Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:40](=[O:39])[CH2:41][OH:42])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(Br)C.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:29][C:30]1[C:40]2[N:39](CC)[C:38](=[O:43])[C:37]([CH3:45])([CH3:44])[N:36]=[C:35]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:34]=2[CH:33]=[C:32]([N+:53]([O-:55])=[O:54])[CH:31]=1>CCOCC.CCCCCC>[Cl:29][C:30]1[C:40]2[NH:39][C:38](=[O:43])[C:37]([CH3:45])([CH3:44])[N:36]=[C:35]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:34]=2[CH:33]=[C:32]([N+:53]([O-:55])=[O:54])[CH:31]=1
Reactant: CCN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCBr
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 10 g (0.028 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and ethyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 8 days and chromatography of the crude product on silica gel (elution agent: methylene chloride), 9-chloro-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 117°-120° (ether/n-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][N:20]([C@H:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][CH2:35]1)[C:21]([C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1)=[O:22].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([N:31]2[CH2:32][CH2:33][CH:28]([C:25]3[S:26][CH:27]=[C:23]([C:21]([N:20]([CH3:19])[C@H:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37][CH2:36][CH2:35]4)=[O:22])[N:24]=3)[CH2:29][CH2:30]2)=[O:11])[N:3]=1
Reactant: O=C(O)Cn1nc(Cl)cc1Cl
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)c1csc(C2CCN(C(=O)Cn3nc(Cl)cc3Cl)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3,5-dichloro-1H-pyrazol-1-acetic acid (70 mg, 0.36 mmol) (i.e. the product of Example 12, Step F) in dichloromethane (1 mL) and a catalytic amount of N,N-dimethylformamide (1 drop) was treated with oxalyl chloride (0.1 mL, 1.1 mmol) and stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and re-dissolved in dichloromethane (1 mL). The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (100 mg, 0.26 mmol), triethylamine (0.1 mL, 0.72 mmol), and potassium carbonate (150 mg, 1 mmol) in dichloromethane (2 mL). The reaction mixture was then heated to reflux for 2 h, and then cooled to ambient temperature. The resulting suspension was diluted with dichloromethane (10 mL), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 80 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])[C:3]1=[O:27].OOS([O-])=O.[K+].[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:1][N:2]1[C:7]2[N:8]=[C:9]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])[C:3]1=[O:27]
Reactant: CSc1ncc2cc(-c3cc(-c4cc(C)no4)ccc3C)c(=O)n(C)c2n1
Reactant: NC1CCOCC1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1cc(-c2ccc(C)c(-c3cc4cnc(NC5CCOCC5)nc4n(C)c3=O)c2)on1

Procedure:
8-Methyl-6-[2-methyl-5-(3-methyl-isoxazol-5-yl)-phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 8-Methyl-6-[2-methyl-5-(3-methyl-isoxazol-5-yl)-phenyl]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: MS (M+H)=432.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:16][C:15]3[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+].Cl>CN(C)C=O.O>[O:20]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][CH2:29][C:30]([OH:32])=[O:31])=[C:12]([Cl:18])[C:11]=2[Cl:19])[CH2:16][C:8]1([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: CC1(c2ccc(F)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc(F)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 80 °C

Procedure:
A stirred mixture of 2-(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (1.04 g., 0.0032 mole), potassium carbonate (0.885 g., 0.0064 mole) and ethyl bromoacetate (1.07 g., 0.0064 mole) in dimethylformamide (30 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (30 ml.)-10 N sodium hydroxide solution (1 ml., 0.01 mole) and heated at 80° C. for one hour. The reaction mixture is added slowly to water (500 ml.) -12 N hydrochloric acid (10 ml.) to precipitate 450 mg. of [1-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 150°-156° C. after crystallization from ethyl acetate:hexane, 1:3.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]2[CH2:14][CH2:15][CH2:16][S:17]2(=[O:19])=[O:18])[CH:11]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(Br)cc1N
Product: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O

