Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6](=[O:24])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](Cl)=[N:9][CH:8]=1.CO>C1COCC1>[CH3:4][O:5][C:6](=[O:24])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10]([O:2][CH3:1])=[N:9][CH:8]=1
Reactant: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OC)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium methoxide (2.20 g, 40.8 mmol) was slowly added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methyl ester in 4:1 MeOH:THF (20 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 17 hours and then warmed to 40° C. and stirred for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The desired product, contaminated with some starting material, was carried forward without purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([Cl:19])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Product: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To 5.00 g (22.7 mmol) of 4,4'-difluorobenzhydrol was added 16.5 ml (227 mmol) of thionyl chloride in the atmosphere of argon, and the mixture was stirred at room temperature for 30 minutes. To the resulting mixture was added water followed by extraction with benzene. The organic layer was successively washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography on silica gel. There was yielded 4.90 g (20.5 mmol) of 4,4'-difluorobenzhydryl chloride from the fraction eluted with benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:13](Cl)([Cl:15])=[O:14]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH3:10])[C:13]([Cl:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: CCCNCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCCN(Cc1ccc(Cl)cc1)C(=O)Cl

Procedure:
A solution of 25.2 g. N-4-chlorobenzyl-N-propylamine in 150 ml. ethyl acetate was added to 150 ml. ethyl acetate under reflux whilst phosgene was passed through. The passage of phosgene was continued for 21/2 hours, after which the ethyl acetate was evaporated to give an oily product. Distillation gave N-4-chlorobenzyl-N-propylcarbamoyl chloride, an oil b.p. 162°-164° C./4.0 mm. Hg.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:35])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]=[CH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[N:10]=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][C:6](=[O:35])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[N:10]=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCN3CCCC3)cc2c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(CCCCN3CCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-(4-pyrrolidin-1-ylbut-1-enyl)-4H-quinazolin-3-yl]acetamide (EXAMPLE 10a) (303 mg, 0.62 mmol) in dry methanol (6 mL) was sparged (5 min) with argon, and 10% Pd/C (24 mg, catalytic) was added. The reaction mixture was stirred under a hydrogen atmosphere(1 atm.) for 4 h at room temperature. The mixture was filtered through CELITE™, and the filter cake was washed with methanol (3×10 mL). The filtrates were evaporated under reduced pressure to afford N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-(4-pyrrolidin-1-ylbutyl)-4H-quinazolin-3-yl]acetamide (EXAMPLE 11a) (223 mg, 0.45 mmol, 73%) as yellow foam.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:44]1[CH:45]=[C:46]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])[C:47]([Cl:50])=[N:48][CH:49]=1.C(=O)(O)[O-].[Na+]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(N(C)C)=O>[Cl:50][C:47]1[N:48]=[CH:49][C:44]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[C:4]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])[CH:3]=2)=[CH:45][C:46]=1[NH:51][S:52]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)(=[O:54])=[O:53]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 80 °C

