Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Br[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=[C:29]([CH3:42])[CH:28]=1.[OH:43][C:44]1([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH2:53][CH2:52][CH2:51][C:50]2[CH:49]=[C:48]([C:54]([O:56][CH3:57])=[O:55])[CH:47]=[CH:46][C:45]1=2.[F-].[Cs+].C(O)(=O)C(C)(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:43][C:44]1([C:58]2[S:59][C:60]([C:27]3[CH:28]=[C:29]([CH3:42])[CH:30]=[C:31]([NH:33][C:34]4[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][N:35]=4)[N:32]=3)=[CH:61][N:62]=2)[CH2:53][CH2:52][CH2:51][C:50]2[CH:49]=[C:48]([C:54]([O:56][CH3:57])=[O:55])[CH:47]=[CH:46][C:45]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2(O)c1nccs1
Reactant: COc1ccnc(Nc2cc(C)cc(Br)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(OC)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
To a solution of Pd(OAc)2 (45 mg, 0.2 mmol) in 1,4-dioxane (20 mL) was added butyldi-1-adamantylphosphine (143 mg, 0.4 mmol) and the mixture was stirred at under nitrogen for 10 minutes, during which time a yellow slurry developed. Then 6-bromo-N-(4-methoxypyridin-2-yl)-4-methylpyridin-2-amine (410 mg, 1.4 mmol), methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (289 mg, 1 mmol), CsF (456 mg, 3 mmol), pivalic acid (153 mg, 1.5 mmol) and 1,4-dioxane (10 mL) were added. The reaction mixture was vacuum-purged with N2 and then heated to reflux under N2 for 20 hours. After cooling to rt, the reaction was filtered through Celite®, and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a solvent system of 2:1 petroleum ether/EtOAc to afford racemic methyl 5-hydroxy-5-(5-(6-((4-methoxypyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (160 mg, 52% total), which was resolved by supercritical fluid chromatography using a Chiralpak AS-H 150*4.6 mm I.D., 5 um column and a mobile phase of 5 to 40% MeOH (0.05% diethylamine) in CO2 with a flow rate 3 mL/min at a wavelength 220 nm to give two enantiomers. MS ESI calcd for C27H26N4O4S [M+H]+ 503. found 503.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[C:9]([NH:17][C:18]1[CH:27]=[C:26]([C:28]#[C:29][Si](C)(C)C)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:9]([NH:17][C:18]1[CH:27]=[C:26]([C:28]#[CH:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(C(=O)OC)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.68 g of potassium carbonate was added, to a solution of 17 mL of methanol and 17 mL of tetrahydrofuran containing 3.5 g of methyl 2-(benzamido)-4-(2-(trimethylsilyl)ethynyl)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 1.6 g of methyl 2-(benzamido)-4-ethynylbenzoate as white solid.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])C.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1>C1(C)C=CC=CC=1>[CH3:32][C:30]1[CH:29]=[C:28]([CH3:33])[N:27]=[C:26]([NH:25][C:4](=[O:17])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:6])[CH:31]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=O)C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
A solution of N-(4-nitro-phenyl)-oxalamic acid ethyl ester (4.9 g, 20.5 mmol), triethylamine (4.2 g, 41 mmol) and 2-amino-4,6-dimethylpyridine (2.5 g, 20.5 mmol) in dry toluene (30 mL) was heated at reflux overnight. The mixture was cooled to 0° C., and a precipitate was filtered and washed with water. Drying under vacuum afforded N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-oxalamide (4.8 g, 74%).
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.O=[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21](OCC)=[O:22].P(Cl)(Cl)(Cl)=O.O>C1(C)C=CC=CC=1>[OH:13][C:1]1[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]2[C:2]=1[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=1[C:21](=[O:22])[O:4]2
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CCCCCc1cc(O)cc(O)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 38 h
Yield: 43.8 %

