Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:20]=[C:19]([O:21][C@H:22]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:23]32[CH2:25][CH2:24]3)[CH:18]=[N:17][CH:16]=1)([CH3:5])C.[C:37](O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH2:25]1[C:23]2([CH2:26][CH2:27][NH:28][CH2:29][C@@H:22]2[O:21][C:19]2[N:20]=[C:15]([C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([CH:3]([CH3:5])[CH2:2][OH:1])[CH:7]=4)[N:11]([CH3:37])[N:10]=3)[CH:16]=[N:17][CH:18]=2)[CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3n[nH]c4ccc(C(C)(C)CO)cc34)n2)C1
Solvent: CO
Solvent: ClCCl
Product: CC(CO)c1ccc2c(c1)c(-c1cncc(O[C@H]3CNCCC34CC4)n1)nn2C
Yield: 52.8 %

Procedure:
A solution of (R)-tert-butyl 4-((6-(5-(1-hydroxy-2-methylpropan-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (18 mg, 0.036 mmol) in TFA (41.6 mg, 0.365 mmol) was stirred at RT for 30 min. The mixture was concentrated and was dissolved in MeOH (˜20 mg/ml) and injected (1×1.000 ml) onto the Shimadzu preparatory LC (Protocol B) before the pure fraction was concentrated via rotary evaporation to give impure product. A preparatory TLC plate was loaded with the crude mixture and run 2 times in 20% MeOH/DCM; scraping the plate, extraction with MeOH, filtration, and concentration via rotary evaporation afforded 2-(3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-1-methyl-1H-indazol-5-yl)-1-propanol (7.6 mg, 0.019 mmol, 53.0% yield) as a beige solid. MS (ESI, pos. ion) m/z: 394.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[N:5]=1)([OH:3])=[O:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C@H:4]1[CH2:13][C@@H:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[NH:5]1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cc(C(=O)O)nc2cc(Cl)cc(Cl)c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 55.5 %

Procedure:
2-Carboxy-5,7-dichloro-4-ethoxycarbonylquinoline (1.6 g) was dissolved in ethanol (100 ml) and platinum oxide (0.16 g) was suspended in the solution. The reaction mixture was stirred under one atmosphere pressure of hydrogen for 1 h at ambient temperature, then filtered and concentrated in vacuo. Chromatography on SiO2 with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane gave, as a colourless solid, cis-2-carboxy-5,7-dichloro-4-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.9 g, m.p. 160°-162° C.); δ (360 MHz, DMSO), 1.15 (3H, t, J=7.1 Hz, CH3CH2), 2.17 (1H, m, CHACHBHCCHD), 2.52 (1H, m, CHACHBHCCHD), 3.85 (1H, dd, J=7.1 and 3.1 Hz, CHACHBHCCHD), 3.98 (3H, m, CH3CH2 and CHACHBHCCHD), 6.65 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.87 (1H, br, s, NH); m/e 317 (M+), 198 (100%, M-CO2H, CO2Et and H); Found: C, 49.12; H, 4.18; N, 4.27. C13H13Cl2NO4 requires C, 49.08; H, 4.22; N. 4.40%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:23])[C:16]([C:18](OCC)=[O:19])=[CH:17][N:11]3[CH:10]3[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH:14]=1.O.[NH2:25][NH2:26]>CO>[OH2:19].[F:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:23])[C:16]([C:18]([NH:25][NH2:26])=[O:19])=[CH:17][N:11]3[CH:10]3[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH:14]=1
Reactant: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)C1CCCCC12
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1cn2c3c(cc(F)cc3c1=O)C1CCCCC12

Procedure:
2 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate was dissolved in 80 ml of methanol, and 5 ml of hydrazine hydrate was added thereto. The mixture was then heated while refluxing. The precipitated yellow needle crystals were separated by filtration, and recrystallized from ethanol to obtain 1.7 g of 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carbohydrazide monohydrate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:33]=[CH:32][C:15]3[N:16]([CH2:20][C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[C:23]([O:25]CC)=[O:24])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:33]=[CH:32][C:15]3[N:16]([CH2:20][C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[C:23]([OH:25])=[O:24])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1ccccc1CN1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccccc2C(=O)O)nc1Cl
Yield: 101.7 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-[(7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (104c) (0.13 g, 0.29 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (3 mL), to obtain 0.13 g of the title compound as a light brown solid (92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([OH:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[CH2:30]1.O>CN(C=O)C>[CH3:34][C:31]1([CH3:35])[O:32][CH2:33][CH:29]([CH2:28][O:20][C:19]2[C:10]([C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[F:1])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:30]1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(O)c1
Reactant: CC1(C)CC(CBr)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC2COC(C)(C)C2)c1
Yield: 99.7 %

