Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CN(C)CC(=O)O
Product: COc1cc(OC[C@@H]2CCCN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 73 %

Procedure:
The procedure described in Example 1 was repeated using N-(3-chloro-4-fluoro-phenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (96 mg) and N,N-dimethylglycine (27 mg) to give the title compound as a white solid in 73% yield; NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.40 (s, 1H), 8.15 (dd, 1H), 7.72-7.62 (m, 1H), 7.40 (t, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.66-4.58 (m, 1H), 4.40 (dd, 1H), 4.19 (dd, 1H), 3.90 (s, 3H), 3.66-3.40 (m, 2H), 3.20-3.06 (m, 2H), 2.40 (s, 6H), 2.10-1.82 (m, 4H); MH+ 488.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[CH2:4][C@H:3]1[OH:10].C(N(CC)CC)C.O=C1CCC(=O)N1[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26]>O1CCOCC1.O.C(OCC)(=O)C>[OH:10][C@@H:3]1[CH2:4][C:5]([CH3:9])([CH3:8])[O:6][CH2:7][C@H:2]1[NH:1][C:25](=[O:26])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC1(C)C[C@@H](O)[C@H](N)CO1
Reactant: C[Si](C)(C)CCOC(=O)N1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H](O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
To a solution of (4R,5R)-5-amino-2,2-dimethyl-tetrahydro-2H-pyran-4-ol (550 mg, 2.40 mmol) and triethylamine (484 mg, 4.80 mmol) in dioxane (5 mL) and water (5 mL) was added 2-(trimethylsilyl)ethyl 2,5-dioxopyrrolidine-1-carboxylate (750 mg, 2.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After that, the solution was diluted with ethyl acetate and washed with brine. The organic layer was concentrated, and the residue was purification by silica gel column with petroleum ether/ethyl acetate=4/1 to 1/1 to afford the title compound (360 mg, 52% for 2 steps) as a gray solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:3]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19]>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=3)[CH:7]=[CH:6][N:5]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(CCNc2nccc(Cl)n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 61 was coupled with 3-acetyl phenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 334.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([NH2:9])[CH3:8])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([C:19](O)=[O:20])=[CH:17][CH:18]=1)=[O:13]>>[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([C:19](=[O:20])[NH:9][CH:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:8])=[CH:17][CH:18]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(N)c1ccc(Br)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(Br)s2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 1 from 1-(5-bromo-thiophen-2-yl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2ccccc2o1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccccc5o4)cc3CC[C@@H]12
Yield: 45.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chlorobenzoxazole (71 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 65 mg (45%) of the title compound as an amorphous foam. FDMS: m/e=78.
Reaction SMILES: II.C([Mg]Br)(C)C.[Li]CCCC.[C:13]([O:17][C:18](=[O:42])[C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22](Br)=[C:21]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C([Cu])#N.[Li+].[Cl-].Br[CH2:49][C:50]([CH3:52])=[CH2:51]>C1COCC1>[C:13]([O:17][C:18](=[O:42])[C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([CH2:51][C:50]([CH3:52])=[CH2:49])=[C:21]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=C(C)CBr
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Br
Agent: II
Solvent: C1CCOC1
Product: C=C(C)Cc1c(OCc2ccccc2)cc(C(=O)OC(C)(C)C)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a suspension of Mg pieces (7.9 g, 0.23 mol) in THF (250 mL) was added a catalytic amount of I2, followed by addition of i-PrMgBr (15 mL, 0.16 mol) drop wise. The mixture was heated slowly until refluxed violently. After stirring for 2 hr, the resulting mixture was added to THF (200 mL) and cooled to 0° C. n-BuLi (128 mL, 2.5 M in hexane, 0.32 mol) was added drop wise at 0° C. The mixture was cooled to −78° C. and 3,5-bis-benzyloxy-4-bromo-benzoic acid tert-butyl ester (200c) (50 g, 0.107 mol) was added drop wise. After the mixture was stirred for 1 hr, CuCN (2.85 g, 0.032 mol), LiCl (2.7 g, 0.064 mol), and 3-bromo-2-methyl-propene (43 mL, 0.43 mol) were added sequentially. After stirring for another 30 min at −78° C., TLC (EtOAc/petroleum ether=1/10) showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl (150 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the title compound as a yellow oil (40 g, 84.4% yield).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:17].[C:25]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C.C(Cl)Cl>[CH2:3]([N:4]1[CH2:5][CH2:6][C@@:7]23[C:8]4[C:9]5[CH2:22][C@@H:21]1[C@:20]2([OH:23])[CH2:19][CH2:18][C:16](=[O:17])[C@@H:15]3[O:14][C:13]=4[C:12]([O:24][CH3:25])=[CH:11][CH:10]=5)[CH:2]=[CH2:1]
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of naloxone (50 g, 125 mmol) in 50 mL of DMF was added K2CO3 (51.8 g, 375 mmol). The resulting suspension was stirred at ambient temperature for 30 min whereupon methyl iodide (7.82 mL, 125 mmol) in 7 mL of DMF was added dropwise via an addition funnel. The suspension was maintained overnight at ambient temperature. The reaction mixture was added to 1 L of H2O and a white precipitate formed. The mixture was stirred for 1 h then filtered to give a white solid. The solid was dissolved in CH2Cl2 (700 mL) and washed with 1 N NaOH (400 mL). The layers were separated and the organic layer was concentrated to give a wet solid. Water was added and the solid was subsequently filtered and dried overnight in a vacuum oven to afford 28.1 g (66%) of Compound 2 as a white solid. LC/MS, m/z=342.2 [M+H]+ (Calc: 342.40).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.S(C1C=CC(C)=CC=1)(O[CH2:12][C@@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1)(=O)=O>CN(C)C=O>[CH3:29][N:15]1[C@H:16]2[C@@H:26]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:28]=3[C:18]([CH2:17]2)=[CH:19][NH:20]4)[CH2:27][C@@H:13]([CH2:12][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2cccn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
0.7 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.5 g of pyrazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.5 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration, washed with water and recrystallized from dichloromethane-isopropyl ether to obtain 1.7 g of the titled compound as colorless flakes having a melting point of 192°-194° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7][C:6]=2[C:5]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:4][CH:3]=1.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+:66]([C:69]1[CH:70]=[C:71]([CH3:78])[CH:72]=[CH:73][C:74]=1[C:75](Cl)=[O:76])([O-:68])=[O:67].C([O-])(=O)C.[Na+].Cl>O.CCOCC>[N+:66]([C:69]1[CH:70]=[C:71]([CH3:78])[CH:72]=[CH:73][C:74]=1[C:75]([NH:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7][C:6]=2[C:5]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:4][CH:3]=1)=[O:76])([O-:68])=[O:67]
Reactant: Cc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c([N+](=O)[O-])c1
Yield: 872.9 %