Procedure:
Olivetol (49.5 g, 261 mmol) and ethyl 2-oxocyclohexanecarboxylate (47.7 ml, 285 mmol) were initially introduced in toluene and, after addition of 28.8 ml (310 mmol) of phosphoryl chloride, were stirred at room temp. for 38 h. The reaction mixture was slowly poured into 400 ml of water and stirred vigorously for 30 min. The precipitated yellow solid was filtered off and washed with water and toluene. The pale-yellow solid was taken up in hot ethyl methyl ketone, washed with aqueous saturated sodium hydrogencarbonate soln. solution and sat. sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo. Crystallisation of the crude product from acetonitrile/toluene gave 32.7 g (82%) of 1-hydroxy-3-pentyl-7,8,9,10-tetra-hydrobenzo[c]chromen-6-one as colourless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:4]=1[NH2:5].[BH4-].[Na+].[OH-].[Na+].[C:18](O)(=O)[CH2:19][CH3:20]>>[CH2:18]([NH:5][C:4]1[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])[CH2:19][CH3:20]
Reactant: CCC(=O)O
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1cc(C(=O)OC)ccc1OC
Reaction time: 2 h

Procedure:
15 g of 2-methoxy-5-methoxycarbonylaniline are dissolved in 500 ml of propionic acid under argon and at room temperature and 15.7 g of sodium borohydride are added in small portions. The reaction mixture is stirred for 2 hours and then hydrolyzed and alkalinized with 10 N sodium hydroxide while the temperature is maintained below 20° C. It is extracted with dichloromethane, the organic phase is washed with a saturated NaCl solution, dried and then evaporated under vacuum. The expected product is obtained in the form of an oil with a quantitative yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]>C1(C)C=CC=CC=1.Cl>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=3)[NH:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COCC(=O)Nc1cccc(-c2n[nH]c3ccc(C(N)=O)cc23)c1
Reaction time: 6 h
Yield: 40.5 %

Procedure:
Through a suspension of 3-[3-(2-methoxyacetylamino)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide in toluene (10 mL), HCl gas was bubbled for 20 min. After 6 hours at room temperature, the reaction was complete. The pH of the reaction mixture was neutralized using a saturated aqueous NaHCO3 solution before the solvent was removed under reduced pressure. The title compound was isolated as a white solid after purification by preparative HPLC (30–100% acetonitrile/water) (0.078 g, 40.5% yield): 1H NMR (CD3OD) δ 8.63 (dd, 1H), 8.19 (t, 1H), 7.94 (dd, 1H), 7.74 (td, 2H), 7.60 (dd, 1H), 7.49 (t, 1H), 4.06 (s, 2H), 3.49 (s, 3H); ES-MS (m/z) 325 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9](=[O:12])[CH:10]=[CH2:11])[CH2:4][CH3:5])[CH3:2].[CH2:13](OC(=O)C(C)=C)CCCCCCCCCCCCCCCCC.[CH3:37][O:38][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9](=[O:12])[C:10]([CH3:13])=[CH2:11])[CH2:4][CH3:5])[CH3:2].[CH3:37][O:38][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: C=CC(=O)OCCN(CC)CC
Reactant: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Agent: C=C(C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: C=C(C)C(=O)OCCN(CC)CC

Procedure:
A copolymer of 2-(N',N'-diethylamino)ethylmethacrylate, stearylmetacrylate, and methylmethacrylate was prepared by charging 0.048 mole of 2-(N',N'-diethylamino)ethylacrylate, 0.002 moles of stearylmethacrylate and 0.15 moles of methylmethacrylate in a retort containing 0.002 moles of AIBN. The retort had in accordance with Example 1 been gassed with nitrogen gas for half an hour before charging. The components were dissolved in dry benzene.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][OH:32])[CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:33]2[CH2:39][CH:38]3[N:40]([C:41](OC(C)(C)C)=[O:42])[CH:35]([CH2:36][CH2:37]3)[CH2:34]2)[C:9]=1[Br:48].Cl.[O:60]1CCOC[CH2:61]1>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][OH:32])[CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:33]2[CH2:34][CH:35]3[N:40]([C:41](=[O:42])[CH2:61][OH:60])[CH:38]([CH2:37][CH2:36]3)[CH2:39]2)[C:9]=1[Br:48]
Reactant: COc1ccc(-c2ccc(-c3cnn4c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c(Br)c(C5CC6CCC(C5)N6C(=O)OC(C)(C)C)nc34)cn2)cc1CO
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: COc1ccc(-c2ccc(-c3cnn4c(N)c(Br)c(C5CC6CCC(C5)N6C(=O)CO)nc34)cn2)cc1CO
Reaction time: 0.67 h

