Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S)C.[H-].[Na+].[H][H].C[O:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]=[CH:15][N:16]3[CH:22]=[CH:21][CH:20]=[C:17]3[C:18](=[O:19])[C:12]=2[CH:11]=1.Cl>CN(C)C=O>[OH:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]=[CH:15][N:16]3[CH:22]=[CH:21][CH:20]=[C:17]3[C:18](=[O:19])[C:12]=2[CH:11]=1
Reactant: COc1ccc2ccn3cccc3c(=O)c2c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=c1c2cc(O)ccc2ccn2cccc12

Procedure:
Ethanethiol (0.62 g., 10 mmoles), dissolved in dimethyl formamide (10 ml.) is added to a suspension of sodium hydride (0.5 g. of 50% oil dispersion) in dry dimethyl formamide (5 ml.). The mixture is stirred until all hydrogen has evolved and 9-methoxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one (2.26 g., 10 mmoles) is added. The solution is refluxed for a period of 3 hours. The cooled reaction mixture is acidified with 0.2N HCl and extracted with chloroform. The organic layer is washed with water, dried over sodium sulfate and concentrated to yield 9-hydroxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([O:45][CH3:46])=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][C@H:62]([OH:65])[C@@H:61]([CH3:66])[CH2:60]2)CC1>>[ClH:1].[ClH:1].[OH:65][C@H:62]1[CH2:63][CH2:64][N:59]([CH2:58][CH2:57][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:42]5[C:41]([O:43][CH3:44])=[CH:40][C:39]([O:45][CH3:46])=[CH:38][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:60][C@@H:61]1[CH3:66]
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (126, see example 99) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:23]([C:20]1[CH:21]=[N:22][C:17]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1)[S:32]([CH3:31])(=[O:34])=[O:33])(=[O:34])=[O:33]
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.89 g, 2.9 mmol), triethylamine (0.61 mL, 4.4 mmol) and N,N-dimethylaminopyridine (catalytic amount) in 20 mL of dichloromethane is cooled to 0° C. and methanesulfonyl chloride (0.30 mL, 3.5 mmol) is added dropwise under nitrogen. The cold bath is removed and the solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of water, and the organic layer is dried (sodium sulfate). The solvent is removed under reduced pressure and the residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound as a white solid; mp 168°-169.5° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[NH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[S:5])[CH3:2]
Reactant: Nc1nccs1
Reactant: CCN=C=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=S)Nc1nccs1
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of ethyl isothiocyanate (1.74 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.48 g (13%) of the title product:
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34])([CH2:26][CH3:27])[CH3:25].N1CCCCC1>ClCCl>[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8])([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)c1ccccc1S
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 2-sec-butylbenzenethiol, and 2.1 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 67°-68° C.). 1H NMR (DMSO-d6) δ0.82 (q, 3H), 1.09 (t, 3H), 1.46-1.61 (m, 2H), 2.26 (m, 2H), 2.35 (m, 1H), 2.62 (m, 1H), 2.98 (m, 1H), 3.47 (q, 2H), 5.90 (t, 1H), 6.56 (t, 1H), 6.94 (t, 1H), 7.07-7.18 (m, 4H), 7.25 (m, 2H), 7.45 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3C3CCN(C)CC3)cc1OCC2
Temperature: 150 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene from Example 135 (160 mg, 0.480 mmol), TEA (0.50 mL), and 1-methyl-4-(pyrrolidin-2-yl)piperidine (161 mg, 0.960 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. The resultant mixture was then purified by reverse phase combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 106 (66 mg, 60% yield). LCMS (ESI): RT=4.11 min, m/z: 463.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6): δ 9.08 (t, J=10.5 Hz, 1H), 7.90 (t, J=10.5 Hz, 1H), 7.84 (t, J=10 Hz, 1H), 5.98 (t, J=20 Hz, 2H), 4.52-4.47 (m, 4H), 4.10 (s, 1H), 3.45 (d, J=6.5 Hz, 1H), 2.78 (s, 1H), 2.11 (d, J=10 Hz, 3H), 1.93-1.66 (m, 8H), 1.50-1.39 (m, 7H), 1.31-1.27 (m, 3H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([CH2:23][OH:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([CH:23]=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Next, to a solution of [(R)-2-(3′-chloro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (2.0 g, 5.53 mmol) in DCM (30 mL) is added Dess-Martin periodinane (2.81 g, 6.63 mmol). After being stirred at room temperature for 2 h, the reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give [(R)-2-(3′-chloro-biphenyl-4-yl)-1-formyl-ethyl]-carbamic acid tert-butyl ester (1.05 g). HPLC retention time=1.27 minutes (condition A): MS (m+1)=360.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:22]>CC(N(C)C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=[C:7]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=3)[CH2:29][CH2:30]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)nc(Cl)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(Oc4ccc(Cl)cc4Cl)cc(C(=O)OC)n3)CC2)ccc1OC
Yield: 17.8 %