Procedure:
To a stirred solution of 22.5 g of 8-amino-1,3,5-naphthalenetrisulfonic acid, trisodium salt in 160 ml of water is added 11.0 g of the preceding product with a small amount of ether. Stirring is continued, and after one hour 1.0 g of sodium acetate trihydrate and 1.0 g of 3-nitro-p-toluoyl chloride are added. The mixture is stirred an additional 3 hours and the above addition of sodium acetate and 3-nitro-p-toluoyl chloride is repeated. The mixture is stirred an additional hour, acidified to Congo Red indicator paper with hydrochloric acid and filtered. The filtrate is neutralized with sodium hydroxide, concentrated, dissolved in 50 ml of water and added to one liter of ethanol with stirring for 16 hours. The solid is filtered and forms a gel on washing with ethanol. The gel is dissolved in water and evaporated. The residue is dissolved in 35 ml of hot water and 320 ml of absolute ethanol is added with stirring. The mixture solidifies and water is added to allow filtration. The solid is washed with ether and dried in vacuo. The filtrate is treated by stirring with one liter of ethanol, the separated solid is collected, washed with ether, and dried to yield a combined total of 23.9 g of 8-(3-nitro-p-toluamido)-1,3,5-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][S:32][C:28]=2[CH:27]=1>>[S:32]1[C:28]2[CH:27]=[C:26]([NH:25][C:21]([C:20]3[CH:24]=[C:16]([N:14]4[CH2:15][C@@H:10]5[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C@@H:11]5[CH2:13]4)[CH:17]=[N:18][CH:19]=3)=[O:22])[CH:34]=[CH:33][C:29]=2[N:30]=[CH:31]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Nc1ccc2ncsc2c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4ccc5ncsc5c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 6-aminobenzothiazole were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 466 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[N:12][C:6]2[S:7][CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1>[O-2].[O-2].[Mn+4]>[O:11]=[C:9]1[CH2:8][S:7][C:6]2[N:12]=[CH:13][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:10]1
Reactant: O=C1CSc2ncc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cnc2c(c1)NC(=O)CS2
Yield: 58 %

Procedure:
The alcohol (d) (1.22 g) was oxidised with manganese dioxide by the method of Example (1j) to afford a solid (0.7 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:8]([C:10]1[N:18]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]2)=[C:12]([C:19]([O:21]CC)=[O:20])[C:11]=1[CH3:24])=[O:9].CC1C(C(OCC)=O)=C2N(C=1)C=CC=C2>O1CCOCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:8]([C:10]1[N:18]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]2)=[C:12]([C:19]([OH:21])=[O:20])[C:11]=1[CH3:24])=[O:9]
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2ccccc12
Agent: CCOC(=O)c1c(C)cn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2c(C)c(C(=O)O)c3ccccn23)ccc1[N+](=O)[O-]
Yield: 105.6 %

Procedure:
26.2 ml of 1 N sodium hydroxide are added to 5 g (13.1 mmol) of ethyl 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarboxylate, a compound of Example 13—prepared according to the procedure of Example 1 by benzoylation of ethyl (2-methylindolizin-1-yl)carboxylate described in J. Chem. Soc., (1963), pp. 3277-3280-, in suspension in 50 ml of dioxane, and the medium is heated under reflux for 17 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water, washed with ethyl ether, and the medium is separated after settling out. The aqueous phase is acidified to pH 6 with a potassium hydrogen sulphate solution and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. 4.9 g of an orange-coloured powder are obtained.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]2=3)[CH2:6]1.[OH-].[Na+].Cl>C(O)C>[CH:24]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]([CH2:12][CH2:11][CH2:10][N:7]3[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([OH:28])=[O:2])[CH2:6]3)[C:14]=2[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Reaction time: 72 h
Yield: 5 %

