Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][CH:22]=1)[NH2:20]>>[C:1]1([C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][OH:29])=[CH:25][CH:26]=3)[N:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Product: OCCc1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 1,3-diphenylpropane-1,3-dione and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (ESI) m/z 341 [M+H]+, 1H-NMR (CDCl3) δ 7.93-7.91 (2H, m), 7.46-7.20 (12H, m), 6.82 (1H, s), 3.87 (2H, br), 2.89 (2H, t, J=6.6 Hz).
Reaction SMILES: C([OH:3])C.[OH-].[K+].[O:6]=[C:7]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][C:9]2[CH:18]=[CH:19][C:20]([CH2:22][C:23](N)=[O:24])=[CH:21][C:8]1=2>O>[O:6]=[C:7]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][C:9]2[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:24])=[O:3])=[CH:21][C:8]1=2
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Reaction time: 5 h
Yield: 77 %

Procedure:
To a mixture of 2 ml of water, 2 ml of ethanol and 0.4 g of potassium hydroxide was added 100 mg of (10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-acetamide, and the resulting mixture was refluxed with stirring for 5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow crystals, which were chromatographed over 9 g of silica gel and eluted with chloroform/methanol (50/1), thereby obtaining 77 mg (yield: 77%) of (10,11-dihydro-11-oxo dibenzo-[b,f]oxepin-2-yl)-acetic acid. This acid was recrystallized from acetone/n-hexane to give colorless crystals having a melting point of 155.7°-157° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:40])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:48][CH2:49][N:50]1[CH2:55][C@@H:54]2[CH2:56][C@H:51]1[CH2:52][S:53]2(=[O:58])=[O:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[O:58]=[S:53]1(=[O:57])[CH2:52][C@@H:51]2[CH2:56][C@H:54]1[CH2:55][N:50]2[CH2:49][CH2:48][NH:1][C@:2]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:40])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S1(=O)C[C@@H]2C[C@H]1CN2CCCl
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 39.2 %

Procedure:
A mixture of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (10 mg, 0.016 mmol), (1S,4S)-5-(2-chloroethyl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (3.36 mg, 0.016 mmol), potassium phosphate (17.01 mg, 0.080 mmol) and potassium iodide (5.32 mg, 0.032 mmol) in acetonitrile (1 mL) was heated up at 120° C. for 16 hours. The reaction mixture was then filtered and purified by HPLC to provide the desired product (5 mg, 39% yield) as a white solid. LCMS: m/e 797.8 (M+H)+, 2.31 min (method 5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:28])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:31](OC(=O)C)([F:33])[F:32]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:31]([F:33])[F:32])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(OC)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [2-ethyl-8-fluoro-3-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: [H][H].C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][C:41](=[NH:43])[NH2:42])=[CH:35][CH:34]=2)=[O:31])[CH2:26][CH2:25]1)=O)C1C=CC=CC=1>C(OCC)C>[NH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([CH:39]=[CH:40][C:41](=[NH:42])[NH2:43])=[CH:37][CH:38]=2)=[O:31])[CH2:26][CH2:25]1
Reactant: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CNC(=O)OCc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CN)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 9 ml of a 30% hydrogen bromideacetic acid mixture and 18 ml of glacial acetic acid, was added 2.7 g of 4-(β-amidinoethenyl)phenyl trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylate methanesulfonate. After stirring the mixture for one hour at room temperature, anhydrous ethyl ether was added to wash out a white solid substance. The solid substance was recrystallized from ethanol to obtain 1.1 g of a white powder of 4-(β-amidinoethenyl)phenyl trans-4-aminomethylcyclohexane carboxylate dihydrobromide.
Reaction SMILES: C[N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][NH:5][CH2:6]2.[CH2:10](N)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:5]1[CH2:6][CH:7]2[NH:2][CH:3]([CH2:9][CH2:8]2)[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CN1C2CCC1CNC2
Product: c1ccc(CN2CC3CCC(C2)N3)cc1

Procedure:
Was prepared in the same manner as 8-methyl-3,8-diazabicyclo[3.2.1]octane, from benzylamine instead of methylamine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][N+:15]([O-:17])=[O:16])[CH2:5][CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[N:26][CH:27]=2)[C:10]1=[N:14][N+:15]([O-:17])=[O:16])[CH2:5][CH3:6])[CH3:2]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(CC)OCN1CCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(CC)OCN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Yield: 20.8 %