Procedure:
DMA (9 ml) was added to a Biotage microwave vial containing N-(6-bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (175 mg, 0.519 mmol), Pd(dppf)Cl2 (85 mg, 0.104 mmol), potassium acetate (153 mg, 1.56 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (86 mg, 0.338 mmol). The vial was sealed, the solution was degassed with nitrogen, then heated in a Biotage Initiator at 80° C. for 20 mins. Pd(dppf)Cl2 (85 mg, 0.104 mmol) was added to the reaction, the vial was sealed, degassed with nitrogen, then heated in a Biotage Initiator at 80° C. for 20 mins. Pd(PPh3)4 (30 mg, 0.026 mmol), N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide (361 mg, 1.038 mmol) and sodium bicarbonate (0.778 ml, 1.56 mmol) were added to the reaction, which was heated in a Biotage Initiator at 150° C. for 15 mins. Saturated sodium bicarbonate (100 ml) was added and the resulting suspension was washed with ethyl acetate (3×100 ml). Sodium chloride was added to improve separation. The organic layers were filtered through a hydrophobic frit, combined and dried under vacuum. The solid obtained was pre-adsorbed on silica and purified by silica chromatography (100 g cartridge) using 0-15% MeOH in DCM over 60 mins. Appropriate fractions were combined and dried under vacuum. The still crude compound was loaded onto an SPE (50 g) cartridge using DCM and the column was eluted with ethyl acetate:toluene:MeOH (200 ml, 14:5:1, v/v/v). Appropriate fractions were combined and the solvent was evaporated. The material obtained was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and further purified by HPLC as follows:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([NH:7][S:35]([CH3:34])(=[O:37])=[O:36])[CH:8]=1
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To the product from Example 13B (0.52 g, 1.214 mmol) and triethylamine (0.423 mL, 3.04 mmol) in dichloromethane (12.14 mL) was added dropwise methanesulfonyl chloride (0.207 mL, 2.67 mmol). The mixture was stirred for 2 hours at ambient temperature, and concentrated. The residue was dissolved in a mixture of dioxane (4 mL) and 1 M sodium hydroxide (1 mL) and heated for 1 hour at 90° C. The mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and the organic layer was separated, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 20-60% ethyl acetate in heptanes) afforded the title compound (0.5 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Cl:10][C:11]1[C:20]([C:21](Cl)=[O:22])=[C:19]([CH3:24])[C:18]2[C:13](=[CH:14][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:16][CH:17]=2)[N:12]=1>O1CCOCC1>[Cl:10][C:11]1[C:20]([C:21]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[O:22])=[C:19]([CH3:24])[C:18]2[C:13](=[CH:14][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:16][CH:17]=2)[N:12]=1
Reactant: NCc1cccc(F)c1
Reactant: Cc1c(C(=O)Cl)c(Cl)nc2cc(C(F)(F)F)ccc12
Solvent: C1COCCO1
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(Cl)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 2.9 g (23.4 mmol) 3-fluorobenzylamine was added dropwise at RT to a solution of 6.0 g (19.5 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carbonyl chloride in dioxane (35 ml). The mixture was then stirred for 60 min at RT and then quenched with water. The reaction solution was extracted with EE and the organic phase was washed with a 1M aqueous NH4Cl solution and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Crystallisation of the residue (EE) yielded 6.4 g (16.1 mmol, 83%) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxamide.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:6][C:5]=1[OH:33].[OH-].[Na+]>>[CH2:26]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:17]1/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[C:5]([OH:33])[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2cc3ccccc3n2Cc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCO/N=C/c2cc3ccccc3n2Cc2ccccc2)cc1O
Yield: 61.6 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 3, starting with 4-[3-({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino}oxy)propoxy]-2-hydroxybenzoic acid methyl ester (0.104 g, 0.23 mmol) and 2.5 M sodium hydroxide solution (3 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90 with 1% formic acid gradient to 20/80 with 1% formic acid) followed by recrystallization one time from methylene chloride/hexanes to give 4-[3-({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino}oxy)propoxy]-2-hydroxybenzoic acid (0.063 g, 62%) as a white solid. mp=175-176° C. (dec). 1H NMR (400 MHz, DMSO-d6); δ 11.50 (bs, 1H), 8.41 (s, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7.48 (d, 1H), 7.25-7.16 (m, 5H), 7.06 (t, 1H), 6.99 (d, 2H), 6.91 (s, 1H), 6.47 (d, 1H), 6.44 (s, 1H), 5.75 (s, 2H), 4.18 (t, 2H), 4.05 (t, 2H), 2.00 (m, 2H). Mass spec; (ES+) m/z 445.1, (ES−) m/z 443.4. Elemental analysis; Calculated for C26H24N2O5: C, 70.26; H, 5.44; N, 6.30. Found: C, 69.86; H, 5.43; N, 6.09.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Na+].[I-]>>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)c1cccc(Nc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)c1
Temperature: 140 °C