Procedure:
Using methyl 2-amino-4-bromobenzoate (5 g) and 3-chloropropane-1-sulfonyl chloride (3.44 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (5.32 g) was obtained.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CCCCCC>[CH:31]1([NH:37][Si:2]([CH3:23])([CH3:22])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[CH3:21])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCCC1
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl) silane (9c)) (5.5340 g, 0.01633 moles) was stirred in hexane (100 mL) as NEt3 (2.9673 g, 0.02932 moles) and cyclohexylamine (1.6373 g, 0.01651 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.8969 g, 89.9 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[C:10]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2[C:25]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:12]=2[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:13]=3[N:14]2[CH2:15][CH2:16][N:17]1[C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc2nc3n(c12)CCN(C(=O)OC(C)(C)C)C3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a stirred solution of tert-butyl (2-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}ethyl)carbamate (Reference example 223, 100 mg, 0.197 mmol) and triphenylphosphine (77.5 mg, 0.295 mmol) in tetrahydrofuran (2 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 0.135 mL, 0.296 mmol) at room temperature. The mixture was stirred at room temperature for 30 min, concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 15-30% ethyl acetate/n-hexane gradient mixture to give a yellow oil (54.8 mg, 0.119 mmol, 60%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]([OH:42])([CH2:27][C:28]2([C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=3[F:41])[CH2:30][CH2:29]2)[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:22](=[O:23])[O:21][CH2:20]3)=[O:15])=[CH:7][CH:6]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:42][C:13]([C:12]#[C:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)([CH2:27][C:28]1([C:31]2[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=[CH:33][C:32]=2[F:41])[CH2:29][CH2:30]1)[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:22](=[O:23])[O:21][CH2:20]2)=[O:15]
Reactant: CC(=O)Oc1ccc(C#CC(O)(CC2(c3cc(C(F)(F)F)ccc3F)CC2)C(=O)Nc2ccc3c(c2)COC3=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1OCc2cc(NC(=O)C(O)(C#Cc3ccc(O)cc3)CC3(c4cc(C(F)(F)F)ccc4F)CC3)ccc21
Yield: 91 %

Procedure:
A solution of the compound described under 6 (45 mg) in 5 ml of methanol was mixed with sodium bicarbonate (130 mg). Stirring was continued for 2 more hours at 23° C. Then, the reaction mixture was diluted with ethyl acetate. Then, it was washed twice with saturated sodium chloride solution. After drying on sodium sulfate, the crude product was purified on silica gel by column chromatography. 38 mg of product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: COc1cc(OC)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 22) (375 mg, 1.0 mmol) in CH2Cl2 (50 mL) was added BBr3 (1.0 M in CH2Cl2, 5.0 mL, 5.0 mmol) dropwise at 0° C., and the resulting mixture was stirred at room temperature overnight, then concentrated to dryness. Water (10 mL) was added at 0° C., followed by EtOAc (100 mL). The organic layer was separated, washed with brine (2×10 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 3:1) gave (1R,10R,11S,16S)-3-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-ol (Compound No. 25) (120 mg, 33%) as a white foam. 1H NMR (CDCl3): δ 6.15 (m, 2H), 4.46 (s, 1H), 3.78 (s, 3H), 3.25 (m, 1H), 2.90 (m, 1H), 2.76 (m, 1H), 1.84-1.32 (m, 6H), 1.30 (s, 3H), 1.29-1.00 (m, 4H), 0.95 (s, 3H), 0.94 (m, 1H), 0.85 (s, 3H), 0.85 (s, 3H). MS m/z 361 (C22H32O2S+H+).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([S:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:15](=[O:26])[NH:16][C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])(=[O:10])[CH3:9]>>[C:8]([S:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)[C:15](=[O:26])[NH:16][C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A 4.0 N hydrogen chloride/dioxane solution (14 ml) is added to t-butyl (2S)-2-[3-[2-(acetylthio)ethyl]-3-(2-cyclohexylethyl)ureido]propionate (Compound No. 5-1, 2.3 g), and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, to the resulting oily matter are added a 5% aqueous sodium hydrogencarbonate solution (30 ml) and ethyl acetate (30 ml), and the aqueous layer is separated from the organic layer. A 5% aqueous citric acid solution is added to the aqueous layer to acidify it, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 826 mg (42%) of the titled compound (Compound No. 7-1) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:35][CH3:36])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(C)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(C)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(4-methylbenzylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.22 ml) and sodium cyanoborohydride (0.25 g) were reacted and treated in the same manner as in Example 136 to give 0.7 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-methylbenzyl)amino)pentyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([O:14]C)=[CH:9][C:8]=1[Cl:16])=O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[Cl:16][C:8]1[C:7]2[N:6]=[C:4]([C:3]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:2]=3[Cl:1])[O:13][C:12]=2[CH:11]=[C:10]([OH:14])[CH:9]=1
Reactant: COc1ccc(C(=O)Nc2c(O)cc(OC)cc2Cl)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2nc3c(Cl)cc(O)cc3o2)c(Cl)c1
Yield: 92.4 %

