Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.54 g, 0.76 mmol) prepared in example 55c in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (1 mL, 5.53 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated with ethyl acetate and hexane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.3 g, 75%).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:13][C:12]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:11][C:10]=1[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:26]([CH3:29])([CH3:27])[CH3:28])[CH:11]=[C:10]([C:30]3[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=3)[C:9]=2[OH:8])=[CH:18][CH:19]=1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C=Cc2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(N)cc2)c1O
Reaction time: 8 h
Yield: 65.8 %

Procedure:
step 4—A mixture of 52 (311 mg, 0.630 mmol) and Pd(OH)2 (20% wt. on carbon, 103 mg, 0.146 mmol) in EtOAc (10 mL) and MeOH (10 mL) was stirred under a H2 atmosphere overnight. The catalyst was filtered, and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25% EtOAc) to afford 156 mg (66%) of 2-[2-(4-amino-phenyl)-ethyl]-4-tert-butyl-6-(2-methoxy-pyridin-3-yl)-phenol (54) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:6])[CH2:5][NH:4][CH2:3]1.[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[F:1][C:2]1([F:6])[CH2:5][N:4]([C:21]([C:20]2[CH:24]=[CH:25][N:26]=[CH:27][C:19]=2[NH:18][C:16]([C:14]2[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=[C:10]([CH:7]3[CH2:9][CH2:8]3)[N:15]=2)=[O:17])=[O:22])[CH2:3]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(Nc1cnccc1C(=O)N1CC(F)(F)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 26 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3,3-difluoroazetidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound as yellow powder (26%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1ccccc1
Product: O=c1c2sc3ccccc3c2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.75 (s, 2H); 7.20-7.45 (m, 6H); 7.56 (ddd, J1=8 Hz, J2=1 Hz, 1H); 7.93 (d, J=9 Hz, 1H); 8.15 (d, J=8 Hz, 1H); 11.06 (br s, 1H); retention time=2.57 min., m/z=325.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11])[CH:12]=[O:13]
Reactant: OCc1ccc(C(F)(F)F)c(I)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(C(F)(F)F)c(I)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
The product from Example 4C in chloroform (60 mL) was treated with manganese dioxide (1.45 g, 16 mmol). After refluxing for 12 hours, the mixture was allowed to cool to ambient temperature, filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 15% ethyl acetate:hexanes to provide the title compound (0.5 g, 42% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]([CH3:21])([CH3:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][S:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:21])[CH3:20])(=[O:17])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCN1CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 4-(2-methanesulfonylethyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (510 mg, 1.59 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white solid (320 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.49 (s, 1H); 3.12-3.03 (m, 5H); 2.92-2.84 (m, 4H); 2.60 (s, 2H); 2.53-2.47 (m, 2H); 1.06 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: COc1ccc(C(=N)N)cc1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1ccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound, MS: m/e=375.3 (M+H+), was prepared from 4-methoxybenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:16]3[C@@H:17]4[C@@H:22]([C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]nnc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 58 %

Procedure:
The title compound is prepared from 1H-benzotriazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 58% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.Cl.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:6]2([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:5]3[CH:4]=[C:3]([CH:2]([F:16])[F:1])[CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:20][CH:19]=1
Reactant: ClCc1ccncc1
Reactant: FC(F)c1ccc2c(c1)Cc1ccccc1-2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: FC(F)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the method of Example 1 from 0.6 g (2.78 mmole) of 2-difluoromethylfluorene, 1.14 g of 4picolylchloride hydrochloride, 32 mg benzyltriethylammonium chloride, 4 ml of 50% sodium hydroxide solution, and 25 ml of toluene by reaction at 50° for 6 hrs. The product was chromatographed (silica, CH2Cl2 /MeOH,10:1) to yield 0.5 g, m.p. >300°; NMR (CDCl3,200 MHz) δ: 3.43 (S,4H), 6.45(d,J=5.7Hz,4H), 6.74(t,J=56.6Hz,1H), 7.26-7.70(m.arom.), 8.1(d,J=5.7Hz,4H), HRMS calculated for C26H20N2F2 : 398.1595 Found: 398.1583.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[N:29][CH:30]=1>>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:38])[F:39])=[CH:30][N:29]=4)=[CH:32][C:33]3=[O:37])[CH:10]=2)[C:6]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 76.8 %

