Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[I:18]C1C=CC=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1I
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccccc1I

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-iodophenol and tert-butyl bromoacetate (Aldrich), the title compound was obtained as a yellow liquid in quantitative yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:21]([O:20][C:18](=[O:19])[C:15]([CH3:17])([S:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:16])[CH3:22]
Reactant: CCOC(=O)C(C)(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)SC1CCNCC1
Yield: 105.6 %

Procedure:
Deprotection of 6.05 g (18.3 mmol) of 4-(1-ethoxycarbonyl-1-methyl-ethylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester is achieved by treatment with 4M aqueous HCl solution (9.13 mL) in 1,4-dioxane (40 mL) at room temperature for 18 h. The reaction mixture is concentrated to afford 4.47 g of 2-methyl-2-(piperidin-4-ylsulfanyl)-propionic acid ethyl ester as its hydrochloride salt as a brown oil. Yield: 92%; ES-MS: m/z 232 [M+H]1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.21 (3 H, t, J=7.13 Hz), 1.45 (6 H, s), 1.80-1.90 (2 H, m), 2.17 (2 H, ddd, J=10.78, 7.31, 3.66 Hz), 2.96-3.05 (2 H, m), 3.07-3.15 (1 H, m), 3.18-3.30 (2 H, m), 4.09 (2 H, q, J=7.12 Hz), 9.44 (1 H, br. s.), 9.54 (1 H, br. s.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:12][CH:11]=[C:10]([C:20](OC)=[O:21])[N:9]=2)=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].[NH2:31][C:32]1([C:42]([OH:44])=[O:43])[CH:39]2[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:41][CH:33]1[CH2:34]3)[CH2:38]2>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:12][CH:11]=[C:10]([C:20]([NH:31][C:32]3([C:42]([OH:44])=[O:43])[CH:39]4[CH2:38][CH:37]5[CH2:36][CH:35]([CH2:34][CH:33]3[CH2:41]5)[CH2:40]4)=[O:21])[N:9]=2)=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29]
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1ccc(-c2ccccn2)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Product: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)C4CC5CC(C4)CC3C5)ccc2-c2ccccn2)ccc1Cl
Product: Cl
Yield: 102.3 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 581 mg (1.36 mmol) of methyl 2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate and 365 mg (1.87 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 435 mg of 2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][S-:24].[Na+].C(O)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:24][CH3:23])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c([N+](=O)[O-])s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c(SC)s1

Procedure:
The procedure described in Example 27: step a was followed using 4-(5-Bromo-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (151 mg, 0.37 mmol, Example 127: step c) and sodium thiomethoxide (1.0 M in EtOH, 26.3 mg, 0.37 mmol). The reaction was quenched with acetic acid (21 uL, 0.37 mol) and the solvents were removed in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layer was dried (Na2SO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography SiO2 (30% EtOAc in hexanes) to yield the title compound. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+1) found: 408.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][CH3:12])[N:7]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C@:26]([OH:30])([C:28]#[CH:29])[CH3:27]>N1CCCCC1.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.[Cu]I>[NH2:19][C:15]1[N:16]=[CH:17][N:18]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:29]#[C:28][C@:26]([C:22]4[S:21][CH:25]=[CH:24][N:23]=4)([OH:30])[CH3:27])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][O:11][CH3:12])[N:14]=1
Reactant: COCc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Reactant: C#C[C@@](C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COCc1nc2ccc(C#C[C@@](C)(O)c3nccs3)cc2n1-c1ncnc(N)n1
Temperature: 70 °C

