Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[C:17]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][C:11]=2[C:12]([O:14]C)=O)=[CH:4][CH:3]=1.[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[NH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[C:17]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:16][C:11]=2[C:12]([NH:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1cc(CN2CCOCC2)c(-c2cnn(C)c2)cc1OCc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(OCc3ccc(F)cc3)c(C(=O)Nc3cccnc3)cc2CN2CCOCC2)cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-4-(1-methyl-1H-pyrazol-4-yl)-5-(4-morpholinylmethyl)benzoate (may be prepared as described in Description 18; 155 mg, 0.353 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (31 mg, 1.29 mmol) followed by water (1 ml). The mixture was heated at 50° C. for one hour. 2M hydrochloric acid (0.79 ml, 1.59 mmol) was added and the solvent removed in vacuo. The residue was redissolved in N,N-dimethylformamide (4 ml) and diisopropylethylamine (0.12 ml, 0.71 mmol), 3-aminopyridine (43.2 mg, 0.46 mmol), 1-hydroxy-7-azabenzotriazole (57.6 mg, 0.42 mmol) and EDC (101 mg, 0.53 mmol) were added. The solution was stirred overnight, then the solvent was removed in vacuo to give a residue. Purification by MDAP yielded the title compound as a white solid. 84 mg.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=2[C:16]#[N:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=2[C:16]#[N:17])=[CH:5][CH:4]=1)(=[O:30])=[O:29]
Reactant: N#Cc1cccc(Oc2ccc(CO)cc2)c1C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1ccc(Oc2cccc(C#N)c2C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 3-[4-(hydroxymethyl)phenoxy]phthalonitrile (900 mg, 3.9 mmol) prepared according to procedures described in literature, and triethylamine (0.75 ml, 5.8 mmol) in anhydrous CH2Cl2 (50 ml), kept at 0° C. under stirring and in an inert atmosphere, methylsulfonylchloride was added (0.33 ml, 4.3 mmol). The mixture was stirred at 0° C. for 1 hour, then it was diluted with CH2Cl2 (50 ml) and washed with 1% HCl solution (60 ml), then with brine (50 ml), the organic layer was dried on Na2SO4 and the solvent was evaporated. 1.1 g (93%) of the title compound were obtained as a viscous fluid that crystallized on standing.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[N+](=[CH2:11])=[N-]>CCOCC.C(O)(=O)C>[CH3:11][O:7][C:1](=[O:8])[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: C=[N+]=[N-]
Reactant: CCC#CCC(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC#CCC(=O)OC

Procedure:
A solution of 5.9 g of 3-hexynoic acid in 50 ml of ether is treated with a slight excess of ethereal diazomethane solution. A few drops of glacial acetic acid are added to the mixture, the mixture is concentrated in vacuo and then distilled. 5.65 g of the title compound are obtained: b.p. 62° C. (5 mm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[C:13](O)(=O)[CH:14]([CH3:16])[CH3:15].Cl.[OH-].[Na+]>>[Br:1][C:2]1[C:3]2[N:12]=[C:13]([CH:14]([CH3:16])[CH3:15])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)C(=O)O
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Temperature: 105 °C
Yield: 85.7 %

Procedure:
A mixture of 3-bromo-5-nitrobenzene-1,2-diamine (4 g, 17.24 mmol) and isobutyric acid (7.99 ml, 86 mmol) in 3M HCl (100 ml, 300 mmol) was heated to 105° C. for 5 days. The mixture was allowed to cool to room temperature and was poured into chilled 5M Sodium Hydroxide (60.0 ml, 300 mmol) solution. The resulting mixture was allowed to stand in an ice bath and the brown solid that precipitated was collected by filtration. The solid was washed several times with H2O and then dried in a vacuum oven at 50° C. leaving desired product as a dark solid (4.2 g, 71% yield). MS (ES+) m/e: 283.0, 284.0 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1>[C:21]([O:20][C:16](=[O:19])[CH:17]=[CH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(C=CC(=O)OC(C)(C)C)cn12
Temperature: 95 °C