Procedure:
A solution of 2-chloro-6-(2,4-dichloro-phenoxy)-pyrimidine-4-carboxylic acid methyl ester (50.0 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 15.0 mg (15%) of the title compound. MS (ISP): 561.2 [M+H]+.
Reaction SMILES: Cl.Cl.C([CH:5]1[C@@H:14]2[N:9]([CH2:10][CH2:11][C:12]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:13]=32)[CH2:8][CH2:7][C@H:6]1NCCCS(N)(=O)=O)#N.[C:30](N1C=CN=C1)([N:32]1C=CN=C1)=O.Cl>>[CH:5]1[CH:6]([C:30]#[N:32])[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]1[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12]=1[CH:11]=[CH:10]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#CC1[C@H]2c3oc4ccccc4c3CCN2CC[C@H]1NCCCS(N)(=O)=O
Agent: Cl
Product: N#CC1C=CN2C=Cc3c(oc4ccccc34)C2=C1

Procedure:
In the second step the first intermediate (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]-ethyl]methanesulfon-amide dihydrochloride (compound IV) reacts with 1,1′-carbonyldiimidazole in the presence of a hydrogen chloride acceptor, whereby a cyclic carbamide, the second intermediate (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzo-furo[2,3-a]quinolizine-2-carbonitrile (compound V) is formed.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[SH:30][C:31]1[CH:32]=[C:33]([C:37]2([OH:43])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][N:13]=1)=[CH:3][C:2]([S:30][C:31]1[CH:32]=[C:33]([C:37]2([OH:43])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)=[CH:11][CH:10]=3
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Reactant: OC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccccn6)n54)c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
5k (201 mg, 0.54 mmol) was suspended in 1,4-dioxane (4.5 mL) and degassed with N2 for 5 minutes. iPr2NEt (0.19 mL, 1.08 mmol) was added, followed by 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (51, 131 mg, 0.60 mmol) in 1,4-dioxane (1 mL). Pd2dba3 (13 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.03 mmol) were added, and the reaction was sealed and heated to 90° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (20-100% EtOAc in hexanes, followed by 0-10% MeOH in EtOAc) to obtain the desired product, 5p. Further purification by preparative HPLC was required, followed by standard aqueous workup of the combined fractions using EtOAc and saturated aqueous NaHCO3 to give clean product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[CH:4]=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[CH2:4][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(Cl)c(C=O)c(OC)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cl)c(CN2CCCCC2)c(OC)c1
Yield: 90.6 %

