Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:19]=[O:20].C(OCC)(=O)C>O1CCCC1>[CH3:6][C:7]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)c2occc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a nitrogen atmosphere, n-butyllithium (1.56 M hexane solution, 18.4 ml) was added at −35° C. to a solution (50 ml) of the 4,7-dimethylbenzofuran (3.5 g) in dry tetrahydrofuran. Then the resulting mixture was stirred for 15 min and N,N-dimethylformamide (5.6 ml) was added dropwise to the mixture. Next, the reaction mixture was heated to room temperature and ethyl acetate was added to the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the resulting crude crystals were washed with n-hexane to give 4,7-dimethylbenzofuran-2-carbaldehyde (2.3 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCN(C)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylate (126.6 mg, 0.34 mmol, 1.00 equiv) in methanol (12 mL), a solution of sodium hydroxide (72.6 mg, 1.81 mmol, 5.00 equiv) in water (2.5 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was sent for prop-HPLC. This resulted in 46 mg (38%) of 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][NH:9][CH2:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:20]([C:19]3[CH:23]=[C:15]([S:12]([CH3:11])(=[O:13])=[O:14])[CH:16]=[CH:17][C:18]=3[O:24][C@@H:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])=[O:21])[CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: Clc1ccc2c(n1)CNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (Example A8(b)) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Yellow foam. MS (m/e): 451.0 ({37Cl}[M+H]+, 41%), 449.2 ({35Cl}[M+H]+, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].[C:29]([CH2:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N1CCOCC1)C.C(Cl)CCl>CN(C)C=O>[CH:17]1([CH2:16][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([CH2:35][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:23][C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A mixture of 880 mg (2.23 mmol) of (S)-α-amino-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]imidazole-4-propionamide, 608 mg (2.45 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EpA 0 184 550), 0.35 ml (2.76 mmol) of 4-ethylmorpholine, 662 mg (4.9 mmol) of HBT and 529 mg (2.76 mmol) of EDC in 20 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is poured into a mixture of ice and 2N sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts are washed in succession with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution and combined. After drying the organic solution over magnesium sulphate the solvent is evaporated under reduced pressure and the residue (1.01 g), for purification, is chromatographed on 70 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/methanol/ether yields 900 mg of (S)-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide, melting point 160° , MS: 624 (M)+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:21])[N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=1)=[O:5])C.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:29][C:27]1[N:28]=[C:24]([NH:23][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:21])[N:15]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=2)=[O:5])[S:25][CH:26]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(C3CC3)nn2C)n1

Procedure:
The tide compound, was prepared from 3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow solid, MS (ISP): m/e=369.0 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.O>CN(C=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([N:27]3[CH2:28][CH2:29][CH:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=4)[CH2:25][CH2:26]3)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2nccnc2c1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc2nccnc2c1)N1CCC(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
0.48 g (2.55 mmol) of quinoxalin-6-ylacetic acid is mixed in 25 ml of DMF, and 1.07 ml of TEA, 0.68 g (2.55 mmol) of 4-(3-(trifluoromethyl)phenyl)piperidine hydrochloride and 1.13 mg of BOP are added thereto. The mixture is heated at ambient temperature overnight, 200 ml of water are added and extraction is carried out with ethyl acetate. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. A dark oil is thus obtained, which oil is purified by flash chromatography on a column of silica gel, elution being carried out with ethyl acetate. 0.76 g of the title product is obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(Cl)Cl>[OH:34][C:31]([CH3:32])([CH3:33])[CH2:30][C@@:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:20][C:19](=[O:35])[N:18]([C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:2]3([NH:1][C:45](=[O:47])[CH3:46])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:11][CH:12]=2)[CH3:17])[CH2:23][CH2:22]1
Reactant: C[C@@H](c1ccc(C#CC2(N)CCCCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC1(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CCCCC1
Yield: 47.2 %