Procedure:
Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-(3-(hydroxymethyl)-4-methoxyphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (219 mg) was treated with 4N HCl in dioxane (4 mL) and water (1 mL) and the resulting mixture was stirred for 40 minutes, concentrated and lyophilized to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13]C(=O)C)(=[O:3])[CH3:2].Cl>C(O)C>[NH2:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(C)=O)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 8.2 %

Procedure:
To a solution N-(2-acetyl-6-nitro-phenyl)-acetamide (0.3 g, 13.5 mmol) in ethanol (5 mL), was added an aq. solution of 5 N HCl (4.5 mL) and the reaction mixture was heated to reflux for one hour. After completion of the reaction, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with a 10% aq. solution of sodium bicarbonate followed by water and dried over anhydrous sodium sulphate, then concentrated to dryness and purified by column chromatography using 15% ethyl acetate in hexane to get the title compound as yellow solid (0.20 g, 82.30%)
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:21]2[CH:20]=[C:19]([Cl:22])[N:18]=[CH:17][C:16]=2[CH:15]=[C:14]1[CH:23]([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:29]=[O:30])C>>[CH2:6]([N:13]1[C:21]2[CH:20]=[C:19]([Cl:22])[N:18]=[CH:17][C:16]=2[C:15]([CH:29]=[O:30])=[C:14]1[CH:23]([CH3:25])[CH3:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)c1cc2cnc(Cl)cc2n1Cc1ccccc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(C=O)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
POCl3 (0.31 ml, 3.42 mmol) was added to anhydrous DMF (5 ml) at 0° C. slowly and stirred for 20 min. To this solution was added a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (Compound 13, 195 mg, 0.68 mmol) in anhydrous DMF (7 ml) at room temperature. The mixture was stirred at room temperature for 2 h and was then heated to 60° C. for 2 h and 80° C. for 0.5 h. The reaction was cooled to room temperature, quenched cautiously with aqueous Na2CO3, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)c2c1C(=O)CCO2
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)c2c1CCCO2
Temperature: 100 °C
Yield: 44303.8 %

Procedure:
A solution of 8-fluoro-5-methyl-3,4-dihydro-2H-1-benzopyran-4-one (10b) (570 mg, 3.16 mmol) in acetic acid (4 mL) was added to a suspension of zinc dust (2.69 g, 41.1 mmol) in acetic acid (4 mL). The reaction mixture was heated at 100° C. for 5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite® and successively rinsed with ethyl acetate (10 mL) and toluene (10 mL). The filtrate was concentrated in vacuo to provide 8-fluoro-5-methyl-3,4-dihydro-2H-1-benzopyran (10c) (233 mg, 1.40 mol, 44%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1.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]>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: CN1CCNCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(N2CCN(C)CC2)ccc1O
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 48.8 %

