Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([C:35]#[N:36])=[CH:29][N:28]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:35]([C:30]1[C:31]([CH2:33][CH3:34])=[CH:32][C:27]([NH:26][C:25]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH:14]=[O:15])=[C:4]([CH:3]([O:2][CH3:1])[O:16][CH3:17])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:24])=[N:28][CH:29]=1)#[N:36]
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)N2CCCc3cc(C=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 90 °C

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 400 mg, 1.69 mmol), phenyl(5-cyano-4-ethylpyridin-2-yl)carbamate (intermediate 111, 773 mg, 2.89 mmol) and DMAP (293 mg, 2.40 mmol) in DMF (3 ml) was heated for 1 h at 90° C. The cooled reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, extracted 2× with EtOAc, the organic layers dried over Na2SO4 and evaporated. The residue was applied to a 40 g RediSep® column and purified by normal phase chromatography, eluting with hetane and then a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound. (UPLC-MS 6) tR 1.23; ESI-MS 410.3 [M+H]+.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: O=C1CCC2(CC1)OCCO2
Product: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Yield: 42 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (15.6 g, 100 mmole) and 3,4-difluorophenyl magnesium bromide (100 mmole) in the usual mariner. The crude product was crystallized from isopropyl ether to give the product (42%, mp: 118°-120° C.).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[C:14](=O)[C:15]([N:17]([CH3:24])[N:18]=[C:19]([CH3:23])[CH2:20][S:21][CH3:22])=[O:16])[CH3:4].O>O1CCCC1>[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[C:14]1[C:15](=[O:16])[N:17]([CH3:24])[N:18]=[C:19]([CH3:23])[C:20]=1[S:21][CH3:22])[CH3:4]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(SC)c(C)nn(C)c1=O
Yield: 40.6 %

Procedure:
To a 200 ml volume four-necked flask, tetrahydrofuran (anhydrous) (27.0 ml) and sodium hydride (1.90 g) were added under a nitrogen atmosphere at about 0° C., and stirred. Then, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39) (14.2 g) dissolved in tetrahydrofuran (anhydrous) (45 ml) was added dropwise over 30 minutes, and then the mixture was stirred at 0° C. for 2 hours. Then, to the mixture was added water (100 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=4:1) to give 5.45 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfanyl-2,3-dihydro-3-pyridazinone.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[CH2:35]([O:42][C:43]([NH:45][C:46]1[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=1)[O:49][CH2:50][C:51](O)=[O:52])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([NH:45][C:46]1[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=1)[O:49][CH2:50][C:51]([NH:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])=[O:52])=[O:44])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)COc1cccc(NC(=O)OCc2ccccc2)c1
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1cccc(NC(=O)OCc2ccccc2)c1
Yield: 50.2 %

Procedure:
Following a procedure similar to that described in Example 14, but using 0.45 g (0.91 mmol) of 1-[(2S,3S)-3-L-asparaginylamino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride and 0.30 g (1.00 mmol) of 3-benzyloxycarbonylaminophenoxyacetic acid, 0.34 g of the title compound were obtained as a colorless powder, melting at 107°-117° C.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:18][CH3:19])=[CH:14][N+:15]([O-:17])=[O:16])[N:7]=1.[CH2:20]([N:22](CC)[CH2:23]C)C.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][NH:18]/[C:13](/[NH:12][CH2:11][CH2:10][S:9][CH2:8][C:6]1[N:7]=[C:3]([CH2:2][N:22]([CH3:23])[CH3:20])[S:4][CH:5]=1)=[CH:14]\[N+:15]([O-:17])=[O:16]
Reactant: CCN(CC)CC
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1csc(CO)n1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Temperature: -20 °C
Yield: 50.5 %