Procedure:
A vial equipped with a flea stir bar was charged with (S)-3-((S)-1-(4-((1-aminocyclohexyl)ethynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (12 mg, 0.025 mmol), i-Pr2NEt (0.015 mL, 0.08 mmol) and CH2Cl2 (2 mL). Acetic anhydride (0.005 mL, 0.043 mmol) was added. The mixture was stirred overnight at rt and evaporated to dryness. The residue was purified by prep HPLC to afford the title compound (6.1 mg, 47%). LC-MS Method 1 tR=1.65 min, m/z=517, 459; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.30 (m, 1H), 1.51 (d, 3H), 1.65 (m, 6H), 1.87 (m, 2H), 1.99 (s, 3H), 2.14 (m, 3H), 2.21 (s, 2H), 2.35 (m, 1H), 2.78 (m, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:43]1([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:5]([N:51]2[CH2:52][CH2:53][CH:48]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:49][CH2:50]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
0.22 g (1.0 mmol) of 3-bromo-2-methyl-benzoic acid was dissolved in 10 ml of DMF and the solution was treated with 0.38 g (1.0 mmol) of HATU. Then, 0.42 ml=0.30 g (3.0 mmol) of Et3N was added and after 30 min, a solution of 0.16 g (1.0 mmol) of 4-pyrrolidin-1-yl-piperidine in 5 ml of DMF. After 3 hours, the reaction mixture was poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.33 g (95%) of the title compound as light red solid. MS: 351.2 (MH+, 1 Br).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)C>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCl
Yield: 99 %

Procedure:
A solution of 100 ml of 6-chloro-1-hexanol, 85 ml of acetic anhydride and 67 ml of pyridine in 300 ml of dry ethyl ether was stirred at room temperature for 1 h. The reaction mixture was washed 3 times with 100 ml of water and twice with 100 ml of saturated brine, dried over Na2SO4, filtered and evaporated. Distillation afforded 133 g of 6-chlorohexanol acetate (99%), b.p. 132° C. (10 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: CCCN1C(=O)Cc2cc(N)cc(F)c21
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.500 g, 2.40 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.417 g, 2.40 mmol) and lithium trifluoromethanesulfonate (0.368 g, 2.40 mmol) in acetonitrile (8 ml) are heated at 90° C. for 8 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow solid. HPLC r.t. 4.30 min; MS for C19H28FN3O4 m/z 382.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0° C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)-pivalamide (6.7 g) as white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:20](O)=[O:21])[CH2:5]1)(=[O:3])[CH3:2].O[N:24]=[C:25]([NH2:30])[CH2:26][CH2:27][O:28][CH3:29]>>[F:18][CH:17]([F:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]2[CH2:7][CH:6]([C:20]3[O:21][N:30]=[C:25]([CH2:26][CH2:27][O:28][CH3:29])[N:24]=3)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: CC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)F)cc2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(C)=O)C2)n1

Procedure:
According to General Method 6A, 153 mg (0.270 mmol, purity 50%) of the compound from Example 59A and 41.3 mg (0.297 mmol, purity 85%) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 46.6 mg (32% of theory, purity 72%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)[C:11](=[O:20])[CH:10]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:24][CH:23]=2)=[O:18])[C:11](=[O:20])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O

Procedure:
117 mg (0.36 mmol) of 2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 83 mg (47% of theory)
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 72 %

Procedure:
A mixture of methyl 20-phthalimidoeicosanoate (5.0 g, 10.6 mmoles), 100 ml of ethanol, 80% hydrazine hydrate (1.0 ml, 15.9 mmoles) was refluxed for 9 hours. After the addition of 26.5 ml of 6N aqueous hydrochloric acid, the reaction mixture was further refluxed for 1 hour. The insoluble matter that formed was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue were added 70 ml of ethanol and 42.4 ml of 1N aqueous sodium hydroxide solution, and the obtained reaction mixture was refluxed for 16 hours. The reaction mixture was neutralized by adding 6N aqueous hydrochloric acid solution under ice-cooled condition. The precipitates that formed were collected by filtration and recrystallized from ethanolacetic acid-water, to give 20-aminoeicosanoic acid (2.50 g, 72%) having the following properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([OH:12])=[CH:5]2.[CH3:13]N(C)C=O.CI>CO.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][CH3:13])=[CH:5]2
Reactant: Oc1cc2cc(Br)ccc2cn1
Reactant: CN(C)C=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CI
Product: COc1cc2cc(Br)ccc2cn1
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 14 %