Procedure:
A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), tert-butyl acrylate (408 uL, 2.79 mmol), tris(dibenzylideneacetone)diplalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4(27 mg, 0.093 mmol) and N,N-dicyclohexylmethylamine (738 uL, 3.48 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and the crude product was purified by silica chromatography to yield ethyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (70). MS m/z 317.14 (M+1)+.
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:8]=1)[C:3](O)=O.C([N:29](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:1][C:2]([NH2:29])([CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:8]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)C(=O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.17 g (6.09 mmol) of the Intermediate 86 are dissolved in 200 ml of acetone. 1.95 ml (13.99 mmol) of triethylamine are added and the solution is cooled to 0° C. A solution of 0.89 ml (6.84 mmol) of isobutyl chloroformiate in 15 ml of acetone is dropped into the system. After 30′ at 0° C. a solution of 0.99 g (15.23 mmol) of sodium azide in 10 ml of water is slowly added, and the stirring at 0° C. is prosecuted for an additional period of 30 min. Excess water is added, the system is extracted with ethyl ether which is washed with water, dried and concentrated at room temperature. The residue is dissolved in 15 ml of toluene and this solution added slowly to 150 ml of refluxing toluene. The reflux is prosecuted for an additional hour and the solution is concentrated. The residue is dissolved in 15 ml of dioxane, 35 ml of 5N HCl are added and the system is stirred at 100° C. for 30′. The solution is neutralised with 2N NaOH and is extracted with ethyl ether. The ethereal layer is washed with water, dried and concentrated. The residue is chromatographied on silicagel eluting with ethyl acetate/methanol 10:1 then 6:1 giving 1.46 g (72%) of yellowish oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-:25][Si](C)(C)C)(C)C.C1COCC1.Cl.[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[NH2:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C)(c2ccc(N)cc2)CC1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
A mixture of ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (2.0 g, 6.13 mmol), biphenyl-2-yldicyclohexylphosphine (0.054 g, 0.153 mmol), 1M LiHMDS in THF (12.26 ml, 12.26 mmol), and Pd2(dba)3 (0.056 g, 0.061 mmol) was heated in a sealed vial at 65° C. overnight. The mixture was cooled to room temperature and treated with 1N aq. HCl (30.7 mL, 30.7 mmol) and stirred for 5 min. The mixture made basic with 1N NaOH and extracted twice with methylene chloride. The combined organic extracts were concentrated and the residue was purified by MPLC (ISCO, hexane/ethyl acetate, 24+40 g stacked silica gel columns) to give 924 mg (57%) of product as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:68])/[CH:4]=[CH:5]\[CH:6]=[CH:7]\[C@@H:8]([CH3:67])[C@@H:9]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:10][C@H:11]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])/[CH:12]=[CH:13]\[C@H:14]([CH3:50])[C@H:15]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C@@H:16]([CH3:41])[CH2:17][C@@H:18]([CH3:40])[CH2:19][CH2:20][C@H:21]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@H:22]([CH3:31])[C@@H:23]([OH:30])[C@@H:24]([CH3:29])/[CH:25]=[CH:26]\[CH:27]=[CH2:28].[OH-].[K+]>>[Si:60]([O:59][C@@H:9]([CH2:10][C@H:11]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:53])[CH3:54])/[CH:12]=[CH:13]\[C@H:14]([CH3:50])[C@H:15]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[C@@H:16]([CH3:41])[CH2:17][C@@H:18]([CH3:40])[CH2:19][CH2:20][C@H:21]([O:32][Si:33]([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34])[C@H:22]([CH3:31])[C@@H:23]([OH:30])[C@@H:24]([CH3:29])/[CH:25]=[CH:26]\[CH:27]=[CH2:28])[C@H:8]([CH3:67])/[CH:7]=[CH:6]/[CH:5]=[CH:4]\[C:3]([OH:68])=[O:2])([C:63]([CH3:64])([CH3:65])[CH3:66])([CH3:62])[CH3:61]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](CC[C@H](C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](CC[C@H](C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C

