Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:8][OH:9])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([N:25]3[CH2:28][CH:27]([O:29][C:30]4[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([CH3:38])[CH:31]=4)[CH2:26]3)=[O:24])=[N:20][N:19]=2)=[CH:14][CH:13]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl.C1COCC1>[OH:9][CH2:8][C:3]1([CH3:2])[CH2:7][CH2:6][N:5]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH:27]3[CH2:28][N:25]([C:23]([C:21]4[O:22][C:18]([C:15]5[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=5)=[N:19][N:20]=4)=[O:24])[CH2:26]3)=[CH:31][C:32]=2[CH3:38])[CH2:4]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Reactant: CC1(CO)CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(C)(CO)C5)c(C)c4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Intermediate 84A (0.097 g, 0.64 mmol) was dissolved in dichloromethane (6 mL), THF (1 mL) and TEA (0.106 mL, 0.76 mmol). Intermediate 73C (0.120 g, 0.31 mmol) was added and the mixture stirred at RT for 5 min. and then sodium triacetoxyhydroborate (0.129 g, 0.61 mmol) was added. The mixture was stirred at RT for 21 h. Aqueous NaHCO3 (8%, 4 mL) was added and the mixture was filtered through a phase separator, dichloromethane (4 mL) was added and the solvent was removed by evaporation. The product was purified by preparative HPLC under basic conditions followed by lyophilisation to give (0.114 g, 76%). 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H), 1.56-1.71 (m, 1H), 1.93-2.21 (m, 2H), 2.22-2.39 (m, 4H), 2.77-2.92 (m, 1H), 2.94-3.09 (m, 1H), 3.25-3.39 (m, 1H), 3.41-3.62 (m, 3H), 3.89 (s, 3H), 4.25-4.39 (m, 1H), 4.54-4.8 (m, 2H), 4.99-5.18 (m, 2H), 6.47-6.66 (m, 2H), 7.02 (d, 2H), 7.08-7.19 (m, 1H), 8.10 (d, 2H), MS (APCI+) m/z 493 [M+H]+, LC Purity: 99%.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].ClC1C=CC=CN=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N+:27]([C:30]([N+:36]([O-:38])=[O:37])([N+:33]([O-:35])=[O:34])[CH2:31]O)([O-:29])=[O:28].O(CC=C)S(C(F)(F)F)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[N+:27]([C:30]([N+:33]([O-:35])=[O:34])([N+:36]([O-:38])=[O:37])[CH2:31][O:4][CH2:1][CH:2]=[CH2:3])([O-:29])=[O:28]
Reactant: C=CCO
Reactant: O=[N+]([O-])C(CO)([N+](=O)[O-])[N+](=O)[O-]
Agent: C=CCOS(=O)(=O)C(F)(F)F
Agent: Clc1ccccn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=CCOCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A solution of allyl alcohol (30 g, 520 mmol) and 2-chloropyridine 60 g, 530 mmol) in methylene chloride (100 ml) was added over 60 min to a stirred solution of trifluoromethanesulfonic anhydride (147 g, 520 mmol) in methylene chloride (350 ml) at 0° C. The mixture was stirred at 0° C. for 3 h and then filtered. The brown allyl triflate solution was stored in a freezer for use in the following reaction. A solution of trinitroethanol (58 g, 320 mmol) in methylene chloride (300 ml) was added, with ice bath cooling, over 30 min to a stirred mixture of one-half of the allyl triflate solution and anhydrous sodium sulfate (80 g). The ice bath was removed. After the mixture was stirred at room temperature for 17 h, sodium sulfate (40 g) and half of the remaining allyl triflate solution were added. After another 24 hrs of stirring at ambient temperature, another 40 g portion of sodium sulfate and the remaining allyl triflate solution were added, and stirring was continued for 24 