Procedure:
300 mg of product obtained in stage 1 above are mixed with 0.83 ml (5 equivalents) of ethyl 3-aminobenzoate and 0.166 mg of NaI, and the mixture is then heated at 140° C. for approximately 4 days.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[CH2:5][C:6]2([CH2:18][CH3:19])[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=3)[C:7]=12)[CH3:2].B(Br)(Br)Br.Cl>C(Cl)Cl.C(OCC)C>[CH2:1]([C:3]1[C:4](=[O:20])[CH2:5][C:6]2([CH2:18][CH3:19])[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[C:7]=12)[CH3:2]
Reactant: CCC1=C2c3ccc(OC)cc3CCC2(CC)CC1=O
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCC1=C2c3ccc(O)cc3CCC2(CC)CC1=O

Procedure:
A solution of 1,3a-diethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[α]naphthalen-2-one (10 mg, 0.036 mmol) in anhydrous CH2Cl2 (0.36 mL) was cooled in an ice bath, stirred under a N2 atmosphere, and treated with 1M BBr3 in CH2Cl2 (0.11 mL, 0.11 mmol). The resulting yellow suspension was stirred at 0-5° C. for 170 minutes and then treated with 1N HCl in diethyl ether (0.20 mL). The resulting mixture was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 1:1 hexane-EtOAc. The UV visible product band was eluted with 5% methanol in CH2Cl2 and the eluant was evaporated under vacuum to afford 1,3a-diethyl-7-hydroxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a white solid.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: CC(C)=O
Reactant: O=Cc1cc(Cl)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)ccc1F
Reaction time: 15 h

Procedure:
To a mixture of acetone (22 ml), sodium hydroxide (0.83 g) and water (55 ml) was added dropwise at room temperature a solution of 5-chloro-2-fluorobenzaldehyde (3.5 g) in acetone (20 ml), and the mixture was stirred at the same temperature for 15 hours. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-chloro-2-fluorophenyl)-3-buten-2-one (4.3 g).
Reaction SMILES: Cl[C:2]1[C:6]2[N:7]([C:17]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]3[CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:36])[CH:3]=1.C.[OH-].[Na+]>C(O)C.[Pd]>[CH2:30]([N:29]([CH2:28][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][N:22]1[CH2:21][CH2:20][NH:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2[N:4]([CH3:36])[CH:3]=[CH:2][C:6]1=2)=[O:18])[CH2:33][CH2:34][CH3:35])[CH2:31][CH3:32]
Reactant: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2c1c(Cl)cn2C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2c1ccn2C
Reaction time: 20 h

Procedure:
4.2 g (8.15 mol) of 3-chloro-4-[[[2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethyl]amino]carbonyl]-1-methyl-1,4,9,10-tetrahydro-pyrrolo[3,2-b][1,5]benzodiazepin-10-one were dissolved in 350 ml of hot ethanol and after the addition of 3 g of palladium on animal charcoal (20%), the mixture was hydrogenated for 20 hours under a hydrogen pressure of 50 bar and at a temperature of 40° C. The catalyst was filtered off, the filtrate was evaporated down in vacuo, the residue was taken up in 20 ml of water, the solution obtained was made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated down and the residue remaining was crystallised once from ethyl acetate and once from acetonitrile. 2.1 g (54% of theory) of colourless crystals were obtained, m.p. 153°-155° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc2oc(-c3ccc(OC)c([N+](=O)[O-])c3)nc2c1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 2-methoxyphenylboronic acid (130 mg, 0.85 mmol) the subtitle compound was obtained (163 mg, 76%). 1H NMR (CDCl3) δ 8.75(d, 1H), 8.45(dd, 1H), 7.93(d, 1H), 7.61(d, 1H), 7.54(dd, 1H), 7.39–7.34(m, 2H), 7.25(d, 1H), 7.09–7.01(m, 2H), 4.07(s, 3H), 3.83(s, 3H).
Reaction SMILES: CCN(CCN[C:9]([C:11]1[CH:12]=[C:13](Cl)[C:14]([NH2:19])=C[C:16]=1[O:17]C)=O)CC.P(Cl)(Cl)(Cl)=[O:22]>C(Cl)(Cl)Cl>[C:16]([OH:17])(=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[N:19][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccnc1

