Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[CH2:31][C:32]([CH3:36])([CH3:35])[C:33]#[N:34].O>CS(C)=O>[CH3:31][C:32]([CH3:36])([CH2:35][N:20]1[C:21]2[C:17](=[CH:16][C:15]([S:12]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)(=[O:13])=[O:14])=[CH:23][CH:22]=2)[C:18]2([O:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:19]1=[O:24])[C:33]#[N:34]
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Reactant: CC(C)(C#N)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
At room temperature, to a stirred solution of potassium t-butoxide (0.287 g, 2.56 mmol, 1.2 eq) in anhydrous DMSO (4 mL) was added 5′-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (0.72 g, 2.13 mmol). After stirring 20 minutes, 3-chloro-2,2-dimethylpropionitrile (3 eq) was added drop-wise and the reaction was heated at 130° C. for 20 hr. The reaction mixture was heated at 126° C. for 16 h. After cooling to room temperature, the reaction was poured into H2O (100 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH H4OH (97/2/1) followed by a second chromatography eluting with 50/50 Pet. ether/EtOAc to give the title compound as a white solid (0.69 g, 77% yield). NMR: consistent.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)=[O:6])([CH3:3])[CH3:2].[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[N:20]=[N:19]1>>[NH:18]1[C:22]2[CH:23]=[CH:24][C:25](/[CH:27]=[C:11]3/[C:12](=[O:17])[NH:13][C:14]4[C:10]/3=[CH:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:16][CH:15]=4)=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: CC(C)NC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CC(C)NC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2

Procedure:
According to the method of Example A20, except substituting 1-isopropyl-3-(2-oxoindolin-5-yl)urea (23 mg, 0.099 mmol) and 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (15 mg, 0.11 mmol), the title compound was obtained as an orange solid (6 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.01 (s 1H), 7.75 (s, 1H), 7.57-7.59 (m, 2H), 7.31 (d, J=7.6 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.76 (d, J=7.6 Hz, 1H), 3.75-3.70 (m, 1H), 1.03-1.00 (d, 6H); MS ESI 363.1 [M+H]+, calcd for [C20H19N5O2+H]+ 363.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[C:16]([NH2:32])[C:15]=2[F:33])[CH2:9]1)=O)(C)(C)C.[ClH:34]>C(O)(=O)C>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[C:16]([NH2:32])[C:15]=2[F:33])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c(F)c(OC2CCNC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
7-(t-Butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (105 mg), 0 5 ml of concentrated hydrochloric acid and 2 xl of acetic acid were used. The compound was treated in a similar manner to Example 1-(2) and recrystallized from ethanol, whereby 82 mg of the title compound was obtained.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(OC(C)C)O[CH:9]([CH3:11])[CH3:10].C(O)(C)C>O.S([O-])(O)(=O)=O.[Na+]>[CH:9]([O:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCCC1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC1=CCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 84.12 grams (1 mol) of cyclopentanone, 195.2 grams (1.03 mol) of triisopropyl orthoformate and 60 grams of isopropanol (1 mol) was stirred in a 500 ml three-neck round bottom flask at room temperature. To this mixture, 3.8 g (0.028 mol) of sodium hydrogensulfate monohydrate was added, and the temperature of the reaction mixture was heated and maintained at 40° C. for about one hour. The progress of the reaction was monitored by GC until the cyclopentanone content was reduced to less than 2%. The isopropanol and isopropyl formate were distilled off under reduced pressure while the temperature of the reaction mixture was increased to a maximum of 65° C. The reaction mixture was cooled to room temperature and the pH value was adjusted to about 7˜8 by adding about 0.2 gram of potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cyclopentanone and 64 grams (0.51 mol) of 1-isopropoxy-1-cyclopentene was isolated as a clear liquid at a yield of 51%. The purity of the product exceeded 98%.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C>[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1
Reactant: CCCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 97.5 %

