Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>>[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=2)[CH2:7][CH2:6]1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 490.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][O:38][CH3:39])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:34]([O:33][CH:29]([O:30][CH2:31][CH3:32])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][O:38][CH3:39])[CH3:36])[CH3:35]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)COC
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](COC)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 46.4 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-3-methoxy-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-25) 58 mg (0.15 mmol) to obtain the title compound 19 mg (23%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[NH:9][N:10]=[C:11]([C:12]([OH:14])=O)[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:36]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[C:39]=1[NH2:40])[CH3:37].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:36]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[C:39]=1[NH:40][C:12]([C:11]1[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:8]=2[NH:9][N:10]=1)=[O:14])[CH3:37]
Reactant: CCc1cccc(CC)c1N
Reactant: O=C(O)c1n[nH]c2c1CCCCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A suspension of 8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylic acid (0.045 g, 0.232 mmol) in anhydrous DMF (2 mL) was treated with HOBt (0.047 g, 0.347 mmol), EDCI (0.065 g, 0.347 mmol), 2,6-diethylaniline (0.253 mL, 0.925 mmol) and DIPEA (0.188 mL, 1.390 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with AcOEt (2×20 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) provided 0.027 g (35% yield) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8](=[S:11])[NH:9][NH2:10])=O)C.[NH3:12]>C(O)C>[C:4]([CH2:6][NH:7][C:8](=[S:11])[NH:9][NH2:10])(=[O:3])[NH2:12]
Reactant: N
Reactant: CCOC(=O)CNC(=S)NN
Solvent: CCO
Product: NNC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
4-Ethoxycarbonylmethyl-thiosemicarbazide (8.33 g) (GANTE and LANTSCH, Chem. Ber., 97, 989 (1964)) are suspended in a saturated solution (250 cc) of ammonia in ethanol, and the reaction mixture is stirred at 25° C. for 22 hours. The insoluble matter is filtered off and washed with alcohol (2×25 cc) and ether (2×50 cc); after drying, 4-carbamylmethyl-thiosemicarbazide (6.2 g), m.p.=188° C., is obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[Cl:26].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[C:5]([Cl:26])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 13.8 g (36.4 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 7.64 g (182 mmol.) LiOH in 200 mL water and 400 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 12.1 g of the desired product is obtained, which is used for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:16][N:17]1[CH2:22][CH2:21][N:20](C[C@@H](NC(=O)C2C=CC(C)=CC=2)C(C)C)[CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])C1=CCCCC1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.5 %

Procedure:
A mixture of 1-nitrocyclohexene (311 mg, 2.45 mmol), dichlorobenzylpiperazine [prepared as described in Example 1] (600 mg, 2.45 mmol), and triethylamine (512 μl, 3.68 mmol) in methylene chloride (10 ml) was stirred at room temperature under nitrogen atmosphere for 17 h. The reaction mixture was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed with hexanes/ethyl acetate (2:1) as the eluant to provide 1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (461 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:27])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[O:25])=[CH:15][C:14]=2[F:26])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].[ClH:35]>C(O)(C)C>[ClH:35].[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:27])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[O:25])=[CH:15][C:14]=2[F:26])[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 28b (5.37 g; 11 mmol) is dissolved in 6 N HCl in isopropanol (42 ml) and the mixture is stirred for 2 h at 25° C. The mixture is evaporated to dryness and the crude product is recrystallized from diethylether several times to yield compound 28c as an off-white solid. Yield: 4.89 g (105.2%), ESI-MS: m/z=374 [M+H]+
Reaction SMILES: OC1C(O)CCN(C(C)[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[C:26]([O:29][CH2:30][C:31]3[C:35]5[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=5[O:33][CH:32]=3)[CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13][CH2:12]2)C1.[CH2:42]1[CH:47]2C(CO)[CH2:49][CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1>>[CH2:42]1[C@@H:47]2[C@H:49]([CH2:10][N:11]3[CH2:12][CH2:13][CH:14]([NH:17][C:18]([C:20]4[NH:21][C:22]5[C:27]([CH:28]=4)=[C:26]([O:29][CH2:30][C:31]4[C:35]6[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=6[O:33][CH:32]=4)[CH:25]=[CH:24][CH:23]=5)=[O:19])[CH2:15][CH2:16]3)[CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1
Reactant: OCC1CCCN2CCOCC12
Reactant: CC(CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(Cl)cc45)cccc3[nH]2)CC1)N1CCC(O)C(O)C1
Product: O=C(NC1CCN(C[C@@H]2CCN3CCOC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from the compound 176 (see example 138) and (9RS,9aSR)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (67) analogously to the method described in example 127.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[CH2:46][OH:47])[CH:36]=[CH2:37].[H-].[Na+]>CN(C=O)C>[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[CH2:46][O:47][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)[CH:36]=[CH2:37]
Reactant: C=CCc1cc(F)c(F)cc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(F)c(F)cc4CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (200 mg, 0.342 mmol) and (2-allyl-4,5-difluorophenyl)methanol (63.0 mg, 0.342 mmol) in DMF (2 mL) at 0° C. was added NaH (13.69 mg, 0.342 mmol). It was stirred at 0° C. for 2 h, then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((2-allyl-4,5-difluorobenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 43.6%) as an oil. LCMS (M+1)=641.5.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH3:21])[C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:20])=[O:9])=[CH:4][CH:3]=1.C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[CH2:32]([O:31][C:29]([CH:28]1[C:27](=[O:26])[C:15]2[C:14](=[C:13]3[C:18](=[CH:17][CH:16]=2)[CH:19]=[C:10]([C:8](=[O:9])[N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:21])[CH:11]=[N:12]3)[N:20]=[CH:34]1)=[O:30])[CH3:33]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN(Cc1ccc(F)cc1)C(=O)c1cnc2c(N)cccc2c1
Product: CCOC(=O)C1C=Nc2c(ccc3cc(C(=O)N(C)Cc4ccc(F)cc4)cnc23)C1=O
Yield: 64 %