Procedure:
In a 100 ml three-necked round bottomed flask, filled with a nitrogen atmosphere, equipped with a thermometer, stir bar and dropping funnel and installed in a temperature controlled cooling bath was placed 2.0 g of N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, prepared according to the process described in U.S. Pat. No. 5,541,335. Into the same flask was added 120 ml of methylene chloride, 2.0 g of triethylamine, and 0.04 g of 4-dimethylaminopyridine. The contents were cooled to -20° C. internal. To this mixture was added dropwise from the pressure-equalized dropping funnel 1.3 g of benzenesulfonyl chloride in 18.0 ml of methylene chloride so as to maintain the internal temperature of the reaction mixture at or below -20° C. When the starting material was almost entirely consumed (2-3.5 hours), as determined by thin layer chromatography on silica gel eluting with 8/2 v/v EtOAc/MeOH, approximately 7.0 ml of dimethylamine was condensed into the reaction mixture. The temperature was held at or near -20° C. When the intermediate had disappeared, as indicated by TLC, the volatile components of the mixture were removed under vacuum and the residue dissolved in 15 ml methylene chloride and 8.0 ml water. The pH of the aqueous phase was adjusted to pH 4.5 by addition of 3N HCl. This acidification aids dissolution. The lower organic layer was separated and the aqueous phase was washed twice with 8.0 ml portions of methylene chloride. The aqueous phase containing the product was retained and adjusted to pH 10.5 using saturated potassium carbonate solution. The separated crude product was extracted with three 15 ml portions of methylene chloride, which were combined and evaporated. To remove trace amounts of methylene chloride, the product was twice evaporated to dryness from a slurry in isopropanol. The residue was then dissolved hot in 20.0 ml of isopropanol and allowed to crystallize. The solid was cooled to 0-5° C. for 16 hours and then filtered and washed with cold isopropanol. The solid was dried at 40° C. under vacuum, to give 1.1 g (50.3%) of nizatidine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CN(C)CCCNc1ccccc1N
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.85 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.06 g) in chloroform (11 ml) and then dodecanoyl chloride (1.28 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.6 ml) was added to a solution containing the residue (2.23 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.14 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.33 g) as pale brown wax.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1ccc(C#C[Si](C)(C)C)cc1
Yield: 87.1 %

Procedure:
To 15.0 g (75.4 mmol) of 1-n-propyl-4-bromobenzene were added 8.8 g (89.8 mmol) of trimethylsilylacetylene and 100 ml of triethylamine (NEt3), and the reaction system was purged with argon. Next were added 81 mg (0.4 mmol) of copper (I) iodide (CuI), 324 mg (1.2 mmol) of triphenylphosphine, and 162 mg of dichlorobistriphenylphosphine palladium (II) [PdCl2(PPh3)2] to the reaction system, and the mixture was subjected to reaction for 24 hours with heating and refluxing. After completion of the reaction, the reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. After the resultant water-insoluble oil was extracted with hexane, the hexane phase was washed with water. By removing hexane from the hexane phase, 14.2 g (65.7 mmol) of 1-(4-n-propylphenyl)-2-trimethylsilylacetylene was obtained.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:36](=[O:38])[CH3:37])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was placed in 1 ml DCM and treated with DIPEA (0.04 ml; 0.23 mmol) and acetyl chloride (0.04 ml; 0.57 mmol). It was stirred at ambient temperature for 4 hours. The crude reaction mixture was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([O:11][CH3:12])=[O:10].Cl.[NH2:15][OH:16].O.Cl>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:15][OH:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: NO
Reactant: COC(=O)C(=O)c1ccccc1O
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(=NO)c1ccccc1O