Procedure:
1.57 g (3.78 mmoles of H-Nle-Asp-D-Phg-NH2.HCl are reacted with 1.52 g (3.78 mmoles) of BOC-Trp-OSu in 50 ml of DMF in the presence of 1.06 ml (7.6 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the residue is admixed with water, and the suspension is filtered. 2.45 g (97.5%) of BOC-Trp-Nle-Asp-D-Phg-NH2 are obtained; m.p.: 217° C. (decomposition), Rf5 :0.35, [α]D -32.7° (c: 1.0, in dimethyl formamide).
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C(Cl)Cl>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:31])([CH3:32])[C:28]([Cl:36])=[O:29])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (prepared according to the procedures described in U.S. Pat. No. 5,081,138 issued Jan. 14, 1992; 0.25 g, 0.53 mmol) suspended in CH2Cl2 (5 mL) was added oxalyl chloride (48 uL, 0.56 mmol) and catalytic DMF. The reaction was stirred at room temperature for 3 hours, and then concentrated to give I-1, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH3:10][C:11]1[C:12]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1>>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:21]2[CH2:22][CH2:23][N:18]([C:12]3[C:11]([CH3:10])=[CH:16][C:15]([CH3:17])=[CH:14][N:13]=3)[CH2:19][CH2:20]2)=[O:9])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1csc(Br)c1
Product: Cc1cnc(N2CCN(C(=O)c3csc(Br)c3)CC2)c(C)c1
Yield: 76.2 %

Procedure:
Using 5-bromothiophene-3-carboxylic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (462 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (700 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][NH:44][S:45](ON1C(=O)CCC1=O)(=[O:47])=[O:46]>C(#N)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:45]([NH:44][CH2:43][CH2:42][O:41][CH3:40])(=[O:47])=[O:46])[CH2:13][CH2:12]1
Reactant: O=C(CC1(c2ccc(-c3ccc(Cl)cc3)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Reactant: COCCNS(=O)(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCNS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(Cl)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-chlorophenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) and triethylamine (22.3 mg) in acetonitrile (2 ml) was added N-(2-methoxyethylaminosulfonyloxy)succinimide (55.6 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned with ethyl acetate and water. The organic layer was separated, washed with 5% citric acid solution, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (200:1, 100:1, 200:3) to give N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-chlorophenyl)-2-thienyl)-4-(2-methoxyethylaminosulfonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (80.0 mg) as a colorless amorphous powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Clc1ncnc2ccccc12
Reactant: OCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.4 %

Procedure:
To a solution of 1.1 g of sodium hydride in 50 ml of DMF was added 3.4 g of 2-(4-chlorophenyl)ethanol, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred overnight. The mixture was then poured into a mixture of ice in water. Solid was collected and recrystallized from pentane giving 0.149 g of the title product. Yield: 2.4%. M.P. 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][CH:20]2[C:22](Cl)=[O:23])=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:22]([C@@H:20]2[CH2:21][C@H:19]2[C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)=[O:23])[CH:3]=1
Reactant: O=C(Cl)C1CC1c1ccncc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccncc3)cc(Cl)n2n1
Yield: 62.1 %

Procedure:
In a 100 mL round-bottomed flask was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 2.74 g, 15.02 mmol) in pyridine (75 ml) to give a yellow solution. Then, at 0° C., 2-(pyridin-4-yl)cyclopropanecarbonyl chloride (7D, 0.19 g, 1.046 mmol) in pyridine (1 ml) was added to give a suspension. After the reaction was complete, saturated NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica using 20% MeOH/CH2Cl2 to provide trans-N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (7E, 213 mg, 4% for 3 steps) as a yellow solid. 1H NMR (DMSO-d6) δ: 11.43 (s, 1H), 8.46 (d, J=6.1 Hz, 2H), 7.97 (s, 1H), 7.15-7.27 (m, 2H), 6.40 (s, 1H), 2.39-2.46 (m, 4H), 2.28-2.35 (m, 1H), 1.46-1.67 (m, 2H). ESI-MS: m/z 328.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.C(Cl)Cl.[CH3:16][CH2:17][O:18]C(C)=O>>[O:12]1[CH2:16][CH2:17][O:18][CH:11]1[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C=O)ncc1[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1cc(C2OCCO2)ncc1[N+](=O)[O-]