h. The mixture was filtered. The solution was washed with saturated sodium bicarbonate solution and with water. The solution was dried over magnesium sulfate and solvent was removed under vacuum. The brown liquid residue was chromatographed using silica gel and methylene chloride, followed by distillation to give allyl trinitroethyl ether, bp. 45° C./0.1 mm Hg, yield 60% (42.7 g) based on the trinitroethanol: HNMR (acetone-d6): 4.30 (t of d, 2H), 5.13 (s, 2H), 5.26 (AB quartet of d, 1H), 5.33 (AB quartet of d, 1H), 5.90 (m, 1H) ppm; IR (neat): 2927 (w), 2877 (w), 1597 (br, vs), 1447 (w), 1425 (w), 1347 (w), 1305 (s), 1194 (w), 1123 (br, m), 1029 (w), 995 (w), 938 (m), 879 (w), 856 (w), 804 (m), 783 (m), 732 (w) cm−1.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([NH:17][C:18](=[O:20])[CH3:19])=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.CO.[OH-].[Na+].Cl>O>[OH2:3].[C:18]([NH:17][C:5](=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[C:4]([OH:21])=[O:3])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(=Cc1c[nH]c2cc(C)ccc12)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NC(=Cc1c[nH]c2cc(C)ccc12)C(=O)O
Reaction time: 0.75 h

Procedure:
three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 159.5 g (0.56 mol) of crude alpha-acetamido-6-methylindole-3-acrylic acid ethylester and 475 ml of methanol. The mixture was heated in an oil bath to 50°. A solution of 66.8 g (1.67 mol) of sodium hydroxide in 320 ml of water was added over 3 minutes and the resulting brown solution was stirred at 50° for 45 minutes. The reaction mixture was cooled with an ice bath to 25° and 600 ml of 4 N hydrochloric acid was added over 20 minutes at 25°. The precipitate was collected on a Buchner funnel, washed with 900 ml of water and dried at 50° overnight and at 60°/0.5 mm for 3 hours. The beige solid (146 g) was dissolved in 1 l of methanol and 175 ml of dimethylformamide at reflux. 10 g of charcoal was added and reflux was continued for 10 minutes. The mixture was filtered through a bed of Celite and the clear brown solution was brought again to reflux. 425 ml of water was added over a 20 minute period, while reflux was maintained. The mixture was refrigerated for 3 hours. The product was collected by suction filtration, washed with 750 ml of 1:1 methanol-water and dried at 50° for 24 hours (const. weight) to yield 119.9 g (69% based on 6-methylindole-3-carboxyaldehyde of product as yellow crystals, m.p. 229° (dec.).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]1>C(#N)C>[CH2:18]([NH:17][C:15]([C:12]1[CH:11]=[N:10][C:9]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]2)=[N:14][CH:13]=1)=[O:16])[CH3:19]
Reactant: CCNC(=O)c1cnc(Cl)nc1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)c1cnc(N2CCC[C@H](O)C2)nc1
Temperature: 80 °C
Yield: 73.9 %

Procedure:
Triethylamine (1.5 mL, 11 mmol) and 2-chloro-N-ethylpyrimidine-5-carboxamide (830 mg, 4.47 mmol) were added sequentially to a solution of (S)-piperidin-3-ol hydrochloride (677 mg, 4.92 mmol) in acetonitrile (25 mL) at 20-25° C. The reaction mixture was heated to 80° C. for 16 hours. The mixture was then cooled to 20-25° C. and was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (25 mL) and washed with saturated NH4Cl (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to provide (S)—N-ethyl-2-(3-hydroxypiperidin-1-yl)pyrimidine-5-carboxamide (827 mg, 73%).
