Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[N:9]=[C:10]([CH2:12][CH3:13])[N:11]=[C:4]2[CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[N:5]2[N:9]=[C:10]([CH2:12][CH3:13])[N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CCc1nc2cc(Cl)nc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc2cc(Cl)nc(Cl)n2n1

Procedure:
In analogy to Example 11A, 285 mg (80% of theory) of the product are obtained from 312 mg (1.57 mmol) of 7-chloro-2-ethyl[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 102A) by reaction with phosphoryl chloride.
Reaction SMILES: C(N1CCO[C@H]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC1C=C(C=CC=1)CBr>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Reactant: O=C1COCCN1Cc1ccccc1
Agent: Cc1cccc(CBr)c1
Product: Cc1cccc(CC2OCCN(Cc3ccccc3)C2=O)c1

Procedure:
N-Benzyl-2-(3-methylbenzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 3-methylbenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:13])=[CH:10][C:11]=1[OH:12])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19](Cl)=O.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19]1[O:12][C:11]2[C:6]([C:4](=[O:5])[CH:3]=1)=[CH:7][CH:8]=[C:9]([OH:13])[CH:10]=2
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (18 mmol, 3.6 equivalents) is added in one portion to a well-stirred solution of 2,4-dihydroxyacetophenone (5 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at about 0° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 3,4-dimethoxybenzoyl chloride (5.9 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 3′,4′-dimethoxy-7-hydroxyflavone. 1H NMR (250 MHz, DMSO-d6): δ=3.85 (d, 6 H), 6.85–8.00 (m, 7 H), 10.72 (s, 1 H); 13C NMR (250 MHz, DMSO-d6): δ=56.08 (s), 56.22 (s), 102.95 (s), 105.82 (s), 109.76 (s), 112.11 (s), 115.19 (s), 116.51 (s), 119.38 (s), 123.97 (s), 126.80 (s), 149.40 (s), 152.10 (s), 157.79 (s), 162.41 (s), 162.94 (s), 176.70 (s); EI-MS (70 eV) m/e (rel. abund.)=298; UV (2-propanol): λ=236 nm, 332 nm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:6]=[CH:7][C:8]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[C:15]([C:17]2[C:18](=[O:25])[NH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=1[O:30][CH3:31].[CH3:37][O-:38].[Na+]>CO>[C:26]([C:13]1[C:12]([O:30][CH3:31])=[C:11](/[CH:10]=[CH:9]/[C:8]2[CH:7]=[CH:6][C:5]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:4][C:3]=2[CH2:2][O:38][CH3:37])[CH:16]=[C:15]([C:17]2[C:18](=[O:25])[NH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:14]=1)([CH3:28])([CH3:29])[CH3:27]
Reactant: C[O-]
Reactant: COc1ccc(-c2cc(/C=C/c3ccc(NS(C)(=O)=O)cc3CBr)c(OC)c(C(C)(C)C)c2)c(=O)[nH]1
Agent: [Na+]
Solvent: CO
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)[nH]c2=O)cc(C(C)(C)C)c1OC

