Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[NH2:13][CH2:14][CH:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1.[BH4-].[Na+]>CO.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:13][CH2:14][CH:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2cccc([N+](=O)[O-])c2)cc1OC

Procedure:
m-Nitrobenzaldehyde (1.8 g) was added to a suspension of α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride in 25 ml methanol, triethylamine (2.8 ml) was further added dropwise at room temperature with stirring, and the resulting solution was heated under reflux for 30 minutes. After cooling, sodium borohydride (1.45 g) was added in small portions with stirring under ice cooling, and the mixture was stirred at room temperature for one hour and concentrated. The residue was treated with chloroform and water, and the chloroform layer was collected, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ether/n-hexane, affording 3.3 g of pure α-[(3-nitrobenzylamino)methyl]-3,4-dimethoxybenzyl alcohol, m.p. 105°-107° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4ccccc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), and 2-hydroxynaphthalene (40 mg, 0.28 mmol) in DMF (1.5 ml) containing potassium carbonate (48 mg, 0.35 mmol) was stirred at 100° C. for 3.5 hours. After cooling, methylene chloride (4.5 ml) was added and the mixture was poured onto a column of silica (SiO2 Isolute®) and eluted with, successively, methylene chloride, methylene chloride/methanol (9/1), methylene chloride/methanol/3M ammonia in methanol (75/20/5). The fractions containing the product were evaporated under vacuum. The residues was triturated with ether, filtered and dried under vacuum to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline (80 mg, 83%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:31]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-4-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane e (example B.c2) the title compound is obtained as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 24.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 2,2-dimethyl-propylamine (34.2 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propyl)-amide (24.6 mg, 24.6%).
Reaction SMILES: C(OCCO)C.[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18](Cl)[N:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Zn].O>[CH2:7]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)[CH2:14][CH2:15]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#N)c(Cl)n2)CC1
Agent: [Zn]
Solvent: CCOCCO
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(C#N)cn2)CC1

Procedure:
2-Ethoxyethanol (200 ml), water (40 ml) and zinc powder (20 g) were added to 2-(trans-4-n-propylcyclohexyl)-5-cyano-6-chloropyridine (17.0 g) of Example 6, followed by heating the mixture under reflux for 28 hours, cooling, thereafter filtering, adding toluene (200 ml) and water (500 ml) to the filtrate, stirring, still standing, separating the toluene layer, twice washing it with water, and carrying out the same procedure as in Example 11 to obtain the objective 2-(trans-4- n-propylcyclohexyl)-5-cyanopyridine (5 g). C-N point: 47.6° C. N-I point: 51.9° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:7](=[O:27])[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4].[C:40]([O:44][C:45]([NH:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:40]([O:44][C:45](=[O:46])[NH:47][C:48]([C:49](=[O:50])[NH:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:12](=[O:13])[NH:14][CH3:15])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:7](=[O:27])[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4])([CH3:53])[CH3:52])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (44 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (44 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford 45 mg (93% yield) of the desired product. MS (ESMS) m/z 716.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[NH2:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1ccc(O)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1N
Temperature: 15 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To a solution of 95% NaH (1.82 g, 72.30 mmol) in DMF (100 mL) at 10° C. was added 2-amino-4-hydroxybenzamide (10.0 g, 66.72 mmol) in portions, maintaining the internal temperature at ca. 15° C. The cooling bath was removed, and the solution was allowed to warm to 40° C. over 25 min. The mixture was cooled to 10° C. and a solution of benzyl bromide (7.8 mL, 66.72 mmol) in DMF (20 mL) was added dropwise, and the mixture was allowed to warm to rt. After stirring for 20 h at rt, the mixture was cooled in an ice bath and quenched by addition of aq ammonium chloride. The solution was concentrated and diluted with water. The precipitate was collected by filtration, and the filtrate was extracted with EtOAc. The precipitate from above and the ethyl acetate extracts were combined and chromatographed on silica gel eluting with 20-80% EtOAc/DCM to afford 2-amino-4-(benzyloxy)benzamide as a solid (6.8 g, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.04 (s, 2 H) 6.14 (dd, J=8.76, 2.54 Hz, 1 H) 6.27 (d, J=2.64 Hz, 1 H) 6.71 (bs, 2 H) 7.26-7.58 (m, 6 H). LC-MS (ESI) m/z 243 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: ClCCCOC(CCCc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCCC(OCCCN2CCOCC2)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 1.5 g of 1-(3-chloropropoxy)-1,4-diphenylbutane, 7 ml of morpholine, 1.5 g of potassium carbonate and 15 ml of dimethylformamide was heated at 100° C. for 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel to give 1-(3-morpholinopropoxy)-1,4-diphenylbutane. M.P., 138°-139° C. (oxalate).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]=[CH:21][N+:22]([O-])=O)=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2.O>CCOCC>[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH2:20][CH2:21][NH2:22])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2
Reactant: COc1cc(C=C[N+](=O)[O-])c2c(c1OC)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CCN)c2c(c1OC)CCC2
Reaction time: 4 h
Yield: 85.6 %

