Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH2:46]1[O:54][C:53]2[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][C:48]=2[O:47]1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:51]2[CH:50]=[CH:49][C:48]3[O:47][CH2:46][O:54][C:53]=3[CH:52]=2)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccc3c(c2)OCO3)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (91.9 mg, 0.135 mmol), 3,4-methylenedioxyphenylboronic acid (112 mg, 0.676 mmol), Pd(PPh)3Cl2 (4.70 mg, 0.0067 mmol), 2 M Na2CO3 (aq., 0.203 mL, 0.405 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 30-100% CH3CN in 0.05% aqueous formic acid) afforded the product (47.7 mg, 49%) as a white solid.
Reaction SMILES: CO.[N+:3]([CH2:6][CH2:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)([O-])=[O:4].C[O-].[Li+].O1CCCC1.C(Cl)[Cl:30]>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[C:6]([Cl:30])(=[N:3][OH:4])[CH3:7].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:20][CH:19]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccccn2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Cl)=NO
Product: c1ccc(Oc2ccccn2)cc1
Temperature: -76 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a methanol solution (30 mL) of 2-(4-(2-nitro-ethyl)-phenoxy)-pyridine (2.0 g, 8.2 mmol) described in Manufacturing Example 209-1-3 was added lithium methoxide (470 mg, 12 mmol), and this mixture was concentrated under a reduced pressure. Toluene was added to the residue, and the solvent was evaporated under a reduced pressure. To a solution of this residue in methylene chloride (40 mL) and tetrahydrofuran (20 mL) was added titanium (IV) tetrachloride (2.3 mL, 21 mmol) while stirring at −76° C. This suspension was stirred for 15 minutes at 0° C., and then for another 20 minutes at room temperature. The mixture was poured into ice water and stirred for 30 minutes. Ethyl acetate was added, and the organic layer was separated, washed with aqueous sodium chloride (one time), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.1 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[NH2:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].Cl>C(#N)C.O1CCOCC1>[ClH:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: Nc1cc(O)ccc1Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Oc1ccc(Cl)c(Nc2ccnc3ccc(Br)cc23)c1
Yield: 88 %

Procedure:
500 mg (2.06 mmol) of 6-bromo-4-chloroquinoline in 20 ml acetonitrile are mixed with 325 mg (2.27 mmol) of 3-amino-4-chlorophenol and 0.5 ml of 1 M HCl solution in dioxane and heated under reflux for 3 days. The crystals which have separated out are filtered off with suction and dried under high vacuum. 700 mg (70%) of the title compound are obtained as hydrochloride.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.C([NH:16][C:17]([O:19]CC)=[O:18])C1C=CC=CC=1.[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.O>[CH2:28]([O:19][C:17]([NH:16][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CCOC(=O)NCc1ccccc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Product: C=C(NC(=O)OCc1ccccc1)C(=O)OCC

Procedure:
288 g of ethyl pyruvate, 250 g of benzylurethane, 2.5 g of p-toluenesulphonic acid and 1 g of hydroquinone are introduced into 2.5 l of toluene and refluxed for 9 h in a water separator. The reaction solution is then filtered through silica gel and washed with 500 ml of toluene. The filtrate is treated with 1 g of hydroquinone and concentrated to the greatest possible extent on a rotary evaporator. 376 g of ethyl N-benzyloxycarbonyl-2-amino-acrylate are obtained as an oil, which according to HPLC has a purity of about 90%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:13]#[C:12][CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cnn(CC#Cc2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(C#CCn2cc(C(=O)O)cn2)cc1
Yield: 90.2 %

Procedure:
1-(3-p-Tolyl-prop-2-ynyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.226 g, 0.84 mmol) was dissolved in a mixture of solvents THF: methanol:water (3:1:1, 10 ml) and LiOH (0.071 g, 1.7 mol) was added to the reaction mixture with stirring. The reaction mixture was then stirred at 20-25° C. for 2 hours. Solvents were evaporated and the residue was diluted with water (0.5 ml) and acidified with dil. HCl, filtered and dried to obtain off white precipitate, 1-(3-p-Tolyl-prop-2-ynyl)-1H-pyrazole-4-carboxylic acid (0.182 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38]>>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([CH2:22][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:19][CH:18]=4)[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CS(=O)(=O)CCN
Reactant: COc1cc(Nc2ncnc3ccc(-c4ccc(C=O)o4)cc23)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)o4)cc23)ccc1OCc1cccc(F)c1