Reaction SMILES: [Si:1]([CH3:5])([CH3:4])(Cl)[Cl:2].N(CC)(CC)CC.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>CCCCC>[Cl:2][Si:1]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(C)(C)N
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Me2SiCl2 (151.50 g, 1.17 moles) was stirred in pentane (2 L) as N(C2H5)3 (119.62 g, 1.18 moles) was added slowly. t-Butylamine (85.85 g, 1.17 moles) in pentane (100 mL) was then added dropwise and the reaction allowed to stir at room temperature for 16 hours. After the reaction period the mixture was filtered and concentrated to 600 mL at which time more salts began to precipitate. The mixture was then refiltered and concentrated to 250 mL and then transferred to a 250 mL roundbottom flask equipped with a microdistillation apparatus and a thermometer. Distillation was performed until the reflux temperature reached 50° C. The clear, colorless liquid remaining was then determined to be pure by NMR and the yield to be essentially quantitative.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH:15]=[C:16]1[NH:20][C:19](=[O:21])[CH2:18][S:17]1>>[NH:15]=[C:16]1[NH:20][C:19](=[O:21])[C:18](=[CH:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][N:4]=[C:3]3[NH:2][CH3:1])[S:17]1
Reactant: N=C1NC(=O)CS1
Reactant: CNc1ncnc2ccc(C=O)cc12
Product: CNc1ncnc2ccc(C=C3SC(=N)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:19]Cl>>[C:1]([N:6]=[N:7][C:8]([Cl:19])([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CCCCOC(=O)CCC(C)=NNC(C)(C)CC
Product: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
To a solution of 90 grams (0.316 moles) of butyl levulinate t-amylhydrazone in 150 mls. of petane in a 500 ml. round bottom flask was passed 10.9 grams (.154 moles) of chlorine holding the temperature at -20°C with a dry ice- isopropanol bath. The chlorine was added over 30 minutes and then the reaction was stirred an additional 15 minutes at -20°C and filtered. The filtrate was dried and the pentane evaporated leaving 46.6 grams of crude butyl 4-t-amylazo-4-chlorovalerate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:32]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3cccs3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 11 μL (0.11 mmol) 2-thiophenecarbonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:22]([N:8]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[CH:6]1[CH2:7][C:2]([CH3:21])([CH3:1])[NH:3][C:4]([CH3:20])([CH3:19])[CH2:5]1)=[O:26])[CH3:25]
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
The N-ethoxycarbonyl-bis(2,2,6,6-tetramethyl-4-piperidyl)-amine is prepared by reacting bis(2,2,6,6-tetramethyl-4-piperidyl)-amine with ethyl chlorocarbonate in chloroform at 10°-20° C. in the presence of aqueous NaOH. The product obtained, which has a purity of 99.2% and melts at 117° C., can be used directly.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[NH:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:12][N:13]=[C:14]=[S:15]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[N:3]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:14]([NH:13][CH3:12])=[S:15]
Reactant: CN=C=S
Reactant: CN(C)NCc1cccnc1
Solvent: Cc1ccccc1
Product: CNC(=S)N(Cc1cccnc1)N(C)C
Yield: 70.6 %

Procedure:
In 30 ml of toluene was dissolved 2.5 g of 1,1-dimethyl-2-(3-pyridylmethyl)hydrazine followed by addition of 1.2 g of methyl isothiocyanate and the mixture was refluxed for 1 hour. The reaction mixture was concentrated and the resulting crystals are collected by filtration, washed with ethyl ether and dried. The procedure gave 2.6 g of 1,1-dimethyl-4-methyl-2-(3-pyridylmethyl)thiosemicarbazide as white prisms.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O.O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1(C)C=CC=CC=1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12 g (0.1 mole) of 4-tolualdehyde and 10.9 g (0.1 mole) of 2-aminophenol in toluene is heated at reflux with azeotropic removal of water. After 20 hours at reflux, the reaction is cooled to room temperature, 44.3 g (0.1 mole) of lead tetraacetate is added, and the mixture is stirred at room temperature overnight. The solids are removed by filtration, and the filtrate is swirled with basic alumina. Removal of the solvent in vacuo affords the solid product which is then purified by recrystallization from benzene.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]3[CH2:22][CH2:21][C@:20]([CH2:29][CH2:30][CH2:31][OH:32])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:19][C:18]3=[O:33])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[NH3:34].[BH4-].[Na+]>CCO.[NH4+].[OH-].C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[NH2:34][CH:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]3[CH2:22][CH2:21][C@:20]([CH2:29][CH2:30][CH2:31][OH:32])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:19][C:18]3=[O:33])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)s1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCO
Product: CC(N)c1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)s1
Reaction time: 24 h
Yield: 3 %

Procedure:
(R)-3-((S)-1-(4-(5-acetylthiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxa-zinan-2-one (40 mg, 0.086 mmol) and tetraisopropoxytitanium (49 mg, 0.17 mmol) are stirred overnight in the solution of NH3 in EtOH. To this solution/paste was added NaBH4 and stirring another 24 h. The reaction was diluted with NH4OH and stirred for 1 h. The mixture was filtered through celite and rinsed with EtOAc. Water and EtOAc were added and the organic layer was separated. The aq layer is extracted with EtOAc for three times. The combined organic layer was dried over Na2SO4, filtered and concentrated to afford (6R)-3-((1S)-1-(4-(5-(1-aminoethyl)thiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (1.26 mg, 3%). LC-MS Method 2 tR=1.014, min, m/z=448.1; 1H NMR (CDCl3, 400 MHz): 1.33 (m, 1H), 1.47 (q, 6H), 1.90 (m, 2H), 2.13 (m, 1H), 2.22 (m, 2H), 2.82 (m, 1H), 3.50 (m, 2H), 4.33 (q, 1H), 5.58 (q, 1H), 6.81 (m, 3H), 6.98 (d, 1H), 7.25 (m, 7H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M12) (301 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (189 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41]O)=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1>C1(C)C=CC=CC=1.O>[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2cc(Cl)cc(Br)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of triphenylphoshine (1.44 g, 5.48 mmol) in toluene (50 mL) cooled to 0° C. was added the diisopropylazadicarboxylate (1.11 g, 5.48 mmol) followed by the phthalimide (0.81 g, 5.48 mmol) and the reaction mixture allowed to stir for 10 min. The (7-bromo-5-chloro-1-benzofuran-2-yl)methanol (1.37 g, 5.22 mmol) was then added and the reaction was allowed to stir at 0° C. an additional 1 h. The reaction mixture was then quenched with water (1 mL) and the solvent was removed in vacuo to provide a crude solid. The solid was suspended in water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL), the combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5) provided 1.73 g (85%) of 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 194-198° C.; HRMS-ESI (m/z). [M+H]+ calcd for C17H9BrClNO3, 388.94545; found, 389.9553.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:15][O:16][CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COCCl
Reactant: Oc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(I)cc1
Yield: 88 %

Procedure:
Paraiodophenol (25 g) was dissolved in DMF (100 ml), followed by the addition of potassium t-butoxide (25 g) and methoxymethyl chloride (13 ml), and the mixture was reacted at 60° C. overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The resulting residue was subjected to a silica gel short column, to give 4-methoxymethoxy-1-iodobenzene as an oil (26.5 g, yield; 88%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]#[C:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C1COCC1.[Pd]>[CH2:8]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:28][CH:29]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnccc2C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCc2cnccc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
tert-Butyl 4-[2-(4-(2-phenylethenyl)-3-pyridyl)ethynyl]benzoate (0.360 g, 0.95 mmol) was dissolved in ethanol/THF 1:1 (10 ml) and treated with palladium on carbon (10%, 0.13 g). The reaction was placed under a hydrogen atmosphere and stirred at ambient temperature for 6 hours. The reaction was then filtered and evaporated to give tert-butyl 4-[2-(4-phenethyl-3-pyridyl)ethyl]benzoate (0.36 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=O)=[CH:3]1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: COC(=O)c1cn(C)c2ccccc12
Reactant: CN
Product: CNC(=O)c1cn(C)c2ccccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of methyl 1-methyl-1H-indole-3-carboxylate (4.30 g, 22.74 mmole) in 40% aqueous CH3NH2 (400 mL) was stirred at RT. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded the product began to precipitate. The reaction was stirred at RT for 3 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (500 mL), and the solid was collected by suction filtration and washed with H2O. Flash chromatography on silica gel (ethyl acetate) gave the title compound (2.4 g, 56%) as a white solid: MS (ES) m/e 189 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[C:27]([CH3:44])([CH3:43])[C:26]1=[O:45]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]6[C:27]([CH3:43])([CH3:44])[C:26](=[O:45])[N:25]([CH3:24])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN1C(=O)C(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)C(C)(C)C(=O)N5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1,3,3-trimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Stage 233.1.1) to give the title compound as a white solid. (HPLC: tR 2.53 min (Method A); M+H=468 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.29 (m, 1H), 8.14-8.09 (m, 2H), 7.96-7.91 (m, 1H), 7.79-7.76 (m, 1H), 7.54-7.51 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.18 (s, 3H), 1.96 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H))
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1.Cl>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([O:14][CH3:17])=[O:13])[CH2:4][CH2:3]1
Reactant: O=C1CCC(C(=O)O)c2ccccc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (3.50 g, 18.4 mmol) in THF (18.4 ml) was added to a dry flask and the solution was purged and then evacuated with argon. Sodium borohydride (1.74 g, 46.0 mmol) was added in one portion and the mixture was stirred at room temperature overnight. The reaction was diluted with aqueous HCl and the mixture was extracted with EtOAc (3×). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily solid was taken-up in methanol/dichloromethane (1:1, 20 ml). Trimethylsilyldiazomethane (18.4 ml, 36.8 mmol) was added drop wise until the solution turned bright yellow and then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford methyl 4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate as a yellow oil.