Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.C([NH:34][CH2:35][CH2:36][OH:37])C1C=CC=CC=1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:34][CH2:35][CH2:36][OH:37])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Reactant: OCCNCc1ccccc1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCNCCO)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with 2-(benzylamino)ethanol, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.79 (2H, t), 3.17 (2H, t), 3.55 (2H, t), 4.20 (2H. t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.17 min; m/z (ES+) 404.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][O:19][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(CCO)CC2)COC1(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(CCOCc3ccccc3)CC2)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15.1 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[1-(2-hydroxyethyl)cyclopropylmethyl]-1,3-oxazolidine are dissolved in 50 ml of tetrahydrofuran, and 14.2 g of a potassium hydride suspension (20% in oil) are added at 0° C. The mixture is stirred at 0° C. for 1 h and 6.3 ml of benzyl bromide are then added dropwise, while stirring. After 90 min., 100 ml of water are slowly added to the reaction mixture and the aqueous phase is extracted with diethyl ether. This gives the title compound: Rf (A)=0.8; FAB-MS: (M+H)+ =390.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(OCC)(=O)C.ClCCl>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccccn1
Yield: 14.8 %

Procedure:
Heat a mixture of ethyl 3-aminoindole-2-carboxylate (250 mg, 1.2 mmol) and 2-bromopyridine (1.0 mL, 10 mmol) at 150° C. for 1 h. Cool the reaction and partition between aqueous ammonium chloride and ethyl acetate. Separate the organic layer and concentrate to afford a crude mixture. Flash chromatograph the mixture on silica gel eluting with 25% ethyl acetate/dichloromethane to afford 50 mg of the title compound: MS 282(M+H).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[N:39]1([C:36]2[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]3[N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=4)=[O:30])=[CH:38][CH:37]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCCC2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 87 %

Procedure:
0.28 ml (1.68 mmol) of diethyl cyanophosphonate is added, dropwise, at 20° C. under argon, to a solution of 0.402 g (1.4 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and of 0.274 g (1.68 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridine (WO 02/48152) in 10 ml of dry dimethylformamide. The mixture is stirred for ten minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours, concentrated under reduced pressure, and then taken up with 50 ml of ethyl acetate. This solution is then successfully washed with three times 20 ml of a saturated sodium hydrogen carbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained is triturated in isopropylether under hot conditions. 0.527 g of a solid is obtained, which solid is dried under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:20][CH2:21]3)[NH:8][C:4]=2[CH:3]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1