Procedure:
step 3—A solution of 324 (93 mg, 0.162 mmol) in MeOH (10 mL) and sodium methoxide (10 mL, 5 mmol, 0.5 M methanol solution) was stirred at RT overnight. The reaction mixture was concentrated, diluted with EtOAc and acidified with 6N HCl (1 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The crude product was purified on a preparative TLC plate developed with 2:1 EtOAc/hexane to afford 26 mg (31%) of I-209 as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:5][C:6]=1[Br:7].CC(C)([O-])C.[K+].[CH3:26][S:27][CH2:28]Cl>O1CCCC1.O.CCOCC>[Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)[N:5]([CH2:26][S:27][CH3:28])[C:6]=1[Br:7]
Reactant: N#Cc1c(-c2ccc(C(F)(F)F)cc2)[nH]c(Br)c1Br
Reactant: CSCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CSCn1c(Br)c(Br)c(C#N)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 4,5-dibromo-2-(α,α,α-trifluorop-tolyl)pyrrole-3-carbonitrile (0.56 g, 1.42 mmol) in dry tetrahydrofuran, under nitrogen, is treated portion-wise with potassium t-butoxide (0.21 g, 1.81 mmol), stirred at 25° C. for 3/4 hour, treated dropwise with chloromethyl methyl thioether (0.18 g, 1.81 mmol), stirred at room temperature for 16 hours, heated at 49°-60° C. until reaction is complete by thin layer chromatography. The reaction mixture is diluted with water and ether. The phases are separated and the organic layer is dried over MGSO4 and concentrated in vacuo to give a black oil residue. The residue is flash chromatographed (silica/100:100:1 ether:petroleum ether:ethyl acetate) to give the title product as a red solid, mp 140°-145° C., identified by H1NMR and mass spectral analyses.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].C(=O)([O-])O.[Na+]>C1COCC1>[OH:32][CH2:31][CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH2:33][CH2:34][OH:35]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: OCCNCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(CCO)CCO)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (10 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added diethanolamine (222 μl). The mixture was refluxed for 34 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/triethylamine=10/1) and recrystallized from ethyl acetate-hexane to give N-[4-[N,N-bis(2-hydroxyethyl)-aminomethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 51) (148 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[O:24][CH3:25]>>[NH2:1][C:2]1[C:3]([C:4]([C:18]2[C:17]([O:24][CH3:25])=[CH:16][CH:21]=[C:20]([F:22])[C:19]=2[F:23])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: COc1cc(F)c(F)cc1Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 2-bromo-4,5-difluoroanisole (Apollo) using the procedure described in Example 7. HRMS, observed: 298.0318, Calcd for M+: 298.0321.
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:12]([O:14]N1C(=O)CCC1=O)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:29][C@H:30](C(O)=O)[CH2:31][CH2:32][C:33](=[O:35])[OH:34].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]>>[CH2:31]([C@H:30]([NH2:29])[C:22]([NH:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5]([OH:6])=[O:11])=[O:24])[CH2:32][C:33]([OH:35])=[O:34].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Hydrocodone was prepared by a similar method to Example 38 except the amino acid starting material was Boc-Glu(OtBu)-OSu and the conjugate starting material was Glu-Hydrocodone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:10](=O)[CH2:11][CH3:12])=[C:5](OC)[CH2:6][CH3:7].Cl.[Br:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.CCN(CC)CC>CO>[CH3:1][O:2][C:3]([C:4]1[C:10]([CH2:11][CH3:12])=[N:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=2)[C:5]=1[CH2:6][CH3:7])=[O:14]
Reactant: NNc1cccc(Br)c1
Reactant: CCC(=O)C(C(=O)OC)=C(CC)OC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1nn(-c2cccc(Br)c2)c(CC)c1C(=O)OC
Temperature: -20 °C
Reaction time: 20 h

Procedure:
A solution of 7.10 g (35.5 mmol) of (E and/or Z)-3-methoxy-2-propionyl-pent-2-enoic acid methyl ester in 10 ml of MeOH was added to a solution of 8.09 g (35.5 mmol) of 3-bromophenylhydrazine hydrochloride in 150 ml of MeOH and the mixture was cooled to −20° C. To this mixture was added a solution of 3.79 g=5.22 ml (37.2 mmol) of Et3N in 40 ml of MeOH drop by drop and the reaction was then warmed up to RT. After 20 hours, it was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 7.62 g of the title compound as light red oil. MS: 337.1 (MH+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:33].[OH-].Cl>C1COCC1.O>[C:29]([O:28][C:26]([N:11]1[CH2:10][C@@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:18]([CH2:19][C:20]([O-:22])=[O:21])[C:17](=[O:25])[C:12]21[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:27])([CH3:32])([CH3:30])[CH3:31].[Li+:33]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C12CCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (8R)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate from Step C (50 mg, 0.11 mmol) in THF (0.75 mL) and H2O (0.25 mL) was added 1 N aqueous LiOH (0.12 mL, 0.12 mmol) and the resulting mixture was stirred at ambient temperature for 6 h. The mixture was adjusted to pH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=369 (M-C4H7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=CC=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][CH3:31])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC=O
Product: CCNc1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 60.5 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (101 mg, 0.24 mmol), acetaldehyde (21.1 mg, 0.48 mmol) and NaBH(OAc)3 (141.99 mg, 0.67 mmol) yielded 66 mg (60.5%) of intermediate 5a. MS (ESI) 455.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(C)cc2)n1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(-n2nc(C(=O)O)cc2-c2cccc(C(F)(F)F)c2)cc1
Yield: 80 %