Procedure:
2-(1,3-Dioxolanyl)-4-methyl-5-nitropyridine was synthesized by the method of Example XLIX except that the starting material was 4-methyl-5-nitropyridine-2-carboxaldehyde. Yield: 2.3 g (91%); mp 77°-79° C.; (lit mp 77° C.); TLC, Rf 0.74 (CH2Cl2 /EtOAc, 3:2, v/v); 1H NMR (90 MHz, CDCl3) δ 2.65 (s, 3H, 4-CH3), 4.10 (s, 4H, CH2CH2), 5.85 (s, 1H, 2-CH), 7.50 (s, 1H, 3-H), 9.12 (s, 1H, 6-H). Anal. (C9 H10N2O4) C, H, N.
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O-:6])=O)C.[C:11](OC(C)C)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC>>[CH2:4]([OH:6])[CH2:3][CH2:7][CH2:8][CH2:9][CH2:10][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: CCCCCCCCCCCCCC(=O)OC(C)C
Product: CCCCCCCCCCCCCCCCCCO

Procedure:
10 Mixture of cetostearyl 2-ethylhexanoate and isopropyl myristate "CERAMOLL" (Creations Aromatiques) 2.0 g
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:21](O)[CH2:20]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li][N:55]=[N+:56]=[N-:57].CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:27]([O:26][CH2:25][C@H:23]1[O:24][C@@H:19]([N:14]2[C:15]3[N:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:11]=3[N:12]=[CH:13]2)[CH2:20][C@@H:21]1[N:55]=[N+:56]=[N-:57])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Reactant: [Li]N=[N+]=[N-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N6 -Benzoyl-9-(5-O-benzoyl-2-deoxy-β-D-threo-pentofuranosyl)adenine (7.0 g, 15.3 mmol), triphenylphosphine (6.0 g, 22.9 mmol), and LiN3 (2.8 g, 56.4 mmol) were dissolved in DMF (100 mL). To this stirring mixture was added diethylazodicarboxylate (3.6 mL, 22.9 mmol) in one portion, the reaction was stirred for 2.5 h at RT, and the reaction was quenched with H2O (10 mL). The solvents were removed in vacuo, the residual oil was redissolved in EtOAc (300 mL) and extracted with H2O (2×200 mL) and saturated. aq. NaCl (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residual oil was purified on SiO2 (2-5% MeOH/CH2 Cl2) to afford 5'-O-Benzoyl-N6 -benzoyl-3'-azido-2',3'-dideoxyadenosine, 1a, as an amber foam, which was taken on directly to hydrogenation.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:22]C1C=C(B(O)O)C=CC=1>>[NH2:22][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: O
Product: Nc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (428 mg, 1.61 mmol) and 3-aminobenzeneboronic acid monohydrate (300 mg, 1.94 mmol) were coupled to yield 2-(3-aminophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 110 mg (25%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO) δ 3.03 (m, 2H), 3.39 (m, 2H), 5.24 (s, 2H), 6.59 (br d, 1H), 6.78 (d, J=7.7 Hz, 1H), 6.84 (m, 2H), 7.18 (m, 2H), 7.52 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 8.04 (br t, 1H), 11.41 (brs, 1H). HRMS (FAB, MH+)Calcd for C17H16N3O: 278.1293. Found: 278.1297. Anal. (C17H15N3O.1.1 H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[NH:9][C:8]([C:13]([NH2:15])=O)=[CH:7]2.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH:7]=[C:8]([C:13]#[N:15])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Product: N#Cc1cc2cccc(Cl)c2c(Cl)n1
Yield: 40 %