Procedure:
tert-Butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (100 mg, 0.417 mmol) and 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (197 mg, 0.542 mmol), were reacted following the procedure of Example 30 (step g) to provide the title compound (168 mg, 66%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.07 (dd, J=8.3, 1.9 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.58 (overlapping dd, J=7.1 Hz, 2H), 7.37 (s, 1H), 7.26 (d, 1H under solvent), 7.08 (dd, J=8.3, 1.7 Hz, 1H), 7.03 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[O:35])[O:33]C(C)(C)[O:31][C:30]=4[CH:38]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:26]3[CH:27]=[CH:28][C:29]([C:34]([OH:35])=[O:33])=[C:30]([OH:31])[CH:38]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O
Solvent: C1CCOC1
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)O)c(O)c1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)hexanamide in the presence of THF as a pale yellow powder (81%). 1H NMR (CDCl3, 300 MHz) δ 10.62 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.15 (m, 4H), 6.69 (m, 1H), 6.55 (m, 0.5H), 6.53 (m, 0.5H), 4.90 (s, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.17 (t, J=7.6 Hz, 2H), 1.68-1.52 (m, 4H), 1.40-1.28 (m, 2H), 1.27-1.13 (m, 4H), 0.93 (t, J=7.3 Hz, 3H), 0.91 (t, J=6.8 Hz, 3H). M− (ESI): 496.7; M1(ESI): 498.1. HPLC, Rt: 5.92 min (Purity: 97.5%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 78 %