Procedure:
To a solution of 4-[6-bromo-2-(methoxymethyl)-1H-1,3-benzodiazol-1-yl]-1,3,5-triazin-2-amine (150 mg at 86% purity, 0.38 mmol) in piperidine (3 mL) was introduced tetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol), copper(I) iodide (7.3 mg, 0.04 mmol) and (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol (118 mg, 0.77 mmol). The reaction was warmed to 70° C. for 1 hr. After cooling to RT, additional tetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol) was introduced and the reaction mixture warmed to 70° C. for a further 1 hr. The reaction mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (DCM containing a 0-3% gradient of methanol) to furnish the title compound as a brown oil: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 5.10 (2H, s), 7.06 (1H, br. s.), 7.31-7.40 (1H, m), 7.64-7.73 (2H, m), 7.75-7.80 (1H, m), 8.02 (1H, br. s.), 8.08 (1H, br. s.), 8.30 (1H, s), 8.40-8.45 (1H, m), 8.65 (1H, s); LC-MS: m/z=+408.00 (M+H)+.
Reaction SMILES: Cl.CN(C)C(=O)O[C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:9]2.CN(C)C([Cl:41])=[O:40].[CH2:43]([N:45]([CH2:49][CH3:50])[C:46](Cl)=[O:47])[CH3:44]>>[ClH:41].[CH2:43]([N:45]([CH2:49][CH3:50])[C:46](=[O:40])[O:47][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:21][CH2:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=3[CH2:25][CH2:26]1)=[O:19])[CH2:9]2)[CH3:44]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3cc(OC(=O)N(C)C)ccc31)CC2
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Product: CCN(CC)C(=O)Oc1ccc2c(c1)CC2CNCCC(=O)N1CCc2cc(OC)c(OC)cc2CC1

Procedure:
The same procedure is used as for the compound of Example 54, but with replacement, in Step 1, of the N,N-dimethylcarbamoyl chloride by N,N-diethylcarbamoyl chloride.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[C:7]([N:14]1[C:23]2[CH:18]([CH2:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]1[CH:24]=O)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8].O.Cl.C1C[O:31][CH2:30][CH2:29]1>>[C:7]([N:14]1[C:23]2[CH:18]([CH2:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]1[CH:24]=[CH:29][C:30]([O:4][CH2:2][CH3:5])=[O:31])([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]
Reactant: CCOC(=O)C(=O)N1C2=CC=CCC2CCC1C=O
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOC(=O)C=CC1CCC2CC=CC=C2N1C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
To a solution of diethylphosphonoacetic acid diethyl ester (10.6 g, 47.1 mmol) in THF (100 mL) was added potassium tert-butoxide (5.04 g, 44.9 mmol) at 0° C. The mixture was stirred for 20 min at room temperature. To the solution was added dropwise N-ethoxalyl-2-formyltetrahydroquinoline (11.18 g, 42.8 mmol)in THF (120 mL) at 0° C. After the complete addition, the mixture was stirred for 15 min at room temperature and water and a small amount of diluted hydrochloric acid were added. The mixture was extracted with ethyl acetate. The organic layer was washed three times with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 3:1 hexane/ethyl acetate to give 7.63 g of N-ethoxalyl-2-ethoxycarbonylethenyltetrahydroquinoline (54%): 1H NMR (270 MHz, CDCl3) δ7.15 (m, 4H), 6.79 (dd, 1H, J=16, 5 Hz), 5.89 (dd, 1H, J=16, 2 Hz), 5.31 (m, 1H), 4.12 (q, 2H, J=7 Hz), 2.73 (t, 2H, J=6 Hz), 2.47 (m, 1H), 1.69 (m, 1H), 1.25 (t, 3H, J=7 Hz), 1.11 (t, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl-].[NH4+].Cl>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Yield: 43 %

Procedure:
6 ml (11.7 mmol) of a 2M solution of 4-fluorophenylmagnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at −50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium is stirred for 1 hour at −50° C. and hydrolysed by addition of a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 7/3 heptane/ethyl acetate). 333 mg in the form of a white powder are obtained with a yield of 43%.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH2:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:51]([C:53]1[N:54]=[C:55]([C:66]([O-])=[O:67])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=1)#[N:52].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:25][C:66]([C:55]2[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=[C:53]([C:51]#[N:52])[N:54]=2)=[O:67])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(C3=CCCCC3)c2)C[C@H](C)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)C[C@H](C)N1
Temperature: 0 °C
Yield: 63 %