Procedure:
The procedure for 48 was used with 56 (56 mg, 55 μmol) and 1N aqueous KOH (0.54 mL) to yield 57, which was used without further purification: IR (CHCl3) 2956, 2929, 2857, 1693, 1634, 1471, 1462, 1254, 1082, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.34 (dd, J=15.1, 11.4 Hz, 1H), 6.64 (ddd, J=16.5, 10.6, 10.5 Hz, 1H), 6.61 (t, J=11.2 Hz, 1H), 6.07 (t, J=11.0 Hz, 1H), 6.01 (dd, J=15.5, 7.2 Hz, 1H), 5.58 (d, J=11.3 Hz, 1H), 5.44-5.34 (m, 2H), 5.23 (dd, J=11.0, 8.2 Hz, 1H), 5.17 (d, J=18.0 Hz, 1H), 5.08 (d, J=10.1 Hz, 1H), 4.50 (m, 1H), 3.92 (m, 1H), 3.69 (m, 1H), 3.35 (m, 1H), 2.75 (m, 1H), 2.54 (m, 2H), 1.74-1.56 (m, 4H), 1.49-1.20 (m, 7H), 1.02 (d, J=6.8 Hz, 3H), 0.98 (d, J=7.2 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H), 0.90-0.82 (m, 45H), 0.09-0.01 (m, 24H); 13C NMR (75 MHz, CDCl3) δ 171.1, 148.2, 147.4, 136.4, 132.7, 132.6, 129.6, 127.0, 117.4, 115.1, 79.8, 78.4, 74.2, 72.1, 66.5, 43.5, 42.6, 41.5, 36.0, 35.9, 35.8, 35.0, 31.9, 30.8, 29.7, 26.3, 26.0, 25.9, 20.4, 19.3, 18.5, 18.13, 18.08, 17.97, 17.4, 15.4, 13.7, 10.8, −3.0, −3.4, −3.7, −4.1, −4.2, −4.3, −4.4, −4.8; LRMS (ESI) 1029.8 [M+Na]+, 832.3, 758.3, 684.3, 610.2, 541.2; HRMS (ESI) calcd for C56H110O7Si4Na 1029.7226 [M+Na]+, found 1029.7255; [α]20D−6.5 (c 0.17, CHCl3).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH3:15]O>>[CH3:15][O:11][C:10]([C:8]1[S:7][C:6]2[CH:13]=[CH:14][C:3]([CH3:2])=[CH:4][C:5]=2[CH:9]=1)=[O:12]
Reactant: CO
Reactant: Cc1ccc2sc(C(=O)O)cc2c1
Agent: Cl
Product: COC(=O)c1cc2cc(C)ccc2s1