Procedure:
The 5-bromo-2-chloro-1H-benzoimidazole (0.115 g, 0.5 mmol, Example 23b), 1-(3-chloropyridin-2-yl)piperazine (0.198 g, 1 mmol, Example 3b) and N,N-diisopropylethylamine (0.35 mL, 2 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 207-208° C. MS (ESI, pos. ion) m/z: 394 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CCCCCC>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (100 mg, 0.37 mmol) and p-chlorobenzoyl chloride (52 μl, 0.41 mmole) were combined at room temperature in 5 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give 150 mg of crude product. Chromatography on silica gel (chloroform - methanol - ammonia, 95:5:0.5 v/v) and trituration with hexane yielded the analytical product as a white powder, m.p. 258°-259° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 44 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 44% of theory, C26H26N6O4 (486.5); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=487; (M+2H)++=244; (M+H+Na)++=255.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25]C(=O)OC(C)(C)C)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:33]
Reactant: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2-methylpyridin-4-ylboronic acid (327 mg, 2.39 mmol), (S)-tert-butyl 1-(3-bromo-5-chlorophenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (542 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (345 mg, 0.30 mmol), cesium fluoride (544 mg, 3.58 mmol) were added to a vial then DME (4778 μl, 1194 μmol) was added and the mixture was heated to 85° C. for 8 h. The reaction was loaded and purified on Phenomenex Geminni C18 HPLC 50 mm×250 mm running ACN/Water/0.1% TFA in a linear gradient. The fractions containing the desired product were combined and concentrated to afford tert-butyl (S)-1-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (367 mg, 66% yield). tert-butyl (S)-1-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (367 mg, 0.78 mmol) was dissolved in DCM (3 mL) and TFA (1 mL) add stirred for 3 h. The solution was concentrated to afford (2S)-2-amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenylpropanamide (280 mg, 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: Cc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cc1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and p-tolylamine according to procedure A followed by deprotection yielded the title compound as an off white solid. MS (ESI): m/z=369.2 [M+H]+.
Reaction SMILES: [Cl-].C[Al+]C.CCCCCC.[CH3:11][C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]([CH3:22])=[CH2:21])[C:14]([CH3:24])([CH3:23])[CH:13]=1.[CH:25](=[O:28])[CH2:26][CH3:27]>ClCCl>[CH2:26]([CH:25]([OH:28])[CH2:21][C:20](=[CH2:22])[CH:15]1[C:16]([CH3:18])([CH3:19])[CH2:17][C:12]([CH3:11])=[CH:13][C:14]1([CH3:24])[CH3:23])[CH3:27]
Reactant: C=C(C)C1C(C)(C)C=C(C)CC1(C)C
Reactant: CCC=O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C(CC(O)CC)C1C(C)(C)C=C(C)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Dimethylaluminum chloride (60 mL of a 1 M hexane solution) was added dropwise to a solution of 1,3,3,5,5-pentamethyl-4-(1-methylethenyl)-1-cyclohexene (7.70g, 0.04 mol) and propionaldehyde (2.30g, 0.04 mol) in dichloromethane (150 mL) at 25°-30° C. over a 15 min period. The mixture was stirred at 25° C. for 16h. Work-up (as described in Example 2) and chromatography provided 2.20g of α-ethyl-2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol, bp (kugelrohr bath) 125° C., 0.5 mm, (GLC purity, two isomers, 40.7% and 57.9%). 1H-NMR (60 MHz, CDCl3) δ0.98 and 1.03 (12H, 2s), 1.02 (3H, t, J =4 Hz), 1.63 (3H, s), 1.1-2.6 (8H, m), 3.5-3.9 (1 H, m), 5.0-5.3 (3H, broad s); IR (film) vmax 3350, 2950, 1640, 1460, 1380, 1360 cm-1 ; MS m/e 250, 235, 217, 125, 107, 96. The mass spectra of the diastereomers were nearly identical.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: Nc1ncnc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)Oc1c(N)ncnc1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
A reaction mixture of 4-Amino-6-chloro-pyrimidin-5-ol (500.00 mg; 3.44 mmol; 1.00 eq.), Cs2CO3 (2238.59 mg; 6.87 mmol; 2.00 eq.), and 2-Iodo-propane (1167.95 mg; 6.87 mmol; 2.00 eq.) in acetone 10 ml was stirred at 65° C. for 3 hr, desired as major, also found dialkylation by product, removed off solvent, treated with ethyl acetate, solid came out, filtered, washed with ether, collected product 6-chloro-5-isopropoxypyrimidin-4-amine 160 mg, yield 24.8%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][C:32]1[O:33][C:34]([CH:38]=[O:39])=[C:35]([CH3:37])[N:36]=1>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:38]([C:34]3[O:33][C:32]([CH3:31])=[N:36][C:35]=3[CH3:37])[OH:39])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C)c(C=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.5 g, 3.48 mmol, Intermediate 5: step d) was added THF (65 mL) and the solution was cooled to −70° C. n-BuLi (2.5 M in hexanes, 1.62 mL, 4.04 mmol) was then added dropwise. After 2 minutes, 2,4-dimethyloxazole-5-carbaldehyde (520 mg, 4.16 mmol in 3 mL THF) was introduced. After 25 minutes the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (10% CH3CN-DCM increasing to 30% CH3CN+1% MeOH) provided the title compound as a white amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][CH:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[C:10]1([C@H:9]([NH:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CBr
Reactant: CC(N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)CN[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R) α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g; 24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate/pentane) to provide the title compound (3.2 g, 63% yield). MS (DCI/NH3) m/z 208 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]CC=C)[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].C(OCC)(=O)C.Cl[C:25]1[CH:30]=CC=C[C:26]=1Cl>CCCCCC>[OH:14][C:13]1[C:12]([CH2:30][CH:25]=[CH2:26])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)cc1CC=C
Reactant: Clc1ccccc1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Yield: 97 %

Procedure:
The product of Step A (3.2 g, 13.8 mmol) was refluxed in 1,2-dichlorobenzene for 3 days in the presence of a catalytic amount of BHT (10 mg). Flash column chromatography of the mixture using hexane and then 10% and 20% ethyl acetate in hexane afforded 3.1 g (97%) of the title compound.
Reaction SMILES: ClC(Cl)C.[CH3:5][N:6]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][C:14](=[O:17])[C:13]3=[O:18])=[C:8]2[CH2:7]1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:17]=[C:14]1[CH:13]2[O:18][CH2:27][CH2:28][O:29][C:11]3=[C:12]2[C:16](=[C:8]2[CH2:7][N:6]([CH3:5])[CH2:20][CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:9]2=[CH:10]3)[NH:15]1
Reactant: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: O
Product: CN1Cc2c(cc3c4c2NC(=O)C4OCCO3)C(c2ccccc2)C1