Procedure:
A solution of 153 mg (0.422 mmol) of 2-cyclohex-1-enyl-4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 295 mg (0.633 mmol) of PyBroP and 142 mg (0.464 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) to form a slurry, which was cooled to 0° C., treated with 184 μL (1.06 mmol) of DIEA, and warmed to RT for 6.5 h. The mixture was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (1×15 mL) and brine (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 163 mg (63%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C30H44N6O4SSi, 613.3 (M+H). found 612.9.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(C)=O.[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[C:35](Cl)=[O:36])([O-:31])=[O:30]>O>[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[C:35]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)=[O:36])([O-:31])=[O:30]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(N3CCN(C(=O)c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)CC3)ccc2N1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2.34 ml of triethylamine was added to 40 ml of dimethyl sulfoxide and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of dimethyl sulfoxide solution containing 3.3 g of 3,5-dinitrobenzoyl chloride. After completion of addition the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate, chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 0.3 g of 6-[4-(3,5-dinitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 262°-264° C., reddish black needles.
Reaction SMILES: [C:1]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:28])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:15]([CH3:17])=O)[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]12.[CH3:35][O:36][C:37](=[O:42])/[CH:38]=[C:39](\[NH2:41])/[CH3:40]>>[CH3:40][C:39]1[NH:41][C:15]([CH3:17])=[C:14]([C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:4](=[O:29])[C:3]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]3[C:1]2=[O:34])=[O:28])[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:38]=1[C:37]([O:36][CH3:35])=[O:42]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]
Yield: 34.5 %

Procedure:
Prepared by a method analogous to that of Example 7(a) from 23.0 g (50 mmol) of 2-(2-nitrobenzylidene)-aceto acetic acid-(6-phthalimidohexyl)ester and 5.7 g (50 mmol) of 3-amino-crotonic acid methyl ester. 9.7 g (35%) of a dark yellow oil obtained after column chromatographic purification on silica gel with dichloromethane/methanol (98:2) as solvent.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]([F:9])[F:8])[CH:6]=1.[Si:10]([C:14]#[CH:15])([CH3:13])([CH3:12])[CH3:11].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.C1CCCCC1>[F:8][CH:7]([F:9])[N:5]1[CH:6]=[C:2]([C:15]#[C:14][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=[N:4]1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)n1cc(I)cn1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Product: C[Si](C)(C)C#Cc1cnn(C(F)F)c1
Temperature: 60 °C