Procedure:
A solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-hydroxynicotinate (700 mg), potassium carbonate (1.10 g) and 4-(bromomethyl)-2,2-dimethyltetrahydrofuran (730 mg) in DMF (5.0 mL) was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (980 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:17][CH2:16][C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(O)(=O)/C=C\C(O)=O.ClC1[N:32]=[N:31]C2CCNCC=2C=1.C(OC(Cl)=O)C=C>>[CH2:1]([O:4][C:5]([N:7]1[CH2:17][CH2:16][C:10]2[N:11]=[N:12][C:13]([NH:31][NH2:32])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: C=CCOC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Product: C=CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid allyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and chloroformic acid allyl ester. The oily crude product is used for the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(O)C>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:2]=1[OH:1])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
A mixture of 15.0 g (70.0 mmol) of 2,4-dihydroxybenzophenone, 10.7 g (70 mmol) of methyl bromoacetate, 19.3 g (0.14 mol) of potassium carbonate, and 125 ml of N,N-dimethylformamide is stirred at 25° C. for 18 hours. The reaction mixture is partitioned between diethyl ether and 0.5 N hydrochloric acid. Solids are removed by filtration, and the filtrate is dried over magnesium sulfate and concentrated. The concentrate is partially dissolved in diethyl ether, and solids are removed by filtration. The solid material is recrystallized from dichloromethane: 2-propanol to afford 13.7 g (69% yield) of the title compound, a pale yellow solid, mp 131°-4° C.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH2:3][S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11])=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C)c(C(=O)CSc2cccc[n+]2[O-])c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(C(=O)CS(=O)c2cccc[n+]2[O-])c1

Procedure:
The procedure employed is identical to that of Example 68 using 8.2 gm (0.03 mol) 2-(2-oxo-2-[2,5-dimethylphenyl]ethylthio)pyridine N-oxide in 50 ml chloroform with 6 gm (0.03 mol) MCPBA (85%) in 100 ml chloroform.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([Cl:2])[CH:4]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1ccc(CCC(=O)O)cc1Cl
Agent: Cl
Product: COc1ccc(CCC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)cc1Cl
Yield: 43.3 %

Procedure:
Proceeding as in Example 1, but substituting 3-(3-chloro-4-methoxyphenyl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 81, (S)-3-(benzyloxy)-2-(3-(3-chloro-4-methoxyphenyl)propanamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (3 mg, 43.3%). MS (EI) for C32H30ClFN2O5. found 578.1 (MH+).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17]Br>O1CCCC1.CN(C)C=O.CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10]
Reactant: OCCCCCCCCO
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCCCCCCCCOCc1ccc(F)c(F)c1
Yield: 46.2 %

Procedure:
A solution of 1,8-octanediol (300 mg, 2.05 mmol) in tetrahydrofuran/N,N-dimethylformamide 2:1 (3 mL) was added dropwise at 0° C. to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.3 mmol) in N,N-dimethylformamide (1.5 mL), then after 2 h 3,4-difluorobenzyl bromide (445 mg, 2.15 mmol) was added. After 4 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded 8-(3,4-difluoro-benzyloxy)-octan-1-ol (258 mg, 46%). Colorless oil, m/e=273.3 ([M+H]+).
Reaction SMILES: Br.[Br:2][CH:3]([CH3:7])[CH2:4][CH2:5][NH2:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Br:2][CH:3]([CH3:7])[CH2:4][CH2:5][NH:6][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)=[O:17]
Reactant: CC(Br)CCN
Reactant: O=C=Nc1ccc(F)cc1
Agent: Br
Solvent: c1ccncc1
Product: CC(Br)CCNC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of 3-bromobutane-1-aminehydrobromide (2270 mg, 9.7 mmol) in pyridine (18 mL) was slowly added 1-fluoro-4-isocyanatobenzene (1600 mg, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and 0.5N aqueous hydrochloric acid solution were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane (=1/1) to give the title compound (1750 mg, 62%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH2:15][OH:16])=[CH:5][CH:4]=1)[CH3:2].O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([CH3:31])[C:19]=1[CH3:32].C(C1C=CC(C2C=C(C)SC=2COC2C(F)=CC(CCC(OCC)=O)=CC=2F)=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH2:15][O:16][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH3:31])[C:19]=2[CH3:32])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc(C)sc2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCOC(=O)CCc1cc(F)c(OCc2sc(C)cc2-c2ccc(CC)cc2)c(F)c1
Product: CCc1ccc(-c2cc(C)sc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 207 by coupling of (3-(4-ethylphenyl)-5-methylthiophen-2-yl)methanol and ethyl 3-(4-hydroxy-2,3-dimethyl phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-methylthiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 2H), 7.26 (s, 1H), 7.18 (d, J=7.5 Hz, 2H), 6.95 (d, J=7.0 Hz, 1H), 6.64 (d, J=7.1 Hz, 1H), 5.05 (s, 2H), 2.95 (t, J=6.5 Hz, 2H), 2.68 (m, J=7.5 Hz, 2H), 2.58 (t, J=6.2 Hz, 2H), 2.51 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.26 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH:16]3[CH:13]([CH2:14][C:15]3=[O:18])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.[BH4-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:17][C@H:16]3[C@H:13]([CH2:14][C@H:15]3[OH:18])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC(=O)C3C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H](O)[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of 3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one (120 mg, 0.45 mmol) in EtOH:DCM (6 mL, 5:1) at 0° C. was added NaBH4 (21 mg, 0.54 mmol) portion-wise. After stirring at 25° C. for 0.5 hr, the solution was concentrated and then partitioned between DCM and water. The aqueous layer was extracted several times with DCM. The organic fractions were combined, concentrated and purified by column chromatography (silica, 0-0.5% MeOH in DCM (0.5% NH4OH)) affording the title compound as a white solid (109 mg, 90%): LC/MS (ES) m/e 268 (M+H)+.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])N)[CH3:16]>C(Cl)Cl>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C@H:19]([C:18]([O:17][CH2:15][CH3:16])=[O:22])[CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Benzophenone imine (53.4 g, 286 mmol) was dissolved in methylene chloride (400 mL) and stirred at room temperature. To the solution was added L-alanine ethyl ester (43.9 g, 286 mmol) and the reaction stirred at room temperature for 48 hours. The reaction was washed 3 times with water (200 mL). The organic layer was separated, dried (MgSO4), and the filtrate was concentrated in vacuo to give a clear oil. The oil was crystallized from pentane to give the title compound (72.1 g, 90%), FAB-MS 282 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]=12.ClC1C2N=CN=CC=2NN=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[N:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)[N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Agent: Clc1n[nH]c2cncnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 16 mL reaction vial was placed sodium hydride (7.8 mg, 60% in oil, 0.195 mmol) and 0.5 mL, of THF. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 0.0487 mmol) was added to the suspension and the mixture was stirred 20 min under N2 at room temperature, followed by the slow addition of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (10 mg, 0.0325 mmol). After stirring overnight under N2 at room temperature, all of the starting chloropyrazolopyrimidine had been converted as indicated by LCMS. The reaction mixture was then concentrated under vacuum and purified by flash column chromatography using 50% EtOAc/Hex as eluent. 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.85 (m, 2H), 2.09 (m, 2H), 3.10 (s, 3H), 3.32 (m, 2H), 3.86 (m, 2H), 5.60 (m, 1H), 8.09 (d, 2H), 8.26 (s, 1H), 8.61 (d, 2H), 8.66 (s, 1H). LCMS: calculated for C22H27N5O5S 473.17, observed 474.4 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[Br:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[Br:21]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 0.75 g (1.79 mmol) of 6-amino-4-[(3,4-dibromophenyl)amino]-3-quinolinecarbonitrile and 0.22 g (2.15 mmol) of triethylamine in 10 mL of tetrahydrofuran was added dropwise 0.195 g (2.15 mmol) of acryloyl chloride. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and solid was collected. The crude product was washed with boiling ethyl acetate dried in vacuo (50° C.) to give 0.609 g of brown solid: high resolution mass spectrum (m/e): 470.9457.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH:14]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:13]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1C=CCC1
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 81.8 %