Procedure:
100 ml of dichloroethane are added to 20.6 g (0.0624 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione, 21 ml (0.374 mol) of ethylene glycol and 0.336 g (0.00176 mol) of toluene-4-sulphonic acid monohydrate, with stirring, and the mixture is heated under reflux for 3.5 hours, using a water separator. Ice is added to the reaction mixture and the mixture is brought to pH 6.8 with aqueous KHCO3 solution. The mixture is extracted with CH2Cl2, the CH2Cl2 phase is washed with H2O and dried over Na2SO4 and the solvent is stripped off in a rotary evaporator. The residue is chromatographed on Al2O3 (aluminum oxide from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate and MeOH (20:0.2). After trituration with ethyl acetate/petroleum ether, the substance becomes crystalline. It is dried over P2O5 at 80° C. in vacuo.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[N:11][CH:10]=[N:9]1.Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([CH3:27])[N:17]=[N:16][C:15]=1[CH3:28]>C(OCC)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]([N:8]3[CH:12]=[N:11][CH:10]=[N:9]3)=[C:15]([CH3:28])[N:16]=[N:17][C:18]=2[CH3:27])=[CH:25][CH:24]=1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(C)c(-n2cncn2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF. To this was added 0.14 g of 1,2,4-triazole, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.39 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.20 g of 5-(4-chlorophenyl)-3,6-dimethyl-4-(1,2,4-triazol-1-yl)pyridazine (hereinafter, described as compound (7) of the present invention.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][O:14][P:15]([O:18]C)[O:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:13][O:14][P:15]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)(=[O:18])[O:16][CH3:17]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc2ccccc2c1)OC
Yield: 92.6 %

Procedure:
A solution of 2-bromomethylnaphthalene (4.42 g, 0.020M) and trimethylphosphite (5 mL, 5.26 g, 0.042M) in dry toluene (100 mL) is heated at reflux temperature for 120 hours The reaction is incomplete, so the volume of the solution is reduced to 25 mL, additional trimethylphosphite (5 mL) is added, and the solution heated to reflux for another 24 hours. Solvent is removed under reduced pressure and the solid white residue is chromatographed over silica gel (40-63 μm, 195 g, ethyl acetate). Elution of the column with ethyl acetate gave title compound (4.63 g) as a white solid which after crystallization from ether-hexane had mp 80°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].N1C=CC=CC=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1coc2cc(Oc3ccnc(N)n3)ccc12

Procedure:
A solution of 9.2 g (28.8 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester and 23.4 ml (0.29 Mol) pyridine in 1 l THF is hydrogenated in presence of 3.9 g Pd/C 10% during 5 h. The mixture is filtered through a pad of celite and char coal, the solid washed extensively with THF and MeOH and the filtrate concentrated. The residue is stirred with 400 ml EtOAc and 200 ml water. Filtration of the suspension and washing with water and EtOAc yields the title compound: m.p.: 194-196° C.; MS: [M+1]+=286. The aq. layer is separated off from the filtrate and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Trituration from ether and EtOAc yields more of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([NH:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-])=O.C(O)C.[ClH:24]>[Fe].O>[ClH:15].[ClH:24].[NH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH3:1])[NH:19][CH3:20]
Reactant: CNC(Cc1ccc(Cl)cc1[N+](=O)[O-])c1ccsc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC(Cc1ccc(Cl)cc1N)c1ccsc1C

Procedure:
A mixture of 5.00 g of α-(2-methyl-3-thienyl)-N-methyl-4-chloro-2-nitrobenzeneethanamine, 9.32 g of iron powder, 100 ml of 95% ethanol, 25 ml of water, and 0.7 ml of concentrated hydrochloric acid was heated at reflux for 1.5 hr. The mixture was filtered through celite, and the organic phase was evaporated. The residue was basified with 10% aqueous sodium hydroxide, and extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in methanol and acidified with ethereal hydrogen chloride. The solution was diluted with ether, and the solid was collected, washed with ether, dried in vacuo, and recrystallized from methanol/ether to give 2.6 g of product, mp 242°-243° C. (dec.)