Procedure:
Hydrogen chloride gas was passed into a solution of 5-methylbenzo[b]thiophene-2-carboxylic acid (7.50 g.) in methanol (250 ml.) until the solution was saturated. The solution was heated under reflux for 1 hour and then evaporated. The residue was washed with water and recrystallized from methanol to give 5-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (7.80 g.) m.p. 78°-79°.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].C([O:12][C:13](=O)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:27][C@H:28]([OH:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:21][C:20]=2[CH:38]=1)C>CN(C)C=O>[ClH:1].[OH:37][C@H:28]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:27][NH:26][CH:22]1[CH2:21][C:20]2[CH:38]=[C:16]([O:15][CH2:14][C:13]([NH:4][C:3]([NH2:5])=[NH:2])=[O:12])[CH:17]=[CH:18][C:19]=2[CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
To a solution of guanidine hydrochloride (463 mg) in N,N-dimethylformamide (20 ml) was added 28% sodium ethoxide (0.22 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 minutes. To the resulting mixture was added 2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (400 mg). After being stirred at room temperature for 2 hours, the precipitates were collected by filtration and treated with 4N hydrogen chloride in ethyl acetate to afford N-[2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetyl]guanidine hydrochloride (243 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N+:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#C[Si](C)(C)C)cc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
A solution of methyl 3-bromo-5-nitrobenzoate (0.331 g, 1.27 mmol), (trimethylsilyl)acetylene (0.27 mL, 1.9 mmol), bis(triphenylphosphine)palladium(II) chloride (45 mg, 0.064 mmol), copper(I) iodide (19 mg, 0.10 mmol) and triethylamine (0.26 mL, 1.9 mol) in DMF (5 mL) was stirred at room temperature overnight. The solution was diluted with ethyl acetate and 1 N HCl. The aqueous layer was extracted with ethyl acetate once, and the combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the desired product (310 mg, 88%). LCMS for C13H16NO4Si (M+H)+: m/z=278.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[NH:17]([C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=2[N:23]=1)[NH2:18]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)[N:18]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(NN)sc2c1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc2nc(-n3nc(CCCO)cc3-c3ccc(Cl)cc3)sc2c1
Yield: 80.9 %

Procedure:
6-(4-Chlorophenyl)-4,6-diketohexanol (14.43 g, 60 mM) was treated with 2-hydrazino-6-methoxybenzothiazole (11.72 g, 60 mM) in pyridine (10 ml) and MeOH (300 ml) at reflux for 72 hr. Work-up as described in Example 1 followed by recrystallization from MeOH afforded the title compound 6 as a white solid (19.4 g), mp=123°-125° C.; NMR(CDCl3) δ 6.3 (s, 1H, C4 -H); MS, m/e 399 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[C:15](=S)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.N([C@H]1[C@H](O)CCOC1)N.[NH:39]([C@@H:41]1[CH2:46][CH2:45][O:44][CH2:43][C@H:42]1[OH:47])[NH2:40].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:17][C:10]1[C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:23][CH:24]=3)[N:7]=[C:6]3[C:4](=[O:5])[N:39]([C@@H:41]4[CH2:46][CH2:45][O:44][CH2:43][C@H:42]4[OH:47])[N:40]=[C:15]3[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NN[C@@H]1CCOC[C@H]1O
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=S
Agent: NN[C@@H]1COCC[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3c(Cl)cccc3c-2nn1[C@@H]1CCOC[C@H]1O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Ethyl-8-chloro-1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate [(Example 60, Step 4) 188 mg, 0.442 mmol] was dissolved in 1,2-dimethoxyethane (1.5 mL) and treated with a mixture of (±)-trans-3-hydrazinotetrahydro-2H-pyran-4-ol and (±)-trans-4-hydrazinotetrahydro-2H-pyran-3-ol (117 mg, 0.885 mmol, 2 equiv) and potassium carbonate (183 mg, 1.327 mmol, 3 equiv). The mixture was placed into an oil bath preheated to 90° C. for 35 minutes, cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed once with brine, dried with sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing an inseparable mixture of regioisomers, which was further purified by chiral HPLC (Chiralcel OJ Column, 100% methanol) to produce a first-, second-, and third-eluting peak. The first-eluting peak was determined to the titled compound (enantiopure, relative trans stereochemical configuration), of which the absolute stereochemistry is unknown: 1H-NMR (400 MHz, CDCl3) δ 8.22 (1H, d, J=8.1 Hz), 7.87 (1H, s), 7.71-7.59 (4H, m), 7.46 (1H, t, J=8.1 Hz), 7.29-7.20 (2H, m), 6.44 (1H, s), 6.33 (2H, s), 4.52-4.43 (1H, m), 4.26-4.17 (2H, m), 4.11-4.04 (1H, m), 3.55 (1H, t, J=12.0 Hz), 3.32 (1H, t, J=10.3 Hz), 2.32-2.19 (1H, m), 2.14-2.06 (1H, br d J=12.4 Hz). ppm; low resolution mass spectrometry (ES+) m/z 477.3 [(M+H)+; calculated for C24H22ClN6O3: 477.5].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccn1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccn1