Procedure:
To a slurry of 15.0 g (0.395 mole) of LiAlH4 and 500 ml of anhydrous ether in a 5 liter, 3-necked flask fitted with a condenser, mechanical stirrer and dropping funnel was added 20.0 g (0.084 mole) of 4,5-dimethoxy-7-nitrovinylindane dissolved in 2 liters of ether. The addition was made over a period of about 4 hours while refluxing the ether slurry. When the addition was completed, refluxing was continued for an additional 1 to 2 hours. After the addition of 20 g of diatomaceous earth and then 70 ml of water slowly, dropwise, with cooling in an ice bath, the supernatant ether was decanted, the salts were washed with fresh ether several times followed by decantation and finally filtration. The solvent was removed by distillation and more thoroughly on a rotary evaporator. Cooling in an ice bath gave 15.91 g (90 percent) of 4,5-dimethoxy-7-aminoethylindane as a slightly yellow solid, m.p., 45°-48° C. High vacuum distillation gave an analytical sample.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH:10]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:27]=[O:28])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C=O)cc(C(C)C)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-bromo-3-isopropyl-5-methoxy-benzene (1.06 g, 4.63 mmol) in dry THF (10 mL) was cooled to −78° C. under nitrogen atmosphere. A 1.6 M solution of nBuLi in hexane (2.9 mL, 4.63 mmol) was added at once, followed within 1 min by DMF (0.356 mL, 4.63 mmol). After 1 min the mixture was poured onto 10 mL 1N aq. HCl, stirred for 5 min and extracted with TBME. The organic phase was washed with brine, dried with MgSO4 and evaporated to give the title compound sufficiently pure for further use: TLC (AcOEt-hexane 1:9) Rf=0.40; HPLC RtH1=2.97 min; ESIMS [M+H]+=179; 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.05 (s, 1H), 3.85 (s, 3H), 2.96 (heptet, 1H), 1.29 (d, 6H).
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH3:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH2:9][CH2:8][O:7][CH3:6])[CH3:24])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:13]=1)[CH3:18]
Reactant: COCCN(C)c1ccc(C(C)=O)cc1C(F)(F)F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COCCN(C)c1ccc(C(C)N)cc1C(F)(F)F
Yield: 26.9 %

Procedure:
Ammonium acetate (1.53 g, 19.8 mmol) was added to a solution of the compound from step 1 (545 mg, 1.98 mmol) in MeOH (8 mL). After stirring at RT overnight sodium cyanoborohydride (149 mg, 2.38 mmol) was added and the reaction was refluxed for 6 h. The solvent was evaporated and the solid, redissolved in ethyl acetate, was extracted with water. The organic layer was separated, washed with brine, dried over sodium sulphate, filtered, evaporated and purified by preparative HPLC. The relevant fractions were lyophilized to give 147 mg (yield: 19%) of the pure product.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20](O)=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].Cl.CN(C)CCCN=C=NCC.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC2(C(=O)NS(C)(=O)=O)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 144 h
Yield: 87.7 %