Procedure:
Using a procedure analogous to that described in Example 2, in the section relating to the preparation of starting materials, 3-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-8-aminoquinoline was reacted with diethyl ethoxymethylenemalonate to give 3-ethoxycarbonyl-8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dihydro-1,10-phenanthroline in 64% yield, mp 206-207° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([I:24])=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=C[C:35]=2N=N1.C(N(C(C)C)C(C)C)C.CO>ClCCl>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([I:24])=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([O:9][CH3:35])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc2sc3c(c2c(I)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 30 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetic acid (Preparation 15, 1.0 g, 2.178 mmol) in dichloromethane (34 mL) was added [(benzotriazol-1-yloxy)-dimethylamino-methylene]dimethyl-ammonium hexafluoro phosphate (1.24 g, 3.266 mmol) and ethyl-di-isopropyl-amine (600 μL, 3.266 mmol) and the resulting reaction mixture was stirred at 30° C. for 2 hours. Methanol (17 mL) was added and the reaction mixture was stirred at 30° C. for 18 hours. The reaction was cooled to room temperature and diluted with dichloromethane (50 mL). The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with 5% ethyl acetate in heptane to give the title compound as a white solid, 963 mg, in a 93% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.85-1.88 (m, 4H), 2.65 (s, 3H), 2.82-2.86 (m, 2H), 3.23-3.26 (m, 2H), 3.68 (s, 3H), 5.94 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:37]=[CH:36][C:8]([C:9]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:10])=[CH:7][CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:16]=3)[CH:11]2[C:9](=[O:10])[C:8]2[CH:36]=[CH:37][C:5]([O:4][CH2:3][CH2:2][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][NH:38]3)=[CH:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: C1CCNCC1
Reactant: O=C(c1ccc(OCCBr)cc1)C1c2ccc(OCc3ccccc3)cc2CCN1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCC2CCCCN2)cc1)C1c2ccc(OCc3ccccc3)cc2CCN1c1ccc(F)cc1
Yield: 73.6 %

Procedure:
A solution of 1-[4-(2-bromethoxy)benzoyl]-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.80 g, 1.43 mmol) and piperidine (0.86 g, 10.1 mmol) in dimethylformamide was stirred at room temperature for 3 hours. The reaction was quenched with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified by chromatography (SiO2, ethyl acetate and 3-5% methanol/ethyl acetate) to provide the title compound (0.594 g, 74% yield): 1H NMR (CDCl3) 8.00 (m, 2H), 7.40 (m, 4H), 6.79-6.92 (m, 10H), 5.87 (s, 1H), 5.02 (s, 2H), 4.15 (t, 2H), 3.72 (m, 1H), 3.48 (m, 1H), 3.07 (m, 1H), 2.79 (t and m, 3H), 2.51 (m, 4H), 1.61 (m, 4H), 1.46 (m, 2H); ES−MS (m/z) 565 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[Cl:35][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(NC(=O)c3ccc(F)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(NC(=O)c2ccc(F)cc2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 59.1 %