Procedure:
1-(5-bromo-2-hydroxyphenyl)ethanone 1.0 g (4.65 mmol) in THF (10 ml), N-methylpiperazine 0.83 ml (7.45 mmol), LiHMDSA 16.2 ml (16.2 mmol), Pd2(dba)3 68 mg (0.074 mmol) and 2-dicyclohexylphosphino-2′-N,N-dimethylaminobiphenyl 29.3 mg (0.074 mmol) were combined under argon in a capped vial and stirred at 70° C. for 40 minutes. The volatiles were removed in vacuo, the obtained residue was dissolved with water and 1 N HCl (pH=6) and portioned with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM gradient to 10% MeOH/DCM) to provide 532 mg (51%) of desired product as a brown solid. LC/MS (254 nm) HPLC method 2 Rt 3.34 min. 1H NMR (401 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.21-7.28 (m, 2H), 6.80-6.93 (m, 1H), 2.98-3.10 (m, 4H), 2.63 (s, 3H), 2.44-2.48 (m, 4H), 2.23 (s, 3H). HRMS (ESI) calcd for C13H18N2O2 [M+H]+ 235.1441 Found 235.1448.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[Cl:28][CH2:29][C:30]#[N:31]>O>[Cl:28][CH2:29][C:30]1[N:31]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:7]2[C:6](=[CH:23][C:22]([O:24][CH3:25])=[C:21]([O:26][CH3:27])[CH:20]=2)[N:5]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: N#CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Powdered aluminium chloride (6.7 g) was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (8.0 g) and chloroacetonitrile (25 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. The solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (=10/1, v/v) gave 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline (4.9 g, 52%) which was then recrystallized from acetone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[C:4]([F:19])[CH:3]=1.[C:20](=[NH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Si:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:33]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:3][C:4]=2[F:19])[CH2:10][CH2:9]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1(c2ccc(Br)cc2F)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc(N=C(c3ccccc3)c3ccccc3)cc2F)CC1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
To a degassed suspension of (1-(4-bromo-2-fluorophenyl)cyclopropoxy)(tert-butyl)dimethylsilane (4.0 g, 11.59 mmol, 1.0 eq) in toluene (50 mL), was added BINAP (0.261 g, 0.347 mmol, 0.03 eq), benzophenone imine (2.1 g, 11.59 mmol, 1.0 eq) followed by Cs2CO3 (5.64 g, 17.38 mmol, 1.5 eq) in a sealed tube, then was added Pd2(dba)3 (0.138 g, 0.15 mmol, 0.013 eq) and the mixture heated to 100° C. for 8 h. The reaction mixture was diluted with EtOAc (120 mL), washed with water (25 mL×2), brine (25 mL) and dried over Na2SO4 and the solvent was evaporated under vacuum to get 4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-N-(diphenylmethylene)-3-fluoroaniline (4.8 g) crude product as a yellow oil (TLC system: EtOAc/PE (1:49), Rf: 0.75).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][C:26]1[O:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[CH3:25][C:26]1[O:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:33])=[O:32]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCN(C(=O)OC(C)(C)C)C4C)c(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,5-dimethyl-3-furansulfonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,5-dimethyl-3-furyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (19 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2 mg). MS m/z 361 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[Cl:13].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]1[CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1
Reactant: CC(C(=O)O)c1ccc(N)c(Cl)c1
Reactant: OC(CCl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N2CCC(O)C2)c(Cl)c1

Procedure:
To the solution of 2.0 g of α-(4-amino-3-chlorophenyl)propionic acid in 20 ml of ethanol, 1.4 g of 1,4-dichloro-2-butanol are added, followed by 4 g of potassium carbonate while stirring. The mixture is stirred for 4 hours at the steam cone and evaporated under reduced pressure. The residue is taken up in water, the solution acidified with N hydrochloric acid to a pH of 5.5 and extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the α-[3-chloro-4-(3-hydroxypyrrolidino)-phenyl]-propionic acid of the formula ##SPC9##
Reaction SMILES: C[N-:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7]>Cl>[NH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)=[O:7]
Reactant: C[N-]c1cccc(C(=O)C2CCN(C)CC2)c1
Agent: Cl
Product: CN1CCC(C(=O)c2cccc(N)c2)CC1
Yield: 75.6 %

Procedure:
A solution of 4-[3-(methylamidyl)benzoyl]-1-methylpiperidine (5.68 g, 21.8 mmol) in 6N hydrochloric acid (140 ml) was heated to reflux for 1.75 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (25 ml) and basified with concentrated ammonium hydroxide. The resulting precipitate and solution were chilled for 1 h, filtered, and dried under vacuum at room temperature for 16 h to give 3.6 g of a tan powder (76%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C(N)=O)cccc32)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C#N)cccc32)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of tert-butyl 4-[(7-carbamoyl-2,3-dihydro-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate in DCM (80 mg, 0.22 rnmol) was added Et3N (60 mg, 0.59 mmol). The solution was cooled to 0° C. and TFAA (60 mg, 0.29 mmol) was added dropwise under nitrogen. After 4 hours stirring at room temperature, the solvents were removed under vacuum to give the crude product tert-butyl 4-[(7-cyano-2,3-dihydro-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate (66 g, yield 87%) which was used for next step without purification.