Procedure:
Prepared according to Procedure D from 5-(4-{3-methoxy-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.22 (s,1H); 8.78 (s,1H); 8.31 (d,1H); 7.88 (d,1H); 7.50–7.08 (m,8H); 6.84 (d, 1H); 5.13 (s,2H); 4.42 (s,2H); 3.80 (s,3H); 3.60 (m,2H); 3.40 (m, 2H, obscured by water peak); 3.10 (s,3H); MS m/z 577 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[N:32]([CH3:34])[CH3:33].[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:28][C:29]1[CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[CH:35]=[CH:36][C:37]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:17])[O:18]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N)c1
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3NC(C)=O)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in Example 13 above, 4.43 g (0.01 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared as described in Example 2, part A above, was interacted with 2.0 g (0.015 mole) of m-amino-N,N-dimethylaniline in the presence of ten ml of acetic anhydride to obtain 3-[2-acetamido-4-dimethylaminophenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R5 =CH3 ; ##STR31## R6 =CH2CH3 ; Y1 =H) which developed a blue-green color when spotted on silica gel in the form of a toluene solution.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (51 mg, 0.13 mmol), 3-methyltetrahydro-4H-pyran-4-one (46 mg, 0.4 mmol) and triethylamine (0.037 mL, 0.27 mmol) in dry methylene chloride (5 mL) was treated with sodium triacetoxyborohydride (85 mg, 0.40 mmol) at room temperature under N2 overnight. The reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (90 mg) was passed through a short silica gel pad (30:70 MeOH/EtOAc). The filtrate was concentrated and separated by chiral HPLC to give two isomers: first isomer; second isomer: MS calculated for C26H36F3N3O2: (M+H) 480; found 480.1 for both isomers.
Reaction SMILES: CC1C=C(Br)C=CC=1S(NC1C=C2N(C)C(N(C)C2=CC=1OC)=O)(=O)=O.[C:27]([N:34]1[CH2:37][CH2:36][C@H:35]1[CH2:38][OH:39])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[Br:40][C:41]1[CH:42]=[C:43](O)[CH:44]=[N:45][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:27]([N:34]1[CH2:37][CH2:36][C@H:35]1[CH2:38][O:39][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([Br:40])[CH:42]=1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: COc1cc2c(cc1NS(=O)(=O)c1ccc(Br)cc1C)n(C)c(=O)n2C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1

Procedure:
A 619.3 mg (3.31 mmol) sample of-1-BOC-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 480 mg (2.76 mmol) of 5-bromo-3-hydroxypyridine, from Example 65b above, were reacted with triphenylphosphine and DEAD (3.31 mmol each) in 10 mL of THF according to the procedure of Example 14a, to give 887 mg of the title compound. MS (DCI/NH3) m/e 243/246 (M+H)+, 260/262 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.35-8.25 (br, 2H), 7.44 (s, 1H), 4.55-4.47 (m, 1H), 4.39-4.29 (m, 1H), 4.16-4.10 (m, 1H), 3.98-3.85 (m, 2H), 2.42-2.33 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[F:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[F:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate (7.3 g, 18 mmol) and N-methyl-2-pyrrolidine (20 mL). N-Bromo succinimide (3.5 g, 19.8 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The mixture poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was triturated with diethyl ether and filtered to give the title compound as a white powder (3.49 g). 1H NMR (400 MHz, CD3OD) δ 8.16 (qd, J=3, 6.8 and 15.6 Hz, 1H), 7.84 (d, J=2.12 Hz, 1H), 7.64 (q, J=8.4 and 14.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.04 (m, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.00 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.51 (1F), −115.98 (1F), −117.43 (1F) ppm. ES-HRMS m/z 494.0387 (M+H calcd for C22H19BrF2NOs requires 494.0409).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:18])(=[O:14])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To 175 mL of dry N,N-dimethylformamide (DMF) was added 63.6 g (0.100 mol) sodium diatrizoate and 14.7 g (0.120 mol) of ethyl chloroacetate and the mixture was heated on a steam bath for 6 hr. The reaction was filtered while hot and the filtrate cooled to room temperature and diluted to 500 ml with water. The mixture was cooled and filtered and the collected solid washed with water. The solid was then dissolved in 350 ml hot DMF, filtered and added to an equal volume of water. The mixture was cooled, filtered, washed with water, and the solid dried at 100° C. overnight to afford 53.0 g (76% yield) of a white powder, mp 269.5°-270.50° C.
Reaction SMILES: Cl.[CH2:2]([C:9]1[S:13][C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:27]([C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([C@H:40]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:42])[CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([C:9]1[S:13][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:27][C@@H:29]3[C@@H:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:32][N:31]([C@H:40]([CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)[C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])[CH2:30]3)[CH2:16][CH2:15]2)=[N:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Cc2cnc(C3CCNCC3)s2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4ncc(Cc5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
To a solution of 24 mg of 4-(5-benzyl-thiazol-2-yl) -piperidine hydrochloride (from Step C) in 3 ml DCE was added 8 mg of triethylamine. After 20 minutes, 35 mg of α-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) was added, followed by 31 mg of sodium triacetoxyborohydride. The reaction was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane followed by 50% EtOAc in hexane to give 44 mg of the title compound.
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1>CO>[Cl-:14].[Cl:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N+:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:18]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: ClCc1ccc(CCl)cc1
Solvent: CO
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(CCl)cc1
Product: [Cl-]