Procedure:
2-Chloro-N-(2-chloro-6-hydroxy-4-methoxy-phenyl)-4-methoxy-benzamide (40 mg) was completely dissolved in THF (5 mL) and PPH3 (46 mg) was added and the mixture was stirred until all PPH3 dissolved. To this mixture was added drop wise DEAD (0.03 mL) diluted in THF (0.5 mL). The mixture was stirred at room temperature for 2 h and the reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 10% to 30% ethyl acetate-hexane afforded 32 mg (85%) of the title compound as a solid. MS: 324 (MH+), HPLC tR: 3.18 min.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[N:23]1([C:21](=[O:22])[CH2:20][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CCl)N1CCCCC1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c2c(c3cccnc31)CN1CCCC1C2)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.32 mmol) in DMF (1 mL) was added a suspension of NaH (40.0 mg, 0.986 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (159 mg, 0.986 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with ice-water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (10% MeOH-DCM) to yield 1-(piperidin-1-yl)-2-(8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)ethanone;
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[C:11](=S)[N:10]([C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni]>[C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[CH2:11][N:10]([C@@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])[CH2:9]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)C=CC[C@@H]2C1=S
Agent: [Ni]
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@H]2CC=C[C@@]2(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 65.5 %

Procedure:
[(1S,5S)-3-[(1R)-1-Phenylethyl]-4-thioxo-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylic acid tert-butyl ester (88.2 mg, 0.27 mmol) was dissolved in ethanol. Raney nickel was added, and the mixture was stirred for one hour. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to give 55.4 mg of the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([NH:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:16][CH2:17][CH2:18][NH:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1F
Reactant: NCCNc1ccccc1
Product: N#Cc1ccccc1NCCNc1ccccc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and N-phenylethylenediamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:20][CH2:19]1.C([O-])(=O)/C=C\C([O-])=O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=3)[C:5]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH2:20][CH2:19]3)=[CH:6]2)=[CH:12][CH:13]=1
Reactant: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-(2imidazolidinon-1-yl)ethyl)-4-piperidyl)-1H-indole, maleate.(Lu 23-174). M.p. 155°-160° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[CH:5]=[N:4][CH:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cncc2cccc(N)c12
Product: Cc1cncc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3)c12

Procedure:
Prepared fiom 4-methylisoquinolin-5-amine (Description 91) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:35]([O-:37])=[O:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:35]([O-:37])=[O:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
32 mg (0.06 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 21.2D) were hydrolysed with TFA according to General Method 2. Yield: 10 mg (36% of theory)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][O:16][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][CH2:13][C:12](=[O:11])[CH2:17][O:16]1
Reactant: CCOC(=O)C1(C)OCC(O)CO1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)OCC(=O)CO1
Reaction time: 0.33 h

Procedure:
To a chilled (−78° C.) DCM solvent (10 mL) under nitrogen was added a 2 M stock solution of oxalyl chloride (6.03 mL, 12.05 mmol), followed by the slow addition of dimethyl sulfoxide (0.927 mL, 13.06 mmol). Once evolution of gases stopped, stirring continued for another 20 minutes forming a snow white suspension. A solution of the crude ethyl 5-hydroxy-2-methyl-1,3-dioxane-2-carboxylate (Step 2, 1.91 g, 10.04 mmol) in 5 mL of DCM was transferred into the cold Swern solution over a period of 2 minutes via a cannula. The reaction was allowed to proceed at −78° C. for 30 minutes, followed by the slow addition of triethylamine (3.36 mL, 24.10 mmol). The resulting pale suspension was stirred at −78° C. for a further 30 minutes, then at 4° C. (ice bath) for 15 minutes. The Rx was quenched with saturated sodium bicarbonate solution (20 mL), followed by extraction with DCM (5×25 mL). The organic layers were combined, evaporated to an oily material (1.81 gm, 96%). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.45-4.37 (m, 2H), 4.31 (q, J=7.3 Hz, 2H), 4.33-4.26 (m, 2H), 1.58 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).