Procedure:
As described for example 73c, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (95 mg, 78%) which was obtained as a light yellow foam. MS: m/e=394.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:30]([CH2:31][CH:32]=O)=[C:29]2[C:24]([C:25](=[O:36])[CH2:26][C:27]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[C:30]([CH2:31][CH2:32][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=4)[CH:9]=[CH:8]3)[CH2:5][CH2:6]2)=[C:29]2[C:24]([C:25](=[O:36])[CH2:26][C:27]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
120 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 163 mg of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolved in 10 ml of methylene chloride. Thereafter, 0.06 ml of acetic acid was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 15 minutes. Thereafter, 157 mg of sodium triacetoxyborohydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (methanol-ethyl acetate), followed by solidification with ethyl acetate, so as to obtain 220 mg of the subject compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O.C1(C)C=CC=CC=1>[C:17]1([CH2:16][O:15][C:13]([NH:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer and internal thermometer, sodium hydroxide (61.65 g, 1.541 mol) was dissolved in distilled water (1000 ml). To this solution, L-methionine (100.0 g, 0.670 mol) was added at room temperature. The solution was cooled in an ice bath (internal temperature 30° C.) and benzyl chloroformate (110 ml, 0.737 mol) was added over 10 minutes. After a 15 minute induction period, the internal temperature rose from 3° C. to 12° C. over 30 minutes and then dropped to 0° C. over 15 minutes. The reaction was stirred at 0° C. for 2 hours, during which time the initially cloudy reaction mixture became homogeneous. The ice bath was removed, and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was transferred into a separatory funnel and washed with hexane (2×300 ml). The aqueous layer was acidified with 6N hydrochloric acid to pH 5 and diluted with ethyl acetate (600 ml). The mixture was further acidified to pH 2. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×600 ml). The organic extracts were combined and washed with brine (750 ml), dried (magnesium sulfate), filtered and concentrated in vacuo to produce a light yellow oil. The crude product (oil) was dissolved in toluene (1500 ml), and the solution was concentrated to half of its volume. A second portion of toluene (750 ml) was added, and concentrated again such that 630 ml of toluene remained. This solution was stored at 5° C. overnight, during which time some of the product crystallized from solution. The solid was redissolved by warming to room temperature. Toluene (134 ml) was then added (a few seed crystals remained). With mechanical stirring, heptane (500 ml) was added in 30 ml portions at 10 minute intervals (approximately 3 hours total addition time). At this point, the product started to crystallize from solution. An additional portion of heptane (1020 ml) was added over 1.5 hours, and the resulting slurry was stirred for 2 hours. The product was collected by vacuum filtration, washed with 1:2 toluene:heptane (3×150 ml) and heptane (3×500 ml) and air-dried to give 158.6 g of title product as a white solid; m.p. 66° C.; [α]D =-1.5° (c=1, 95% ethanol). TLC (ethanol:water, 3:1) Rf =0.78.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:18]21[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), cyclopentanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 h at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0434 g, 28%) as a yellow solid:
Reaction SMILES: [OH-].[K+].BrC(Br)(F)F.[C:8]1([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C(O)CCC>[C:8]1([CH2:14][C@H:15]([NH2:17])/[CH:16]=[CH:14]\[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)Cc1ccccc1
Agent: FC(F)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: N[C@H](/C=C\c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
552.7 mg (9.85 mmol) potassium hydroxide was dissolved in methanol, absorbed onto 1.1 g aluminum oxide and then dried in a high vacuum. At 5-10° C., 307 μL (3.3 mmol) dibromodifluoromethane was added by drops to a solution of 240 mg (0.82 mmol) (2S)-1-benzylsulfonyl)-3-phenylpropan-2-amine and 1.56 g of the potassium hydroxide prepared in this way on aluminum oxide in 6.2 mL n-butanol. The reaction mixture was stirred for two hours at RT, then filtered through Celite, and the residue was rewashed well with dichloromethane. The filtrate was concentrated and the resulting residue was dried in vacuo. The resulting raw produce was purified by preparative HPLC, yielding 98 mg (35% of the theoretical) of the title compound with an E/Z diasteromer ratio of 4:1.
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.BrCCCC1C=CC(C)=NC=1.CC1N=CC(CCCN(C2C=CC(C)=CC=2)N)=CC=1.C(OC(OCC)CCCNC)C.[CH3:53][NH:54][CH2:55][CH2:56][C:57]1[C:65]2[C:60](=[CH:61][CH:62]=[C:63]([CH3:66])[CH:64]=2)[N:59]([CH2:67][CH2:68][CH2:69][C:70]2[CH:71]=[N:72][C:73]([CH3:76])=[CH:74][CH:75]=2)[CH:58]=1.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[CH3:53][N:54]1[CH2:55][CH2:56][C:57]2[C:65]3[C:60](=[CH:61][CH:62]=[C:63]([CH3:66])[CH:64]=3)[N:59]([CH2:67][CH2:68][CH2:69][C:70]3[CH:71]=[N:72][C:73]([CH3:76])=[CH:74][CH:75]=3)[C:58]=2[CH2:3]1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1cn(CCCc2ccc(C)nc2)c2ccc(C)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cc1ccc(CCCBr)cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccc(C)nc2)CN(C)CC1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 5-(3-bromopropyl)-2-methylpyridine, and triethylamine (General Method 1), 1-(3-(6-methylpyridin-3-yl)propyl)-1-p-tolylhydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and N-methyl-2-(5-methyl-1-(3-(6-methylpyridin-3-yl)propyl)-1H-indol-3-yl)ethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13](O)=[C:12]([N+:21]([O-:23])=[O:22])[C:11]1=[O:24])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13]([Cl:3])=[C:12]([N+:21]([O-:23])=[O:22])[C:11]1=[O:24])[CH2:7][CH2:8][CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(O)c2cccnc21
Product: CCCCn1c(=O)c([N+](=O)[O-])c(Cl)c2cccnc21
Temperature: 25 °C
Yield: 56.1 %

Procedure:
Phosphorus oxychloride (20 ml, 0.21 mol) was added to 2.0 g (7.6 mmol) of 1-n-butyl-4-hydroxy-3-nitro-1,8-naphthyridin-2(1H)-one [J. Heterocyclic Chem., 22, 193 (1985)], and the mixture was heated to reflux for 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure and ice water was added to the resulting residue. The mixture was neutralized with 4N aqueous solution of sodium hydroxide, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=20/1) to give 1.2 g (yield 56%) of Compound d as colorless crystals.