Procedure:
Starting from 450 mg (1.2 mmol) of ethyl 1-(4-methylphenyl)-5-[3-(trifluoro-methyl)phenyl]-1H-pyrazole-3-carboxylate from example 15A and 135 mg (2.4 mmol) of potassium hydroxide, 334.7 mg (0.97 mmol, 80% yield of theory) are obtained as crystals according to method described in example 7A.
Reaction SMILES: C(O)(=O)C.Cl.[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C@@H:12]([CH2:18][CH3:19])[C:13]([O:15]CC)=[O:14])=[CH:9][C:8]=1[NH:22][C:23](=[O:38])[C@H:24]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27]>O>[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C@@H:12]([CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[NH:22][C:23](=[O:38])[C@H:24]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27]
Reactant: CCOC(=O)[C@H](CC)Cc1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](Cc1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C(=O)O
Temperature: 140 °C

Procedure:
15.2 ml of acetic acid and 7.6 ml of concentrated hydrochloric acid were added to 1.96 g (3.89 mmol) of ethyl (+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)butanoate. The reaction mixture was stirred under reflux for 5 h (bath temperature 140° C.). After cooling, water was added. The mixture was extracted repeatedly with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. Chromatography of the residue on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→2:1) gave 1.46 g (78.6% of theory) of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(C[O:46][S:47]([CH3:50])(=O)=[O:48])=CC(C2C=CC(S(C)(=O)=O)=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:47]([CH3:50])(=[O:48])=[O:46])=[CH:23][CH:22]=2)=[N:17]1)[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Agent: CN1CCNCC1
Product: Cc1c(-c2ccc(S(C)(=O)=O)cc2)nn(CC(C)C)c(=O)c1N1CCN(C)CC1
Yield: 88.5 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 88.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:13]#[C:14][Si](C)(C)C)[CH:7]=[CH:8][N:9]=2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:13]([C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)#[CH:14]
Reactant: COc1ccc2nccc(C#C[Si](C)(C)C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccnc2ccc(OC)nc12
Reaction time: 1.5 h

Procedure:
A solution of 2-Methoxy-8-trimethylsilanylethynyl-[1,5] naphthyridine in methanol (80 mL) was treated with potassium carbonate (4.49 g, 32 mmole) and stirred 1.5 hrs. The reaction mixture was concentrated to dryness, redissolved in ethyl acetate, and partitioned with brine. The biphasic mixture was filtered to facilitate separation. Organic layer was dried over sodium sulfate, filtered, concentrated and chromatographed in 1:1 ethyl acetate:hexane to give the product as a cream colored solid. δH (CDCl3, 400 MHz), 8.73 (d, J=4Hz, 1 H), 8.20 (d, J=9 Hz, 1 H), 7.68 (d, J=4 Hz, 1H), 7.16 (d, J=9 Hz, 1 H), 4.15 (s, 3H), 3.67 (s, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C=O)C>[O:3]=[C:2]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: NC(=O)CCl
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)C(=O)c2ccccc21
Temperature: 90 °C
Yield: 60.5 %

Procedure:
To a mixture of isatin (5.0 g, 35 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetamide (3.74 g, 40 mmol) in a 100 mL of flask was added DMF (25 mL). The resulting mixture was heated at 90° C. (oil temp.) for 2 h. After cooling to rt, it was poured onto ice/H2O (200 mL) and the resulting precipitate was collected by suction filtration to give 2-(2,3-dioxoindolin-1-yl)acetamide (4.32 g) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.30 (s, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 4.25 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:43])[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1)[CH3:34]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([CH:33]([CH3:34])[C:32]([OH:43])=[O:31])=[CH:40][CH:39]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)C(C)c1ccc(C=O)cc1
Product: CC(C(=O)O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-(4-formyl-phenyl)-propionic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 555.
Reaction SMILES: C(OC([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH2:17][CH3:18])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O)C.[OH-].[Na+]>>[CH2:17]([C:11]1[N:10]=[C:9]2[C:14]([C:15]([OH:16])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1)[CH3:18]
Reactant: CCOC(=O)c1c[nH]c2nc(CC)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(O)ccnc2n1
Yield: 73 %