Procedure:
A mixture of tri-n-butylamine (6 g, 32.2 mmol) and α,α'-dichloro-p-xylene (8 g, 46.0 mmol) in methanol (50 mL) was refluxed for 15 h after which time TLC examination showed completion of the reaction. Methanol was removed under reduced pressure to give an oily residue. The colorless oil was washed several times with toluene and hexane and then dried. The product obtained was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[F-].[Na+]>C(O)C>[CH2:14]([O:13][C:8]1[C:9]([O:3][CH2:1][CH3:2])([O:10][CH2:11][CH3:12])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([O:10][CH2:9][CH3:4])([CH3:16])[CH:7]=1)[CH3:15]
Reactant: CCOc1cc(C)cc(OCC)c1OCC
Agent: [F-]
Agent: [Na+]
Solvent: CCO
Product: CCOC1=CC(C)(OCC)C=C(OCC)C1(OCC)OCC

Procedure:
A 224 mg quantity of 3,4,5-triethoxytoluene and 20 mg of sodium fluoride were dissolved in 10 ml of ethanol. Electrolysis was conducted by immersing a carbon electrode as the anode and a stainless steel electrode as the cathode each having an electrolytic area of 3 cm2 , stirring the solution at room temperature and passing through the solution constant current of 30 mA at an electric charge of 3 F/mol. Subsequently the same procedure as in Example 1 was repeated producing 287 mg of 1,3,5,6,6-pentaethoxy-3-methyl-1,4-cyclohexadiene in 91.5% of theoretical yield. The compound thus obtained was identified by MNR.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([Cl:22])[CH2:7]1)=[O:5])[CH3:2].[CH3:23][NH:24][CH3:25]>>[ClH:22].[ClH:22].[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([N:24]([CH3:25])[CH3:23])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(Cl)C1
Product: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(N(C)C)C1
Product: Cl
Yield: 77 %

Procedure:
5-Dimethylamino-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester dihydrochloride was prepared from 5-chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and dimethylamine analogous to Example 173.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][CH:29]=[CH2:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: C=CCBr
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
First, 400 mg (1.2 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (intermediate 1) was dissolved in 2.0 ml of N,N-dimethylformamide, to which 257 mg (1.86 mmol) of potassium carbonate and 165 mg (1.36 mmol) of allyl bromide were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography, which afforded 405 mg (1.1 mmol) of 2-{4-chloro-2-fluoro-5-(2-propenyloxy)phenyl}-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (hereinafter referred to as intermediate 2), m.p. 79.8° C.
Reaction SMILES: S1C=CC=C1.C(O)C.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([NH:17][CH2:18][CH2:19][OH:20])=[C:12]([N+:21]([O-])=O)[CH:11]=1.[H][H]>[Pt].CO>[NH2:21][C:12]1[CH:11]=[C:10]([Cl:9])[C:15]([Cl:16])=[CH:14][C:13]=1[NH:17][CH2:18][CH2:19][OH:20]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCO
Reactant: [H][H]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)cc1NCCO
Yield: 81 %

Procedure:
To 2 parts of a solution of 2 parts of thiophene in 40 parts of ethanol are added 71 parts of 2-[(4,5-dichloro-2-nitrophenyl)-amino]-ethanol and 400 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again. The solid residue is stirred in 2,2' -oxybispropane. The product is filtered off and dried, yielding 50 parts (81%) of 2-[(2-amino-4,5-dichlorophenyl)amino]ethanol; mp. 120° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)[CH3:2].BrN1C(=[O:17])CCC1=O.C([O-])([O-])=O.[K+].[K+].[OH:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>C(O)(C)(C)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:17])[CH2:10][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(CC)cn1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a flask fitted with an overhead stirrer, a thermometer and a condensor was added 500 g (3.759 mol) 5-ethyl-2-vinyl-pyridine dissolved in 7500 mL of 25% aqueous tertiary butanol. To this was added 802 g (4.5 mol) N-bromosuccinimide at 25˜30° C. in 30 min. Reaction mixture was stirred for 2 hr. The progress of reaction was monitored by TLC and after complete consumption of the 5-ethyl-2-vinyl-pyridine, 762 g (5.52 mol) of K2CO3 was added in one lot along with 537 g (4.4 mol) 4-hydroxy benzaldehyde. Reaction mixture was stirred for 18 hr. at 75-80° C. Subsequent work-up in water, extraction with ethyl acetate and purification yielded 805 g (79%) of the titled product. m.p. 83° C.