Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:8](OCC)=[O:9])=O)[CH3:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[N:18]=[C:19]([NH2:21])[NH:20][C:8](=[O:9])[CH:6]=1)=[O:13])[CH3:2]
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: O=C(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)[nH]c(N)n1

Procedure:
A solution of oxalacetic acid diethyl ester (8.5 g, 45.2 mmol) in ethanol (100 mL) was treated with guanidine carbonate (8.1 g, 45.2 mmol) and this was stirred under reflux for 2 hours. The mixture was diluted with water, concentrated to removed ethanol, and the solid was collected by filtration. The solid was then suspended in ethanol (40 mL) and concentrated hydrochloric acid (1 mL) and refluxed for 15 minutes. The mixture was then cooled, basified with potassium carbonate, diluted with water and concentrated to removed ethanol. The white solid was collected by filtration and vacuum dried to give J1.1 (1.67 g, 20%). 1H-NMR (DMSO-d6) δ: 10.34 (1H, br s), 8.92 (1H, br s), 7.46 (1H, br, s), 5.42 (1H, s), 4.18 (2H, q, J=7 Hz), 1.24 (3H, t, J=7 Hz).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH:31]1[CH2:35][CH:34]=[CH:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:31]5[CH2:35][CH:34]=[CH:33][CH2:32]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: C1=CCNC1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CC=CC4)c3)c2s1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 15.6 mg (0.23 mmol) of 3-pyrroline are reacted together by general method E. 20 mg (35.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1cccnc1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1cccnc1)CC3
Yield: 19 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 3-pyridinecarboxaldehyde. Yield 19%; mp 107°-110° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=C(C(C)C)C=C(C(C)C)[C:5]=1S(N/N=C(/C(C)C)\C)(=O)=O)(C)[CH3:2].C([Li])CCC.[Si:31]([O:38][CH2:39][C@@H:40]([N:43]([CH2:51][C:52](N(OC)C)=[O:53])[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=[CH2:42])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CCCCCC.CN(CCN(C)C)C>[Si:31]([O:38][CH2:39][C@@H:40]([N:43]([CH2:51][C:52](=[O:53])[C:1](=[CH2:2])[CH:4]([CH3:9])[CH3:5])[C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:49])[CH3:47])[CH:41]=[CH2:42])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: C/C(=N\NS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (E)-2,4,6-triisopropyl-N′-(3-methylbutan-2-ylidene)benzenesulfonohydrazide (Intermediate 33, 8 g, 21.82 mmol) in hexane (65 mL) and TMEDA (6.50 mL) at −78° C. was added dropwise n-butyllithium (1.6M in hexanes) (34.1 mL, 54.56 mmol). The reaction mixture turned orange and was stirred for 30 minutes at −78° C., then was warmed to 0° C. and bubbling started immediately. The suspension became a yellow solution. After ˜15 minutes the bubbling stopped and (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)-amino)-2-oxoethyl)carbamate (Intermediate 5, 4.39 g, 10.91 mmol) was added as a solution in hexane (2 mL). After ˜15 minutes LC/MS shows desired product and no remaining Weinreb amide starting material. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ether twice. The ether extracts were dried over magnesium sulfate, filtered and concentrated to afford a yellow oil. Silica gel chromatography (0%-10% ethyl acetate/hexanes) afforded the desired product (2.219 g, 49.4%) as a light yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:31]=1)=[N:17]C(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:32]1[CH:31]=[C:30]([CH:26]2[CH2:27][CH2:28][CH2:29][N:25]2[C:16](=[NH:15])[NH2:17])[O:34][N:33]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCCC1c1cc(-c2ccccn2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N1CCCC1c1cc(-c2ccccn2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TFA (30 ml) was added to a cooled solution of N,N′-di(tert-butyloxycarbonyl)-2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine-1-carboximidamide (Method 39) in DCM (150 ml) at 0° C. The mixture was stirred 0° C. for one hour, allowed to warm to ambient temperature and stirred for a further 18 hours. The volatiles were removed by evaporation and the residue triturated from DCM/ether/hexane. The product was collected by filtration to give the title compound (2.2 g, >100%).