Procedure:
(0.075 mole) and metoclopramide (14.9 grams; (0.95 mole) having the melting point of 148° C. are dissolved in 100 ml. of chloroform. At ambient temperature, 5.6 grams of phosphorous oxychloride are added drop by drop and the batch is heated for three more hours under reflux. After extraction with 80 ml. of 10% caustic soda solution, and subsequently with water, the chloroform solution is concentrated in a vacuum and the distillation residue having a boiling point of 100 to 140° C. is recrystallized from benzene. There is thus obtained 10.4 g. (51.4% of theory) of 4-nicotinoylamino-5-chloro-2-methyoxy-N-[2-(diethylamino)ethyl]benzamide having a melting point of 99° to 100° C.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1cccc2nnccc12
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cccc2nnccc12

Procedure:
Prepared from cinnolin-5-amine [Sci Pharm. 1982, 50, 246] and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 363 (M+H)+.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH2:10](Br)[CH2:11][Br:12].[OH-].[Na+]>>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:10][CH2:11][Br:12]
Reactant: BrCCBr
Reactant: COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1OCCBr
Reaction time: 0.5 h

Procedure:
0.2 mole(22.4 ml) of guaiacol and 0.4 mole (34.6 ml) of ethylene dibromide are heated to 100° C. while stirring vigorously, and within 30 minutes, 125 ml of 1.6 N sodium hydroxide solution is added to continue the stirring and the pH value is adjusted to 7. Upon cooling, the mixed solution's organic layer is extracted with chloroform and rinsed with 2N sodium hydroxide before rising again with saturated sodium chloride solution and magnesium sulfate. Upon reduction, the solution is filled into the silicone tube for separation. Using the ratio of hexane: ethyl acetate=9:1 as the diluent, white crystallized product, 2-(2-methoxyphenoxy ethylbromide, is obtained.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[CH:14](=O)[CH2:15][CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)[CH2:15][CH3:16]
Reactant: CCC=O
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
2,3,4,9-Tetrahydro-1H-beta-carbolin (2.5 g, 14.5 mmol) and propionaldehyde (1.06 ml, 14.5 mmol) were dissolved in THF (100 ml). Acetic acid (1.25 ml, 21.8 mmol) and sodium trisacetoxyborohydride (4.615 g, 21.8 mmol) were sequentially added to the reaction mixture and stirred for 1 h at room temperature. The reaction mixture was concentrated and the residue was dissolved in H2O (10 ml) and ethyl acetate (50 ml). The pH was adjusted to 9 by adding NaOH (2M). The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield the title product (2.84 g, 91%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH:9]1[CH3:33])C1C=CC=CC=1>CO.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[O:32]1[C:25]2[CH:24]=[C:23]([CH2:22][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH:9]([CH3:33])[CH2:10]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:28]=[CH:27][C:26]=2[O:29][CH2:30][CH2:31]1
Reactant: CC1CC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC1CC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CCN1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of 0.24 g of tert-butyl (1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 3 mL of methanol, 90 μL of acetic acid and 0.32 g of 20% palladium hydroxide were added. The reaction mixture was stirred for 4 hours 30 minutes under a hydrogen atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 0.16 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(2-methylpiperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reaction time: 3 h
Yield: 102.2 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 150 mg dry weight) and a solution of 119a (1.02 g, 3.76 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 100% yield (928 mg) of 119b as a white solid: mp 54-55° C.; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, 1H, J=2.0 Hz), 5.36 (d, 1H, J=2.0 Hz), 4.54 (br s, 2H), 3.90 (t, 2H, J=5.5 Hz), 3.81 (t, 2H, J=5.5 Hz), 0.84 (s, 9H), −0.35 (s, 6H). MS (APCI+) m/z 242.6 (M+H).