Procedure:
The product from Example 3d (4.70 g, 19.1 mmol) was reacted with NaOH (0.808 g, 20.2 mmol) following the procedure of Example 1c giving the title compound as a light green solid (2.43 g, 73%).
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[I:15]Cl>C(O)(=O)C>[I:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: ClI
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Solvent: CC(=O)O
Product: O=C1C(=O)N2CCCc3cc(I)cc1c32
Temperature: 0 °C

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (5 g) and iodine monochloride (5 g) in acetic acid (30 ml) was refluxed for 5 hours. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and then dried over anhydrous sodium sulfate. Evaporation of chloroform afforded the title compound. The compound was recrystallized from ethanol to give 6.2 g (73.8%) as dark red needles.
Reaction SMILES: [Na+].[I-].Cl[CH2:4][CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH3:23][NH2:24]>>[N:13]1([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][NH:24][CH3:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: CN
Reactant: ClCCC(c1ccccc1)n1ccc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CNCCC(c1ccccc1)n1ccc2ccccc21
Temperature: 100 °C
Yield: 90 %

Procedure:
A suspension of NaI (0.235 g, 1.56 mmol) and 1-(3-chloro-1-phenyl-propyl)-1H-indole (0.141 mg, 0.52 mmol) in ethanolic methylamine solution (33%, 2 mL) was heated at 100° C. for 1 hour under microwave irradiation (sealed tube). The reaction mixture was poured into water (30 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4), and evaporated under vacuum. Purification by chromatography (SiO2, CH2Cl2-MeOH—NH4OH, 18:1:0.1) gave 0.125 g (90% yield) of pure (3-indol-1-yl-3-phenyl-propyl)-methyl-amine as an oil. Treatment of this amino compound with an ethereal solution of HCl (2M, 0.26 mL) gave the corresponding hydrochloride salt (0.127 g) as a white powder: mp=218-219° C.; 1H NMR (DMSO) δ 2.53 (s, 3H), 2.60-2.89 (m, 4H), 5.86-5.91 (m, 1H), 6.585 (d, 1H, J=3.22 Hz), 6.98-7.12 (m, 2H), 7.20-7.34 (m, 5H), 7.52-7.54 (m, 2H), 7.71 (d, 1H, J=3.22 Hz), 9.0 (broad s, 1H); MS (EI) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5](C([O-])=O)[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)COCCO.CCOCC.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[CH:5][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)[O-])C1c1ccccc1OCc1ccc(C)cc1
Solvent: O
Solvent: CCOCC
Solvent: OCCOCCO
Product: COC(=O)C1=C(C)NC(C)=CC1c1ccccc1OCc1ccc(C)cc1
Yield: 59.6 %

Procedure:
3 g of monomethyl 1,4-dihydro-2,6-dimethyl-4-[2-(4-methylbenzyloxy)-phenyl]-pyridine-3,5-dicarboxylate were suspended in 30 ml of diethylene glycol, and the suspension was heated to 170° to 180° C. while stirring, a clear solution being formed with evolution of gas. The mixture was stirred for approx. 5 minutes at 180° C., and was cooled. The viscous solution was dissolved in an ether/water mixture with vigorous shaking, the mixture was separated, the aqueous phase was extracted with ether, and the combined ether phases were washed with 1N sodium hydroxide solution and twice with water. The ether phase was dried, filtered and concentrated. The resulting syrupy residue was crystallized in an ice-bath, using isopropanol or acetonitrile, and the crystals were filtered off under suction. 1.6 g of methyl 1,4-dihydro-2,6-dimethyl-4-[2-(4-methylbenzyloxy)-phenyl]-pyridine-3-carboxylate of melting point 107° C. to 109° C. were obtained.