Procedure:
4-Iodo-1-difluoromethylpyrazole (521 mg, 1.81 mmole) was dissolved in DMF (3 mL). TMS-acetylene (0.43 ml) was added followed by di-isopropylamine (395 uL), copper(I) iodide (27 mg) and triphenylphosphine (112 mg). The reaction was flushed with nitrogen. Palladium acetate (32 mg) was added and the reaction flushed again with nitrogen (×3) and was heated at 60° C. for 65 minutes. The reaction was cooled and diluted with ethyl acetate (20 mL). The solution was washed with water (3×10 mL) and with brine then dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 1:1 dichloromethane:cyclohexane to afford the title compound (413 mg 1.92 mmole). 1H-NMR (CDCl3, 500 MHz): δ 0.25 (s, 9H), 7.15 (t, J=60.2 Hz, 1H), 7.71 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc(F)cc4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
(4-Fluoro-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (45 mg, 0.16 mmol), acetic anhydride (16 μL, 0.16 mmol), and triethylamine (66 μL, 0.48 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 62 (7 mg, 13% yield) as a oily residue. LC-MS (M+H=325, obsd.=325).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[CH3:21]I.[H-].[Na+]>CC(N(C)C)=O.C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2N(C)C1=O
Temperature: 3 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 10-chloro-4,4-diethyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 197; 2.7 g, 9.1 mmol) in DMA (50 mL) under nitrogen was added methyl iodide (0.627 mL, 10.0 mmol). The mixture was cooled on an ice/water bath to 3° C., and sodium hydride (60% mineral oil dispersion; 0.567 g, 11.8 mmol) added in one portion. The reaction was stirred overnight. The reaction was evaporated to dryness to afford a yellow solid, this was quenched with saturated NH4Cl(aq) (50 mL), extracted with DCM (3×100 mL), dried (MgSO4) and evaporated to yield a yellow solid. This was dissolved in a minimum amount of DCM, diethyl ether was added and the system was sonicated to afford an off white solid. (2.24 g, 80%)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1(c2ccc(OCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (389 mg, 1.65 mmol), 1-(2-chloro-ethyl)-pyrrolidine (210 mg, 1.57 mmol), DMF (4.5 ml) and K2CO3 (885 g, 6.40 mmol) was heated to 130° C. for 30 minutes. The mixture was cooled to ambient temperature; water (9 ml) was added and the mixture was extracted with EtOAc (3×4.5 ml). The organic phase was washed with brine (10 ml), NaOH solution (2M, 10 ml) and water (10 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo at 35° C. and the residue subjected to chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (150 mg, 27%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.89 (d, 2H), 4.10 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.89 (t, 2H), 2.67-2.58 (m, 4H), 2.40 (s, 2H), 2.13-2.05 (m, 2H), 1.97 (s, 6H), 1.88 (ddd, 2H), 1.84-1.77 (m, 4H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]2[O:21][C@H:20]2[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=1.[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH2:38][CH2:37]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]([N:39]2[C:40]3[C:36](=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:37][CH2:38]2)[C@H:20]([OH:21])[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=1
Reactant: OC[C@@H]1O[C@H]1c1cccc(Br)c1
Reactant: c1ccc(COc2cccc3c2NCC3)cc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OC[C@@H](O)[C@@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
Magnesium perchlorate (16.63 g, 74.52 mmol) was added in portions to a magnetically stirred solution of (2S-trans)-3-(3-bromophenyl)oxiranemethanol (16.32 g, 71.26 mmol) in dry acetonitrile (100 ml) at 5° C. under nitrogen . After stirring for 10 min. all of the magnesium salts had dissolved and the resulting intense yellow solution was treated with 7-benzyloxyindoline (16.77 g, 74.52 mmol) in acetonitrile (30.0 ml) dropwise at 0° C. (ice-H2O). The dark brown solution was stirred at 25° C. for 20 h, quenched with saturated aqueous NaHCO3 (300 ml), extracted with ethyl acetate (3×200 ml), the combined organic phases were washed with brine (3×200 ml), dried (Na2SO4) and the solvent removed in vacuo to provide a yellow/brown gum. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 3:7) provided the title compound (27.37 g, 87%) as a grey/green oil which crystallised on standing. Recrystallised from diethyl ether at -20° C. as white crystals, m.p. 61°-66° C. (Found: C, 63.51; H, 5.78; N, 2.84. C24H24BrNO3 requires C, 63.44; H, 5.32; N, 3.08%); [α]D25 -311.1 (c=0.009 gml-1, CHCl3); νmax (nujol)/cm-1 3353.0 (br. OH), 1584.0, 1565.0; δH (270 MHz) 2.27 (1H, bs, OH); 2.66 (3H, m, OH, 2×indoline 2-H); 3.10 (1H, m, indoline 3-H); 3.30 (1H, m, indoline 3-H); 3.85 (2H, dq, 2×1-H, 2J1,1 =11.5, 3J1,2 =4.0 Hz); 4.22 (1H, m, 2-H); 5.16 (2H, s, CH2Ph); 5.38 (1H, d, 3-H, 3J3,2 =10.2 Hz); 6.65-7.49 (12H, m, 12 ArH). δC (67.8 MHz) 29.2 (indoline 2-C); 46.5 (indoline 3-C); 61.7 (3-C); 64.8 (1-C); 69.9 (C-2); 70.9 (CH2Ph); 112.2 (indoline 6-C); 118.1 (indoline 5-C); 120.3 (indoline 4-C); 122.4 (3'-C); 136.4 (1'-C); 138.5 (indoline 7a-C); 139.5 (benzyl ipso-C); 145.0 (indoline 7-C). The remaining signals lie between 127.5-136.4 ppm and could not be assigned with any certainty; m/z 455.3, 453.3 (0.58, 0.74, M+), 394.2, 392.2 (7.81, 7.90), 304.1, 302.1 (4.80, 9.32), 225.2 (8.35), 171.0, 169.0 (5.29, 5.79), 134.1 (34.82), 118.1 (1.35), 59.1 (100).