Procedure:
The above ester (0.85 g, 0.0022 mol) was dissolved in ethanol (6 ml) and 0.5N NaOH was added. By continued addition of 0.25N NaOH pH was kept at approximately 12 for 3 days. Dilute HCl (approx. 1N) was added until pH=7, and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (50 g) using a mixture of dichloromethane, methanol and acetic acid (20:2:1) as eluent. The product fractions were stripped with dichloromethane, affording 0.04 g (3.8%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid as an amorphous product.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][C:10](=[O:12])[C:9]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([CH:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(Cc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A solution of (RS)-3-benzyl-2,2-dichlorocyclobutanone (0.3 g. 1.3 mmol) in acetic acid (3 ml) was refluxed for 1 hour in the presence of zinc (0.86 g, 13.1 mmol. powder). The reaction mixture was cooled to room temperature and filtered over decalite. The filtrate was neutralized with saturated NaHCO3. The organic phase was washed successively with H2O and brine, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 4:1) to provide 3-benzyl-cyclobutanone (0.16 g, 76%) as a colorless oil, MS: m/e=160.2 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C([Li])CCC.CCCCCC.[CH2:20]([O:24][C:25]1[C:29](S(C)(=O)=O)=[N:28][S:27][N:26]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:20]([O:24][C:25]1[C:29]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[N:28][S:27][N:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CN1CCC[C@H]1CO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC[C@@H]1CCCN1C

Procedure:
A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115-116° C. (Compound 31).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[N:6][CH:7]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[CH3:14][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH2:8][O:9][CH3:10])[N:4]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COCc1ncc(Br)c(C(=O)O)n1
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COCc1ncc(Br)c(C(=O)OC)n1
Yield: 26.5 %

Procedure:
To a solution of 5-bromo-2-methoxymethyl-pyrimidine-4-carboxylic acid (2.5 g, 10.1 mmol) in acetone (100 ml) was added Cs2CO3 (19.8 g, 60.7 mmol) followed by methyliodide (3.8 ml, 60.7 mmol). The mixture was heated to reflux for 8 h. The reaction mixture was then filtered, and the filtrate was evaporated. The crude material was purified by silica gel chromatography using a ethyl acetate/hexane eluent to yield 700 mg (27%) of the title compound as yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([OH:7])=O.[CH2:16]([NH:18][CH3:19])[CH3:17]>ClCCl>[CH2:16]([N:18]([CH3:19])[C:5](=[O:7])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH3:17]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCNC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(C)C(=O)c1ccc(C=O)cc1
Reaction time: 8 h
Yield: 37.7 %

Procedure:
Thionyl chloride (26 mL, 0.36 mol) was added dropwise to a solution of 4-carboxybenzaldehyde (50.0 g, 0.33 mol) in 2000 mL of dichloromethane:N,N-dimethylfonamide (4:1 mixture). The mixture was stilTed overnight at room temperature. Ethylmethylamine (75.0 g, 1.3 mol) was added dropwise, and stirring was continued at room temperature for 90 minutes. The solvent was removed under vacuum, the residue was dissolved in 500 mL of 0.1M sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum to give 23.8 g (38%) of N-ethyl-4-formyl-N-methylbenzamide as a yellow oil.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[F:17])([CH3:4])([CH3:3])[CH3:2].C[Li].[CH3:22][Si](C)(C)Cl>C1COCC1.C(OCC)C>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:14])[CH3:22])=[CH:10][C:9]=1[F:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)O)cc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)(C)O[SiH2]C(C)(C)C)c(F)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 540 mg (1.90 mmol) 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid (preparation 16d) in 20 mL THF is degassed and cooled to −30° C. 3.56 mL (5.67 mmol) 1.6 M methyl-lithium solution in diethylether is added, the mixture is stirred 2 h at −30° C. and 3.12 mL (24.7 mmol) trimethyl-chloro-silane are added. The mixture is stirred 2 min and is transferred to a pH 7 buffer solution (0° C.). The aqueous phase is extracted with EtOAc and diethylether. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (9:1) as eluent.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1cccc(N)n1)c1ccc(OCC(F)(F)F)nc1
Yield: 28 %

Procedure:
The title compound is prepared in 28% yield (75 mg, slight brown syrup) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.78 mmol, Amine-1, single enantiomer) and 6-aminopicolinic acid (108 mg, 0.78 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[CH2:11][CH2:10][CH2:9]2.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=4)[CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCC3)N=C(N)OCC2(F)F)nc1
Yield: 38 %

Procedure:
The condensation of (R)-5′,5′-difluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazine]-2′,7-diamine (intermediate A7.1) and 5-cyanopicolinic acid yielded the title compound (38% yield) as a white solid. MS (ISP): m/z=398.2 [M+H]+.