Procedure:
15.0 g of 1-(1-ethoxy-1-propoxy)methyl-2-nitroiminoimidazolidine, 11.6 g of anhydrous potassium carbonate, 11.3 g of 2-chloro-5-chloromethylpyridine and 60 ml of dimethyl sulfoxide were agitated at 75° C. for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The resultant oily residue was purified by column chromatography [silica gel, eluant: hexane/ethyl acetate (1:2)] to give 4.7 g of 1-(1-ethoxy-1-propoxy)methyl-2-nitroimino-3-(2-chloropyridin-5-ylmethyl)imidazolidine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13]C(OC)=O)=[CH:4][C:3]=1[NH:18][C:19]([CH:21]1[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=2[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22]1)=[O:20].CC1(C)C(C)(C)OB([C:46]2[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:50][CH:51]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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>[C:55]([O:54][C:52]([N:49]1[CH2:48][CH:47]=[C:46]([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:5]([OH:13])=[CH:4][C:3]=2[NH:18][C:19]([CH:21]2[O:26][C:25]3[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=3[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22]2)=[O:20])[CH2:51][CH2:50]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2Br)Oc2ccc(C#N)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC(C(=O)Nc2cc(O)c(C3CCCC3)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Temperature: 90 °C
Yield: 55.9 %

Procedure:
Ethyl 2-(2-bromo-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (166 mg, 0.29 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (90 mg, 0.29 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol), and Cs2CO3 (189 mg, 0.58 mmol) were combined in DMF (4 mL) and heated at 90° C. for 4 h. The reaction was quenched with water (50 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded ethyl 2-(2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-cyclopentyl-5-hydroxyphenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (100 mg, 56% yield). LC/MS m/z 617.4 [M+H]+.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][C:5]=1[N+:18]([O-])=O>[Fe].CC1C=CC=CC=1>[NH2:18][C:5]1[CH:6]=[C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:8]=[CH:9][C:4]=1[Cl:3]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Nc1cc(C(=O)c2ccccc2)ccc1Cl

Procedure:
To a stirred and refluxing mixture of 11.2 parts of iron, 100 parts of ammonium chloride solution 0.8N and 20 parts of methylbenzene are added 10.5 parts of (4-chloro-3-nitrophenyl)phenylmethanone and the whole is further stirred at reflux temperature for one hour. Methylbenzene (80 parts) is added and the whole is filtered over Hyflo. The organic layer is separated, dried, filtered and evaporated. The residue is washed with cyclohexane, yielding 8.4 parts of (3-amino-4-chlorophenyl)phenylmethanone; mp. 91.9° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: C=CCI
Reactant: O=c1cnc2ncc(F)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)cnc2ncc(F)cc21
Yield: 46.5 %

Procedure:
7-Fluoropyrido[2,3-b]pyrazin-2(1H)-one (306 mg, 1.855 mmol) was suspended in dry DMF (10 mL) under argon at rt, and the stirred suspension was treated with K2CO3 (845 mg, 6.12 mmol) and allyl iodide (223 μl, 2.41 mmol). It was then stirred for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (2×200 ml) and 5% MeOH/DCM (100 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated and purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a yellow solid (177 mg, 47%).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])[CH:13]=1>>[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:3]([O:5][C:21]([CH3:26])([CH3:22])[CH3:19])=[O:4])[CH2:23][CH2:22]2)=[O:20])[CH:13]=1
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CCNCC3)c2)c(F)c1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1