Procedure:
The product from Example 238d (0.88 g, 1.6 mmol) was reacted with Fe and NH4Cl as described for Example 9E to give the desired product (0.50 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][OH:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:30]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>O.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][OH:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:30]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:31])[CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCCC1
Reactant: Nc1nc2cc(Br)ccc2c2c1nc(CO)n2CC1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC#N
Solvent: O
Product: Nc1nc2cc(-c3cccc(C(=O)N4CCCC4)c3)ccc2c2c1nc(CO)n2CC1CCOCC1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a mixture of [4-amino-7-bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (400 mg, 1.00 mmol), 3-pyrrolidinylcarbonyl phenyl boronic acid (328 mg, 1.50 mmol), potassium carbonate (455 mg, 3.30 mmol), dimethoxyethane (4 mL), and water (2 mL) under a nitrogen atmosphere was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The resulting suspension was refluxed for 18 hours. The reaction was cooled to ambient temperature. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-40% CMA/CHCl3) gave material that was stirred in acetonitrile and filtered to provide 100 mg of [4-amino-7-[3-(pyrrolidin-1-ylcarbonyl)phenyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol as a white powder, m.p. 281-284° C. MS (APCI) m/z 486.3 (M+H)+; Anal. calcd for C28H31N5O3: C, 69.26; H, 6.43; N, 14.42. Found: C, 68.99; H, 6.16; N, 14.46.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]1)[CH:22]=[CH2:21]
Reactant: CC(=O)N1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(C2CCN(C(C)=O)CC2)nc2ccccc21

Procedure:
The title compound was prepared from 1-(4-(1-H-benzoimidazol-2-yl)-piperidin-1-yl)ethanone (from Step A), sodium hydride, allyl bromide and DMF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:15][C:14]3([CH2:18][CH:17]([NH:19][C:20]([O:22][CH2:23][C:24]4[O:28][N:27]=[C:26]([C:29](OCC)=[O:30])[CH:25]=4)=[O:21])[CH2:16]3)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:34][NH2:35]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][C:14]3([CH2:16][CH:17]([NH:19][C:20](=[O:21])[O:22][CH2:23][C:24]4[O:28][N:27]=[C:26]([C:29](=[O:30])[NH:35][CH3:34])[CH:25]=4)[CH2:18]3)[CH2:15]1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(C2)CN(c2ccc4cc(F)ccc4n2)C3)on1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1cc(COC(=O)NC2CC3(C2)CN(c2ccc4cc(F)ccc4n2)C3)on1

Procedure:
In a sealed tube, a solution of 0.130 g (0.28 mmol) of ethyl 5-[2-(6-fluoroquinolin-2-yl)-2-azaspiro[3.3]hept-6-ylcarbamoyloxymethyl]isoxazole-3-carboxylate, prepared in step 11.9., in 4.13 mL (28.01 mmol) of a solution (8M) of methylamine in ethanol, is stirred at room temperature for 5 hours. The mixture is evaporated to dryness. The residue obtained is crystallized from hot ether. The precipitate thus formed is filtered off and rinsed thoroughly with ether. After drying under vacuum at about 60° C., 0.05 g of pure product is obtained in the form of a white powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:24]1[C:33]2[C:28](=[CH:29][C:30]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:31][CH:32]=2)[NH:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1nc(Br)ccc1OCCCOc1ccccc1
Reactant: CN1CCNc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCN3C)ccc1OCCCOc1ccccc1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
Methyl 6-bromo-3-(3-phenoxypropoxy)picolinate (26C) (141 mg, 0.38 mmol) in 1,4-dioxane (1.0 mL) was added dropwise to a mixture of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoxaline (25F) (105 mg, 0.38 mmol), K2CO3 (207 mg, 1.52 mmol), tetrabutylammonium bromide (12.1 mg, 0.038 mmol), and dichlorobis(triphenylphosphine)palladium(II) (11.3 mg, 0.015 mmol) in 1,4-dioxane (2.5 mL) and water (1.3 mL) at rt. The mixture was microwave (150W) heated to 100° C. for 5 min, cooled, diluted with water and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-70:30, to provide 27 mg (16%) of the desired product methyl 6-(1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinate (26D): 1H NMR (300 MHz, CDCl3) δ 7.71-7.23 (6H, m), 6.92 (3H, m), 6.58 (1H, d), 4.31-4.13 (6H, m), 3.98 (2H, t), 3.92 (3H, s), 2.30 (2H, t).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.BrN1C(=O)CCC1=O.[OH-].[K+]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)C>[F:6][C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[CH:10]=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCc1ccc(-c2ccccc2)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: C=Cc1ccc(-c2ccccc2)c(F)c1
Yield: 55.6 %

Procedure:
In 750 ml. of carbon tetrachloride was dissolved 10 g of 2-fluoro-4-ethylbiphenyl. Then to the solution were added 10 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide. After cooling, a solid substance was filtered off, and from the filtrate containing α-(2-fluoro-4-biphenylyl)ethyl bromide was distilled off the carbon tetrachloride. The residue thus obtained was dissolved in 500 ml. of ethyl alcohol, and then added with 17 g of potassium hydroxide. The resultant mixture was refluxed under heating for 1 hour. After cooling, the reaction mixture was poured into 2.5 l. of water, and then subjected to extraction with benzene. The benzene layer was washed with water, and dried with magnesium sulfate. The benzene in the layer was distilled off, and the resulting residue was subjected to column chromatography. From hexane eluate was obtained 5.5 g of 2-fluoro-4-vinylbiphenyl.