Procedure:
3.3 g (0.016 mol) of methyl 2-hydroxyphenylglyoxylate (HPLC: 88%, log p=1.87) (Example VI-1a) and 1.3 g (0.019 mol) of hydroxylamine hydrochloride in 50 ml of methanol are heated under reflux for one hour. The reaction mixture is poured into water, acidified with 2N hydrochloric acid and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 2.4 g of crude product which, according to HPLC, contains 17.1% of methyl E-2-(2-hydroxyphenyl)-2-hydroxyimino-acetate of log p=0.95 and 68.9% of methyl Z-2-(2-hydroxyphenyl)-2-hydroxyimino-acetate of log p=1.68.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:49][CH:48]=[CH:47][CH2:46][CH2:45][N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:49][CH:48]=[CH:47][CH2:46][CH2:45][N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3C/C=C\CCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21
Agent: N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S,Z)-1-benzyl-2-oxo-1,2,3,4,7,8-hexahydroazocin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (8.0 mg, 0.014 mmol) and Intermediate 44 (6.5 mg, 0.028 mmol) to give a white solid (6.8 mg, 61% yield). Anal. Calcd. for C45H54N4O6S m/z 778.7. found: 779.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.05 (m, 17H), 5.48-5.26 (m, 4H), 5.18-5.06 (m, 1H), 5.05-4.93 (m, 3H), 4.84 (d, J=14.8 Hz, 1H), 4.17 (d, J=14.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.67 (s, 3H), 3.14 (dt, J=14.3, 8.7 Hz, 2H), 2.87-2.66 (m, 5H), 2.61-2.32 (m, 6H), 2.25 (dt, J=16.4, 8.0 Hz, 1H), 2.06-1.97 (m, 2H), 1.86-1.44 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13](N)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:19].N([O-])=O.[Na+]>[Cu]Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccnc2N)CC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)[C@H]1CC[C@H](c2cccnc2Cl)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-amino-pyridin-3-yl)-cyclohexanecarboxylic acid ethyl ester (0.21 g, 0.86 mmol) in concentrated hydrochloric acid (3.7 ml, 43 mmol) was added solid sodium nitrite (1.49 g, 21.5 mmol) at 0-5° C. The cooling bath was removed and copper(I) chloride (3.58 g, 36.2 mmol) was added at room temperature. After stirring for 2 h the mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer was collected. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.093 g, 44%) as yellow oil. MS m/e: 268 ([M+H]+)
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Br)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.42 h
Yield: 81.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 110 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyazetidine hydrochloride, and 100 mg of N-methy-lpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 25 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 101 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CN(C)C=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>[Cu]I.CO>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:33]=[N:34][NH:35][CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (80 mg, 0.254 mmol) and copper(I) iodide (2.423 mg, 0.013 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and Methanol (0.200 mL). Trimethylsilyl azide (0.059 mL, 0.509 mmol) was added and the resulting mixture was stirred under microwave irradiation at 100° C. for 5 h then cooled to room temperature. The solution was partitioned between AcOEt and water/brine (1/1) and the layers were separated. The aqueous phase was extracted three times with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using MDAP (modifier: ammonium bicarbonate). The appropriate fractions were concentrated in vacuo and the residue dissolved in DCM. The organic phase was dried using a phase separator then concentrated in vacuo to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (30 mg, 0.084 mmol, 33.0% yield) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29].O>CN(C)C=O>[C:28]([O:27][CH2:26][CH2:25][O:8][C:4]1[C:3]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:30])[CH3:29]
Reactant: Cn1nc(O)c(-c2ccc3c(c2)OCO3)c1N
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
5-Amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-ol (Preparation 34) (11.39 g) was dissolved in dimethylformamide (40 ml), cesium carbonate (15.9 g) was added followed by 2-bromoethylacetate (8.16 g). The mixture was stirred at room temperature for 16 hours. The mixture was treated with water (750 ml) and extracted with ethyl acetate (2×250 ml). The organic fractions were combined washed with water (3×350 ml), brine (250 ml), dried over magnesium sulfate, filtered and evaporated. The crude product was purified on silica (300 g) eluting with ethyl acetate:hexane (3:1) to yield the title compound as a white solid (5.57 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([CH:15]=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C)C=O.O>[Br:29][C:15]1[C:16]2[C:21]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:9]3[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Brc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.6 %

Procedure:
9-(4-Bromophenyl)anthracene (6.3 g, 19 mmole) was dissolved in anhydrous dimethylformamide (DMF) (100 ml). To the resultant solution, a solution (15 ml) of NBS (3.7 g, 21 mmole, 1.1 eq) in anhydrous DMF was added and the obtained mixture was stirred at the room temperature for 7 hours and left standing for one night. After the reaction mixture was diluted with water (30 ml), the formed solid was separated by filtration and washed with methanol and a yellow solid (6.0 g, 77%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2].[Br:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:44][C:41]2[CH:42]=[CH:43][C:38]([Br:37])=[CH:39][C:40]=2[C:45]([F:48])([F:46])[F:47])[CH2:8][C@H:7]1[CH2:16][O:17][C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(Br)cc2C(F)(F)F)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 68 step 8 using (1R,2R)-4-methanesulfonyloxy-2-trityloxymethyl-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, example 152 step 3) and 4-bromo-2-trifluoromethyl-benzenethiol (example 58, intermediate 1). Colorless oil (43%). MS (EI): 691.0 (M+Na)+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4](N)=[C:3](N)[CH:2]=1.[OH2:10].NN.[OH2:13]>>[CH3:9][C:1]1[CH:2]=[C:3]([OH:13])[CH:4]=[CH:5][C:6]=1[OH:10]
Reactant: Cc1ccc(N)c(N)c1
Reactant: O
Agent: NN
Product: Cc1cc(O)ccc1O

Procedure:
In an Erlenmeyer flask of approximately 500 ml capacity 0.263 g 3,4-toluene diamine (2.15 millimoles) is combined with 56 milliliters of distilled water and 66 milliliters of hydrazine hydrate. Subsequent additions of 2.2 millimoles CoCl2 · 6H2O in 2.62 milliliters of aqueous solution and 0.288 g of methylhydroquinone give, after shaking, a yellow-orange composition containing approximately 35% hydrazine and 0.6% of 3,4-toluene diamine/cobalt/methylhydroquinone catalyst. The molar ratio 3,4-toluene diamine/cobalt (II) is approximately 1.0 in this composition.