Procedure:
To a pre-stirred solution of 2-chloro-4,6-dimethoxybenzaldehyde (2.7 g, 13.5 mmol) and piperidine (1.46 mL, 14.9 mmol) in DCM (50 mL) at 0° C. was added sodium triacetoxyborohydride (4.29 g, 20.0 mmol) in portions. The reaction mixture was then allowed to warm to ambient and stirred for an additional 3 h before the addition of water (50 mL). The pH of the aqueous phase was adjusted to 2 by the addition of hydrochloric acid and then washed with DCM (50 mL). The pH of the aqueous phase was then adjusted to 9 by the addition of saturated aqueous sodium carbonate and then the organic component was extracted into DCM (50 mL), dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as a beige solid (3.3 g, 91%) that was used without further purification. 1H NMR (CDCl3, 300 MHz): 6.60 (d, J=2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.6-2.57 (v br m, 4H), 2.29-1.88 (br m, 4H), 1.71-1.40 (br m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([F:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>CCOC(C)=O>[CH2:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=2)[CH:17]=[C:8]([C:6]2[C:5]([F:23])=[CH:4][C:3]([F:24])=[C:2]([NH:1][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])[CH:7]=2)[C:9]1=[O:22])[CH3:21]
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(NC)cc21
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3n(CC)c2=O)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A suspension of Example A8 (0.078 g, 0.236 mmol) in EtOAc (1.5 mL) was treated with satd. NaHCO3 (1.5 mL) followed by isopropenyl chloroformate (0.036 mL, 0.331 mmol) and the bi-phasic mixture stirred vigorously at RT overnight. The layers were separated, the organic layer washed with brine, dried over MgSO4 and concentrated to dryness to afford prop-1-en-2-yl (5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (86 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 7.36 (t, J=10.2 Hz, 1H), 7.06 (m, 1H), 6.23 (s, 1H), 4.71 (d, J=7.9 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 415.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccnc1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
To a stirred solution of 200 mg (0.7 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (10 mL), 3-aminopyridine (0.098 mg, 1.04 mmol) was added portionwise. The resulting mixture was stirred at room temperature for five hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichloromethane/methanol 97:3) to yield the title compound (60 mg, 26% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(COCC(OCC)OCC)OCC
Temperature: 25 °C

Procedure:
Glycolaldehyde diethyl acetal (45.4 g, 338 mmol) was added dropwise to a stirred solution of sodium hydride (14.3 g, 60% dispersion in mineral oil, 357 mmol) in xylene (100 ml), and the reaction heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and bromoacetaldehyde diethyl acetal (100 g, 507 mmol) was added. The resulting solution was heated under reflux for 20 hours, then cooled to room temperature. The solvent was removed under reduced pressure, and the residual solution was distilled under reduced pressure (80° C. @ 6 mm Hg), to afford the title compound as a colourless oil, 60.8 g.
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[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[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]([CH2:35][C:32]4[CH:33]=[CH:34][O:30][CH:31]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 85.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-furaldehyde (365 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (310 mg) as yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33]>>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])=[CH:26][CH:27]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ccccc12
Reactant: CCOC(=O)CCNC
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2ccccc12
Yield: 73.2 %

Procedure:
Using 4-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example A10(3) and ethyl 3-(methylamino)propanoate (124 mg) and in the same manner as in Example A1(4), the title object compound (269 mg, 73%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[C:25]([CH3:27])([CH3:26])[O:24][C:23]([NH:28][C:29]45[CH2:36][CH:35]6[CH2:37][C:31]([C:38](=[O:40])[NH2:39])([CH2:32][CH:33]4[CH2:34]6)[CH2:30]5)=[N:22][S:21]3(=[O:42])=[O:41])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)CCC.[H][H].Cl>CO.[Pd]>[CH3:26][C:25]1([CH3:27])[O:24][C:23]([NH:28][C:29]23[CH2:36][CH:35]4[CH2:37][C:31]([C:38]([NH2:39])=[O:40])([CH2:32][CH:33]2[CH2:34]4)[CH2:30]3)=[N:22][S:21](=[O:41])(=[O:42])[C@@H:20]1[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CCCCOC(=O)N1CC=C(c2ccc([C@@H]3C(C)(C)OC(NC45CC6CC4CC(C(N)=O)(C6)C5)=NS3(=O)=O)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-{4-[(R)-2-(2-carbamoylhexahydro-2,5-methanopentalen-3a-ylamino)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid butyl ester (100 mg) in methanol (10 mL) was admixed with palladium on carbon (10%, 100 mg) and the mixture was stirred in a hydrogen atmosphere for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and TFA ester formed was cleaved by treatment with 1 N HCl. Extraction with ethyl acetate gave the crude product, which was used without further purification.