Reaction SMILES: [Br:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][C@H:8]([C@@H:18]2[CH2:20][C@@H:19]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=3)[CH2:23][CH2:22]2)[CH2:9][O:10][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][C@H:8]([C@@H:18]2[CH2:20][C@@H:19]2[CH:21]2[CH2:22][CH2:23][N:24]([C:27]3[N:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][N:32]=3)[CH2:25][CH2:26]2)[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](CO[Si](C)(C)C(C)(C)C)OCc3ccc(Br)cc3)CC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](CO)OCc3ccc(Br)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the compound prepared in step E (0.37 g, 0.64 mmol) in THF (3 mL) was added TBAF (0.96 mL of 1.0 M solution in THF, 0.96 mmol). Upon stirring at RT for 1 h, silica gel was added to the reaction mixture and a slurry was prepared, which was purified by column chromatography on silica (elution with 2:1 hexane:ethyl acetate) to yield the desired compound. MS (ESI) m/z 460/462 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]([CH2:9][C@H:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][C@@H:12]([CH2:23]O)[O:11]1)=[N+:7]=[N-:8].[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26]>C(Cl)Cl.C(OCC)C>[N:6]([CH2:9][CH:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][CH:12]([CH2:23][N:27]2[CH2:28][CH2:29][CH2:26][CH2:25]2)[O:11]1)=[N+:7]=[N-:8]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C)c2c1CC(CN1CCCC1)OC2CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.146 mL, 1.89 mmol) is added dropwise to a solution of 0.453 g (1.72 mmol) of [1R,3S] 1-azidomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran, the product of Step 4 of Example 142, and 0.36 mL (2.58 mmol) of triethylamine in 15 mL of methylene chloride at 0° C. The reaction mixture is stirred for 30 min at 0° C. then transferred to a separatory funnel and diluted with 45 mL of diethyl ether. The layers are separated and the organic layer is washed with 2×20 mL of water, 2×20 mL of 1 N hydrochloric acid and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in 20 mL of N,N-dimethyl formamide (DMF) and an excess amount of pyrrolidine is added to this solution. The reaction mixture is heated at 95° C. for 2.5 h then poured into 75 mL of water. The aqueous solution is extracted with 3×40 mL of diethyl ether. The combined ether extracts are washed with 2×30 mL of water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluted to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOCC>[CH2:13]([O:9][CH:6]1[CH2:7][O:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1CCC(O)CO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1CCC(OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of 6-methoxytetrahydro-2H-pyran-3-ol (222 mg, 1.680 mmol) in DMF (2 mL) was added 60% NaH (81 mg, 2.02 mmol) and the mixture was allowed to warm to rt and stirred at rt for 30 min. A solution of (bromomethyl)benzene (345 mg, 2.016 mmol) in DMF (1 ml) was added and the mixture was stirred at rt for 18 h. The reaction mixture was diluted with ether and quenched with water. The crude product was purified by silica gel FCC (20% EtOAc in hexanes) to afford 5-(benzyloxy)-2-methoxytetrahydro-2H-pyran. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.41 (5H, m), 4.53-4.64 (3H, m), 3.90 (1H, dd, J=12.05, 2.51 Hz), 3.56-3.65 (1H, m), 3.46-3.53 (1H, m), 3.43 (3H, s), 1.97-2.14 (2H, m), 1.69-1.81 (1H, m), 1.48-1.60 (1H, m).