Procedure:
A solution of 8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (0.5 g, 1.99 mmol) in POCl3 (10 mL) was heated to reflux for 4 hours. The reaction mixture was subsequently concentrated in vacuo and the crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=5:1-2:1 gradient) to give the title compound (200 mg, 40%). ESI-MS m/z [M+H]+ 223.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=O>Br>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[NH:1][C:2]3[C:3]([C:8](=[O:20])[CH:9]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2N)cc1
Agent: Br
Product: O=c1cc(-c2ccc(O)cc2)[nH]c2ccccc12
Yield: 99 %

Procedure:
1-(2-Amino-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (375 mg, 1.49 mmol) was dissolved in 48% HBr (15 mL) and refluxed for 16 h. The solvent was removed at reduced pressure. The solids were taken into water and neutralized by NaHCO3. Solids were collected and purified by column chromatography using 5% MeOH in DCM to give 350 mg of 2-(4-hydroxy-phenyl)-1H-quinolin-4-one (98%). MS (ES): m/z: 238.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1C=O.[CH:14](OC)([O:17][CH3:18])[O:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:16][O:15][CH:14]([O:17][CH3:18])[C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[F:1]
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(OC)c1ccc(C(F)(F)F)cc1F
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A solution of 2-fluoro-4-trifluoromethylbenzaldehyde (10.0 g, 52.0 mmol), trimethyl orthoformate (55.0 g, 520 mmol) and a catalytic amount of p-toluene sulfonic acid (5 mol %) was stirred at room temperature for 24 hours. The resulting solution was saturated with the addition of solid Na2CO3 and stirred for 15 minutes. The mixture was then filtered and the solution was evaporated. The residue was diluted with ether and evaporated yielding 12.1 g (98%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[N:14]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc2[nH]c3c(c2cc1OC)CC(OC(=O)c1ccccc1)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(OC)c(OC)cc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-6,7-dimethoxy-9-carbethoxymethyl-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 but using 17.6 g. of 3-benzoyloxy-6,7-dimethoxy-1,2,3,4-tetrahydrocarbazole (see Example 4) and 2.14 g. of sodium hydride (56% in mineral oil) in 200 ml. of dimethylformamide, and 8.4 g. of ethyl bromoacetate. The crude product in ethyl acetate was filtered through alumina, the filtrate was evaporated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate to give 3-benzoyloxy-6,7-dimethoxy-9-carbethoxymethyl-1,2,3,4-tetrahydrocarbazole, m.p. 125°-127°C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[F:26][C:22]1[CH:21]=[C:20]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][N:7]3[N:6]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(F)c3)c(C(N)=O)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(-c2cccc(F)c2)nn2c1CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of Intermediate 4I (3.0 g, 8.32 mmol) in dichloromethane (20 mL) at 0° C. was added TFA (10.26 mL, 133 mmol) dropwise and stirred at room temperature for 1 h. TFA was removed from the reaction mixture and the residue was quenched with 10% NaHCO3 solution. The solid was filtered to obtain Intermediate 4J (2 g, 92%) as off-white solid, which was used in the next step without purification. MS(ES): m/z=261 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52-7.57 (m, 1H), 7.46-7.52 (m, 1H), 7.40-7.46 (m, 1H), 7.14-7.27 (m, 2H), 7.08 (bs, 1H), 4.03 (d, J=5.02 Hz, 4H), 3.13 (d, J=5.02 Hz, 2H), 2.64 (d, J=6.02 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20]O)[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20][Br:41])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(C=CCO)cc1-c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 2-(4-fluorophenyl)-4-(3-hydroxyprop-1-en-1-yl)benzoate (17 g), triphenylphosphine (22.8 g; 87 mmol) and tetrabromomethane (28.8 g; 87 mmol) in dichloromethane (200 ml) was stirred at 0° C. for 1 hour. After filtration of the insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with dichloromethanelpetroleum ether (30/70) to give methyl 2-(4-fluorophenyl)-4-(3-bromoprop-1-en-1-yl)benzoate as a mixture of E and Z isomers.