5% ethyl acetate hexanes as the eluent gave 4′-methoxy-4-nitro-biphenyl (4.55 g, 81%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][C@@H:32]([OH:33])[C@H:28]([NH:27][C:25]([C:21]2[C:17]3=[N:18][CH:19]=[CH:20][C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:16]3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1nc(-c2ccccc2)cs1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-4-phenylthiazole (12.5 g, 80.9 mmol), 1-fluoro-2-nitrobenzene (12.5 g, 89.0 mmol), potassium carbonate (13.4 g, 97.1 mmol) was stirred at 150° C. for 24 h. Water (100 ml) was added and the mixture was extracted twice with 1,2-dichloroethane (50 ml). The crude extract was purified by chromatography on silica gel using toluene as eluent. The product was isolated as the free base. Yield 7.95 g, 33%. M.p. 114-116° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[NH:7][CH:6]([CH3:23])[CH2:5]1.C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[N:7]([CH3:26])[CH:6]([CH3:23])[CH2:5]1
Reactant: [BH3-]C#N
Reactant: CCCCSCCCc1cc(O)c2c(c1)NC(C)CC2CCO
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO

Procedure:
To a stirred solution of dl-4-(2-hydroxyethyl)-5-hydroxy-2-methyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline (337 mg, 1.0 mmole) in 5 ml acetonitrile cooled to 15° C. is added 0.5 ml aqueous formaldehyde and 100 mg sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH unit the reaction is complete. The reaction mixture is partitioned between water and ethyl ether, the organic phase dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.Br[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Reactant: CC(Br)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(N)=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 85 %

Procedure:
The title compound was prepared in analogy to Example 10 from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and (RS)-2-bromo-propionamide with potassium carbonate as the base. Yield: 85% of theory as a white solid; MS: m/e=343 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)(Cl)Cl>[CH2:37]([O:36][C:34]([NH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]=2[CH2:6][CH2:5]1)=[O:35])[CH3:38]
Reactant: NCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a cooled solution of 3-(2-aminoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 21b (5.5 g, 0.016 mole) and triethylamine (1.8 g, 0.018 mole) in chloroform (75 ml) was slowly dropped a solution of ethyl chloroformate (2.0 g, 0.018 mole) in chloroform (25 ml). After stirring twenty hours at ambient temperature the reaction mixture was concentrated to a semisolid which was dissolved in ether, washed with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to yield an oil. A sample of the resultant oil was distilled to yield an oil of 3-(2-ethoxycarbonylaminoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, bp 235°-238° C./0.10 mm.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2.O>CC#N>[Br:8][C:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[C:10]=1[CH3:9]
Reactant: Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Cc1c(Br)c2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.1 %

Procedure:
72 mg of NBS in 2 ml of CH3CN are added to a solution of 100 mg of 2-methyl-1-(benzenesulfonyl)-7-azaindole in 3 ml of CH3CN. The mixture is stirred at room temperature for 20 h, poured into water, the precipitate which has precipitated out is separated off and dried, giving 93 mg of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole, M˜351.22 g/mol, M+H found 351.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH:3]=1)=[O:14]
Reactant: C1=COCCC1
Reactant: CC(C)(C)C(=O)Nc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-amino-phenol (60 g, 6.55 mol) in 2 N NaOH (1 l), cooled to 10° C., pivaloyl chloride (68 ml, 0.55 mol) in toluene (200 ml) is added within 1 h. After stirring for 15 h at 25° C., the mixture is cooled to 0° C. and acidified to pH 1 with conc. HCl. Extraction with EtOAc washing with water, 10% NaHCO3, water, and brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (EtOAc/hexanes) gives N-(3-hydroxy-phenyl)-2,2-dimethyl-propionamide. N-(3-Hydroxy-phenyl)-2,2-dimethyl-propionamide (49 g, 0.254 mol) in dichloromethane (1 l) is treated with dihydropyrane (66 ml, 0.762 mol) and pyridinium p-toluenesulfonate (957 mg, 3.8 mmol). After stirring for 6 days at 25° C., the solvent is removed and the residue crystallized from EtOAc/hexanes to give 2,2-dimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-phenyl]-propionamide.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36].O1CCOCC1>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.O>[C:35]([C:37]1[CH:42]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[C:18]([C:28]([NH:29][CH3:30])=[O:31])[C:17]=3[CH:32]=2)[CH:40]=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
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: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Temperature: 90 °C

Procedure:
Cesium carbonate (187 mg, 0.575 mmol) was added to Pd(Ph3P)4 (22 mg, 0.019 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (160 mg, 0.383 mmol), 3-cyanophenylboronic acid (85 mg, 0.575 mmol). Dioxane (3 mL) and water (600 mL) was added at rt. The reaction was degassed 3× and heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was taken up in DCM. A white precipitate formed which was filtered to give the titled compound. The filtrate was purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf ˜0.4:50% EtOAc/Hex, fraction collection at λ=254 nm) to give the titled compound which was combined with the previously collected precipitate (85 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.46-8.53 (1 H, m), 8.24 (1 H, s), 8.09 (1 H, d, J=7.93 Hz), 7.99-8.05 (2 H, m), 7.96 (1 H, d, J=1.53 Hz), 7.85 (1 H, d, J=7.63 Hz), 7.74-7.82 (2 H, m), 7.70 (1 H, t, J=7.78 Hz), 7.40 (2 H, t, J=8.85 Hz), 2.87 (3 H, d, J=4.58 Hz). LC-MS retention time: 2.17 min; m/z (MH+): 371. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.59 min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=12.29 min, purity=99%.