Procedure:
A mixture of 6-bromoisoquinolin-3-ol (606 mg, 2.70 mmol), silver carbonate (1.5 g, 5.3 mmol), and N,N-dimethylformamide (12 mL) was stirred at room temperature for 16 minutes. Methyl iodide (186 μL, 2.97 mmol) was added and the reaction was left stirring for 18 hours. The reaction was diluted with methanol and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give the title compound (90 mg, 14%). +ESI (M+H+1) 240.0; 1H NMR (400 MHz, CDCl3, δ): 8.91 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 1.8 Hz, 1H), 6.90 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH2:28][CH2:29][CH3:30]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[O:19]=[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]=O)=[CH:28][C:23]=2[CH2:22][O:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:30][CH2:29][C:27]3[CH:26]=[CH:25][C:24]4[C:20](=[O:19])[O:21][CH2:22][C:23]=4[CH:28]=3)[CH2:17][CH2:18]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: CNc1cc(CCN2CCNCC2)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
A solution of crude 2-(methylamino)-4-(2-piperazin-1-ylethyl)benzonitrile (˜18 mg, 0.05 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (9 mg, 0.05 mmol) and NaBH(OAc)3 (100 mg, 0.47 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(methylamino)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.8, 1H), 7.22˜7.32 (m, 3H), 6.42˜6.47 (m, 2H), 5.22 (s, 2H), 4.50˜4.58 (m, 1H), 2.84˜2.91 (m, 7H), 2.72˜2.77 (m, 2H), 2.53˜2.67 (m, 10H). (0.43 μM)
Reaction SMILES: [CH:1]1[C:17]2[C:16]([C:18]([OH:20])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:26]O>>[CH:1]1[C:17]2[C:16]([C:18]([O:20][CH3:26])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1c2nc3ccccc3c-2[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1c2nc3ccccc3c-2[nH]c2ccccc12

Procedure:
To a suspension of quindoline-11-carboxylic acid (2.3 g, 8.77 mmol) from Example 1 in MeOH (50 mL) was added concentrated H2SO4 (1.5 ml, 28 mmol). The resulting solution was refluxed for 8 hours, cooled, and partitioned between benzene (100 mL) and water (50 mL). After adjusting the pH to 9 with a saturated solution of K2CO3, the benzene layer was separated, washed with water, dried and concentrated. Purification by LPLC (EtOAc-hexane 1:3) gave 0.28 g of the title compound as greenish-yellow crystals (from hexane), mp 152-153.5° C. [lit 152.5-154° C. (Degutis, Y. A.; Ezyarskaite, A. B. Khim. Geterotsik. Soedin. 1986, 1375)]; 1H NMR (CDCl3) δ 9.75 (s, 1H), 9.09 (d, J=6.4, 1H), 8.51 (d, J=8.0, 1H), 8.38 (d, J=7.2, 1H), 7.72-7.62 (m, 3H), 7.49 (d, J=8.0, 1H), 7.38 (t, J=8.0, 1H); 13C NMR (CDCl3) δ 168.19, 147.81, 144.43, 143.56, 133.91, 130.50, 130.27, 127.40, 126.18, 125.05, 123.66, 122.23, 121.65, 121.06, 111.19, 109.21, 52.54; MS (EI, m/z) 276 (M+). Acidification of the water layer with HCl gave 1.8 g (78.3%) of recovered starting material.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
A mixture of 3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.548 g; 1.35 mmol) and sodium azide (0.262 g; 4.04 mmol) in DMF (8 mL) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. The residue was diluted in ethyl acetate, washed with brine, dried and concentrated under reduced pressure to afford 0.500 g (quantitative yield) of the title compound as a brown oil.
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[NH:1]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCOc1ccc(Nc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCOc1ccc(Nc2ccccc2)cc1

Procedure:
Methyl 4-(p-anilinophenoxy)butyrate prepared by the method of Example 1 was hydrolyzed in a mixture of aqueous potassium carbonate and N,N-dimethylformamide. The reaction mixture was acidified with hydrochloric acid and the solids precipitated thereby were collected and recrystallized from ethanol. The 4-(p-anilinophenoxy)butyric acid thus obtained was a greyish crystalline solid, m.p. 110°-111° C.