Procedure:
Condensation of N-tert-butoxycarbonyl-L-inethionine (1a) with 2-aminopyridine (2j) according to General Procedure A, resulted, after purification on a SILICA GEL column (hexane-acetone 3:1), in (3o) (C15H23N3O3S1, 62%), Rf=0.33 (hexane-acetone 3:1), m.p. 135°-137° C., [α]D23 =-28.2° (c 0.11, CHCl3), IR (KBr) ν: 432, 459, 471, 496, 527, 623, 681, 737, 775, 829, 847, 864, 924, 964, 999, 1028, 1053, 1099, 1165, 1252, 1283, 1304, 1366, 1389, 1435, 1462, 1532, 1580, 1603, 1674, 1711, 2363, 2832, 2915, 2953, 2974, 2999, 3046, 3127, 3262 cm-1, 1H NMR (CDCl3) δ: 8.647-8.655 (br s, 1H, Ar--NH), 8.264-8.290 (m, 1H, ArH), 8.1705 (d, 1H, J 8.1 Hz, ArH), 7.659-7.718 (m, 1H, ArH), 7.016-7.055 (m, 1H, ArH), 5.210-5.227 (m, 1H, NH), 4.440 (m, 1H, Hα), 2.540-2.638 (m, 2H, CH2γ), 2.138-2.253 (m, 1H, Hβ), 2.099 (s, 3H, CH3ε), 1.968-2.040 (m, 1H, Hβ), 1.436 (s, 9H, t-Bu); EIMS (70 eV) m/z (%): 325 (M+, 5).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[S:15]1[C:19]2[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1>>[S:15]1[C:19]2[CH:20]=[C:21]([NH:24][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CCNc2ccc3ncsc3c2)cc1

Procedure:
In analogy to example 33, step 1, (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with benzothiazol-6-ylamine (commercially available) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:19]=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ncc(Br)cc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC1CNCCc2ncc(Br)cc21
Reaction time: 16 h
Yield: 38.8 %

Procedure:
A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (490 mg, 1.80 mmol), tBuNO2 (315 μl, 2.70 mmol), CuBr2 (481 mg, 2.20 mmol) and MeCN (10 ml) was heated to 70° C. for 5 h. The reaction mixture was parted between H2O and EtOAc, the organic layer was dried and then concentrated in vacuo. The resulting residue was purified by column chromatography to yield 100 mg (16%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.46 (s, 1H), 7.64 (s, 1H), 4.25-3.20 (m, 7H), 1.39 (d, 1.3H), 1.35 (d, 1.65H) ppm. A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (90 mg, 267 μmol), K2CO3 (100 mg), MeOH (6 ml) and H2O (1 ml) was stirred for 16 h at room temprature. The reaction mixture was parted between aq. NaHCO3 and DCM, the organic layer was dried and then concentrated in vacuo. The resulting residue was purified by column chromatography to yield 25.0 mg (39%) of 3-bromo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (MeOH-d4) δ 8.49 (s, 1H), 7.90 (s, 1H), 3.55-3.40 (m, 3H), 3.37-3.27 (m, 2H), 3.20 (dd, 1H), 3.11 (dd, 1H), 1.48 (d, 3H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:39])=[CH:36][C:37]=2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:37]1[CH:36]=[C:35]([CH3:39])[N:34]=[CH:33][C:32]=1[C:28]1[CH:27]=[C:26]([C:24]2[CH2:23][C:22](=[O:40])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=3[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C)cc3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnc(C)cc3C)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M232) (340 mg, 0.595 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (148 mg, 55%).