Procedure:
t-Butyl 4-{4-[2-fluoro-4-(3-phenylacetylureido)phenoxy]pyridin-2-ylcarbamoyl}piperidine-1-carboxylate (60 mg, 0.101 mmol) and trifluoroacetic acid (0.50 ml) gave a crude product of piperidine-4-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylureido)phenoxy]pyridin-2-yl}amide (ESI-MS (m/z):492). The crude product, formalin (37% aqueous solution; 0.0376 ml, 0.505 mmol), acetic acid (0.0231 ml, 0.404 mmol) and sodium triacetoxyborohydride (42.8 mg, 0.202 mmol) gave the titled compound (51.1 mg, 22.5%) as colorless powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][N:27]1[C:32]2[N:33]=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][C:31]=2[CH2:30][O:29][C:28]1=[O:46]>>[CH:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:35]5[CH:34]=[N:33][C:32]6[N:27]([CH3:26])[C:28](=[O:46])[O:29][CH2:30][C:31]=6[CH:36]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN1C(=O)OCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)COC(=O)N5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.125 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.1) to give the title compound as a beige solid. (HPLC: tR 2.59 min (Method A); M+H=484 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.35-8.33 (m, 1H), 8.21 (s, 1H), 8.15-8.11 (m, 1H), 7.91-7.83 (m, 2H), 7.52-7.49 (m, 1H), 5.36-5.29 (m, 2H), 4.56 (qt, 1H), 3.58 (s, 3H), 3.35 (s, 3H), 1.95 (s, 3H), 1.46 (d, 6H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH:32]([CH3:34])[CH3:33])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 41A (100 mg, 0.30 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (81 mg, 0.42 mmol) to yield 86 mg (61%).
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:60]=[CH:59][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1COCC1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:28]([OH:29])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:32][CH:31]=2)=[CH:59][CH:60]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To 4,4′-didocosyloxy-benzophenone (28.3 g, 34.1 mmol) were added THF (300 mL) and methanol (15 mL), and the mixture was heated to 60° C. Sodium borohydride (6.10 g, 161 mmol) was slowly added, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was ice-cooled, and 1N hydrochloric acid (80 mL) was added dropwise. THF was evaporated, water (450 mL) was added, and 1N hydrochloric acid was added to adjust the pH to 5-7. The slurry was filtered, and the obtained crystals were washed with water and methanol to give the title compound (28.5 g, 34.1 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=[CH:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C

Procedure:
3-Chloro-4-cyclohexylbenzaldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 l round-bottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature ovenight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The crystals of product are collected by filtration, washed with water (4×150 ml) and air dreid. Recrystallization from acetone-water gives 3-chloro-4-cyclohexylcinnamic acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:10][CH2:9]1.I[CH3:16].Cl>O1CCCC1>[Br:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH2:6][NH:7][CH2:8][CH:10]1[CH2:9][CH2:16]1
Reactant: CI
Reactant: Brc1ccccc1CNC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccccc1CNCC1CC1
Temperature: 0 °C

Procedure:
53 mg of sodium hydride in 3 ml of tetrahydrofuran are added to 300 mg of (2-bromobenzyl)cyclopropylamine in 2 ml of tetrahydrofuran with ice-cooling. 207 μl of iodomethane are subsequently added, and the mixture is heated at 600 for 1 h. The mixture is allowed to cool and poured onto 20 g of ice and 5 ml of 1N hydrochloric acid, washed 4 times with 10 ml of ethyl acetate each time, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: Fc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Four-hundred milligrams (9.9 mmols) of 60% sodium hydride were washed with petroleum ether, and then suspended in 40 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.6 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. To this reaction solution was added dropwise a solution of 2.2 g (9.1 mmols) of (S)-(+) -3-chloro-1-(4-fluorophenethyl)piperidine[[α]D25=+9.5° (c=1.0, ethano 1)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 4 days. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 1.4 g of (R)-(+)-5,11-dihydro-5-[1-(4-fluorophenethyl)-2-pyrrolidinyl methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 44%.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:23].Cl>C(O)C>[ClH:23].[CH3:1][C:2]1[CH:9]=[CH:8][C:5]2[C:6]([NH2:7])=[N:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Combine 4-methyl-2-(2-nitro-phenylamino)-benzonitrile (2.46 g, 9.71 mmol), tin(II) chloride dihydrate (6.57 g, 29.71 mmol), 5N HCl (40 ml), and ethanol (40.0 ml). and stir the mixture at reflux. After 8 hours, cool to ambient temperature. Allow the mixture to stand at ambient temperature overnight and chill for an additional 3 hours in the refrigerator. Remove the resulting precipitate by vacuum filtration and dry it under vacuum to give 1.24 g (49%) of the desired compound as a yellow solid: mass spectrum (ion spray): m/z=224.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@@H:3]([N:5]([CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13])[C:6](=[O:9])[O:7][CH3:8])[CH3:4].[Br-].[CH2:24]1[CH2:28]OC[CH2:25]1>>[CH3:22][C:2]([CH3:21])([CH3:1])[C@@H:3]([N:5]([CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([OH:13])[CH2:28][CH:24]=[CH2:25])[C:6](=[O:9])[O:7][CH3:8])[CH3:4]
Reactant: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)C(C)(C)C
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CCC(O)(CCN(C(=O)OC)[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (S)-methyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (4.5 g, 0.015 mol) in THF (60 mL) was added allymagnesium bromide (1 M, 30 mL, 0.03 mol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at it overnight. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give methyl (S)-3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-hydroxyhex-5-enyl)carbamate (4.80 g, 92%), which was used for the next step without further purification.