Reaction SMILES: [NH:1]1[C:5]([SH:6])=[N:4][CH:3]=[N:2]1.[H-].[Na+].F[B-](F)(F)F.[NH2:14][C:15]1[C:57]([Cl:58])=[CH:56][C:18]([C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N+]3C(C4C=CC=CC=4)=CC(C4C=CC=CC=4)=CC=3C3C=CC=CC=3)[CH2:24][C@H:23]2[O:54][CH3:55])=[O:20])=[C:17]([O:59][CH3:60])[CH:16]=1>CC1C=CC=CC=1>[OH2:20].[NH2:14][C:15]1[C:57]([Cl:58])=[CH:56][C:18]([C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][S:6][C:5]3[NH:1][N:2]=[CH:3][N:4]=3)[CH2:24][C@H:23]2[O:54][CH3:55])=[O:20])=[C:17]([O:59][CH3:60])[CH:16]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)C[C@H]1OC
Reactant: Sc1ncn[nH]1
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCSc2ncn[nH]2)C[C@H]1OC
Product: O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A mixture of 2.16 parts of 1H-1,2,4-triazol-5-thiol, 1.03 parts of a sodium hydride dispersion 50% and 18 parts of methylbenzene was stirred for 3 hours at room temperature. A solution of 6.3 parts of cis-1-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-2,4,6-triphenylpyridinium tetrafluoroborate in 9 parts of methylbenzene was added and stirring was continued first for 4 hours at reflux temperature and then over weekend at room temperature. The whole was extracted five times with 100 parts of a hydrochloric acid solution 1N. The combined acid aqueous phases were treated with potassium hydroxide and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.24 parts (33%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(1H-1,2,4-triazol-5-ylthio)ethyl]-4-piperidinyl]benzamide monohydrate; mp. 161.8° C. (compound 48).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=2)[C:61]#[N:62])[CH2:53][CH2:52]1>CN(C=O)C.O>[C:61]([C:60]1[CH:59]=[C:58]([CH:65]=[CH:64][CH:63]=1)[O:57][CH:54]1[CH2:55][CH2:56][N:51]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:52][CH2:53]1)#[N:62]
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 0.03 h
Yield: 14.6 %

Procedure:
DIPEA (316 mg, 2.5 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (181 mg, 0.7 mmol) in DMF (3 mL) followed by HOBt (108 mg, 0.8 mmol) and EDCI.HCl (160 mg, 0.8 mmol). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (50 mg, 0.7 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) afford 44 mg (14.3% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(3-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 473.17, 99.16%, 1H NMR (300 MHz, DMSO-d6): δ 8.1 (m, 1H), 7.8 (m, 2H), 7.6 (m, 4H), 7.4 (m, 3H), 7.1 (b, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN.Cl.[CH3:15][N:16](C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:16][CH3:15])=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of 2-bromophenyl acetic acid (2.15 g) in dichloromethane (100 ml) was added methylamine (2M solution in tetrahydrofuran, 6 ml), 4-dimethylaminopyridine (1.32 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.055 g). The mixture was left to stir at room temperature for 16 hours, after which the organic portion was washed with 2M aqueous hydrogen chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated to give a solid (2.04 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.O.[Br:18][CH2:19][CH2:20][CH2:21]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: BrCCCBr
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 59.5 %

Procedure:
To a solution of ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (0.166 g, 0.754 mmol) (Example 6) in DMF (0.5 mL, containing 1% v/v of water), were added 1,3-dibromopropane (0.27 mL, 2.64 mmol) and Cs2CO3 (0.295 g, 0.905 mmol). The mixture was stirred at rt for 13 h and then at 80° C. for 1 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc, filtered, and the filter cake was washed with EtOAc. The combined filtrate was dried, concentrated and purified by silica gel chromatography (100% hexanes to EtOAc/hexane (v/v) 1:19 gradient) to give 153 mg (60%) of the title compound containing minor impurities. This material was used in later steps without further purification. 1H NMR (300 MHz, CDCl3): δ 7.08 (d, 1H), 6.78 (s, 1H), 6.70 (dd, 1H), 4.19 (q, 2H), 4.08 (t, 2H), 3.60 (t, 2), 3.58-3.44 (m, 1H), 2.96-2.64 (m, 3H), 2.50-2.21 (m, 4H), 1.93-1.68 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: CC[N:3]([CH2:6]C)CC.ClC(OCC)=[O:10].