Procedure:
A 30 mL vial is charged with 2-[(2-cyclobutoxy-3-methyl-benzoyl)-amino]-indan-2-carboxylic acid (245 mg, 0.67 mmol) and dry DCM (5.0 mL). A stirring bar is added and stirring is initiated. The methanesulfonamide (89 mg, 0.936 mmol) is added. To the resultant suspension, (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (120 mg, 0.624 mmol) and 4-dimethylaminopyridine (76 mg, 0.62 mmol) are added. After 6 days, tlc analysis (silica, 10% MeOH in DCM) indicates that the starting acid is consumed. The reaction mixture is diluted with EtOAc (50 mL), transferred to a separatory funnel and washed with dilute aqueous HCl (3 N, 3×20 mL) and brine, dried over MgSO4, filtered and evaporated by pumping to constant weight gives 0.26 g of amorphous white foam. This material is dissolved in DCM (5 mL) and applied to a 12 g column (silica) on an ISCO Companion. The column is eluted with 1% iPrOH in DCM for 3 column volumes followed by a linear gradient to 30% iPrOH in DCM over 15 column volumes. 12 mL fractions of UV active eluent are collected. Fractions 4 through 9 are combined and evaporated to a constant weight to give 0.2 g of white solid.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (22%); 1H NMR (d6-DMSO) δ 12.31 (br s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.39–7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 527 (M−H−).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[N:6]=1)=O.[BH4-].[Na+]>CO>[CH3:12][O:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0° C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0° C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3×, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30%) as an oil. MS M+H calculated 140.1. Found 140.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][NH:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:14]=1)=[C:5]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: NCCN1CCOCC1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CNCCN2CCOCC2)no1
Yield: 37 %

Procedure:
From 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde and 2-morpholin-4-yl-ethylamine according to procedure 24. Yield 37%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1>[F:37][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C)c1ccc2ncccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(F)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of methyl 2-(quinolin-6-yl)propanoate (0.868 g, 4.03 mmol) in THF (1.1M, 3.7 mL) at −78° C. was added LiHMDS (1M in THF) (5.24 ml, 5.24 mmol). The reaction was stirred at −78° C. for ˜15 minutes, then to it was added a solution of N-fluorobenzenesulfonimide (1.40 g, 4.44 mmol) in THF (1.0M, 4.5 mL). The reaction was allowed to warm to −10° C. over 2 h. The reaction was filtered through a plug of Celite, washed with EtOAc and the filtrate was then concentrated in vacuo. The concentrated material was rediluted with EtOAc and washed with saturated NH4Cl solution. The aqueous layer was then extracted with EtOAc, and the organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with isocratic 40% EtOAc:Hexanes to yield methyl 2-fluoro-2-(quinolin-6-yl)propanoate (0.709 g, 75.4% yield) as a yellow oil. To synthesize the corresponding acid, methyl 2-fluoro-2-(quinolin-6-yl)propanoate was saponified in a method similar to that of 2-(quinolin-6-yl)propanoic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2.[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc3ccccc3c(=O)n2n1
Yield: 70.9 %

Procedure:
2-Chloro-10H-pyridazino[3,2-b]quinazolin-10-one (2.3 g) and sodium methoxide (1.1 g) in 100 ml of methanol was heated at 60° C. for 5 hours. After completion of the reaction, the solvent was removed by distillation, followed by addition of an aqueous solution of acetic acid. The precipitates were collected by filtration and recrystallized from methanol to give 1.6 g of 2-methoxy-10H-pyridazino[3,2-b]-quinazolin-10-one (Compound No. 1). M.P., 222.5°-223.0° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CN(CCNCc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
128 g (0.7 mol) of the compound obtained in Step b dissolved in 600 ml of ethanol are added dropwise to 150 g ( 1.4 mol) of benzylamine diluted in 200 ml of warm ethanol. The mixture is stirred at room temperature for 24 hours and the solvent is evaporated off in vacuo. Benzylamine hydrochloride crystallises from a mixture of methylene chloride and acetone, and is removed by filtration. The tiltrates are saturated with gaseous hydrogen chloride and the hydrochloride of the desired compound crystallises from a methylene chloride/ether mixture. 105 g of white crystals are obtained.