[O:14]([C:19]([N:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)C(O)=O)[CH3:22])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C1(C)C=CC=CC=1>[O:14]([C:19]([N:21]([C:23]1[CH:24]=[C:25]([N:3]=[C:6]=[O:10])[CH:29]=[CH:30][CH:31]=1)[CH3:22])=[O:20])[C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(N=C=O)c1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Et3N (3.71 g, 36.7 mmol) and a solution of ethyl chloroformate (4.31 g, 39.7 mmol) in acetone (10 ml) were successively added dropwise to a solution of 3-(N-tert-butoxylcarbonyl-N-methylamino)benzoic acid (8.0 g, 31.8 mmol) in acetone (64 ml) below 5° C. After stirring for 30 min, a solution of NaN3 (3.10 g, 47.7 mmol) in water (10 ml) was added to the solution below 5° C. The mixture was stirred at the same temperature for a further 1 h, then poured into toluene (80 ml) and water (160 ml). The organic portion was washed with brine, refluxed for 2 h and evaporated. The residue was distilled (100°-105° C./0.9-1.0 mmHg) to afford the title compound (6.2 g, 78%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C1C=CC=CC=1.CO>O(CC)CC>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[O:3][CH2:1][CH3:2])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: CCOc1ccccc1C(=O)N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CO
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOc1ccccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 0.96 parts of 1-(2- ethoxybenzoyl)aziridine, 1.06 parts of 4-(4-chlorophenyl)-4-piperidinol, 5.4 parts of benzene and 0.8 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. Upon the addition of 1,1'-oxybisethane, the product is precipitated. It is filtered off, crystallized from 2-propanol, filtered off again and dried overnight in vacuo at 80° C, yielding 1.4 parts of N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-2-ethoxybenzamide; mp. 171°-173° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH2:16](Br)[CH:17]=[CH2:18].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:18]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2]=2[NH2:1])[CH2:7]1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Nc1c2c(cc3ccccc13)CNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCN1CCc2c(cc3ccccc3c2N)C1
Temperature: 25 °C

Procedure:
A mixture of 7.9 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline, 5.3 g of allyl bromide, 2.6 g of triethylamine in 50 ml of anhydrous chloroform is heated to the boil for 4.5 hours while stirring. 100 ml of water are added to the resulting solution after cooling to room temperature, the solution is made alkaline with 40% caustic soda solution, and the organic phase is separated off. The organic solution is washed neutral with water, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallized twice from methanol. M.Pt. of the title compound: 74° - 76°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:36])[CH:30]=1)([CH3:28])[CH3:27]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 47 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol) to give 1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (69.5 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 7.52 (s, 2H), 7.45-7.36 (m, 2H), 7.25 (d, 1H), 6.99 (d, 1H), 6.5 (s, 1H), 4.35 (bs, 2H), 4.00 (s, 3H), 3.89 (bs, 2H), 3.36 (s, 3H), 3.01-2.99 (m, 1H), 1.22 (d, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[C:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[C:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC#CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
In THF (5.0 ml)/methanol (5.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-butynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution was added 2N potassium hydroxide (5.0 ml), and the mixture was stirred at 50° C. for 3 hours. pH was adjusted to approximate 4 with 6N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-butynyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.40 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1
Agent: Cl
Solvent: CCO
Product: NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1.02 g (2.64 mM) of l-[trans-4-[N-(tert-butoxycarbonyl)aminomethyl]-1-cyclohexylmethyl]-4-phenylpiperidine in ethanol (10 ml) was added 10 ml (120 mM) of 12N-hydrochloric acid at room temperature and the mixture was stirred for one hour. This reaction mixture was concentrated under reduced pressure (crystals separated out) and diethyl ether was added to the residue. The resulting crystal crop was harvested by filtration and rinsed with ethanol and diethyl ether to provide the title compound as light-purple crystals.