Procedure:
This compound was prepared in the same manner as for Intermediate 2, using 5-cyanoindole (4.26 g, 30 mmol) and 2-cyclopenten-1-one (2.95 g, 36 mmol) to give 5.5 g (82%) of the desired product: mp 136-138° C.; MS (ESI) m/z 224 [M]+.
Reaction SMILES: S1[C:5]([CH2:6][C:7]#N)=[CH:4][CH:3]=[C:2]1[CH2:9][C:10]#N.[S:12]1[C:16](C=O)=[CH:15][CH:14]=[C:13]1C=O>>[CH2:10]([C:15]1[CH:14]=[CH:13][S:12][CH:16]=1)[CH2:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:9][CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(C=O)s1
Reactant: N#CCc1ccc(CC#N)s1
Product: CCCCCCCCCCCCc1ccsc1

Procedure:
Heterocycles can also be easily included in the copolymer chain. The literature records the preparation of an insoluble cyano-substituted alternating polymer derived from thiophene-2,5-diacetonitrile and thiophene-2,5-dicarboxaldehyde (Kossmehl, G. Ber. Bunsenges. Phys. Chem., 1979, 83, 417) and copolymers based on the thiophene-2,5-dicarboxaldehyde and 2,5-dimethoxyterephthaldehyde (H. Horhold, Z. Chem., 1972, 12). The bischloromethylation of 3-dodecylthiophene gave the unstable product (17), which was immediately treated with cyanide to give the bisnitrile (18). Alternatively, the bis-aldehyde (19) can be synthesized from (17) in 3 steps in an analogous fashion to before. Condensation of (18) with (7) gave a purple polymer (onset of absorbance of 670 nm).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: CN(C)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formylbenzoic acid (24) (300 mg, 1.99 mmol) in DCM (4 mL) were added N,N-dimethylethane-1,2-diamine (193.8 mg, 2.19 mmol), HATU (911.8 mg, 2.4 mmol), NMM (505 mg, 5.0 mmol), and DMAP (24 mg, 0.199 mg) at RT. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. After 16 h, RM was washed with water and organic layer was concentrated after drying over Na2SO4. Column purification of crude material afforded pure product as oil.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](N)=[CH:17][C:16]=1[F:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:17][C:16]=1[F:22]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ccc(Cl)c(F)c1
Product: O=S(=O)(Cl)c1ccc(Cl)c(F)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-fluoro-phenylamine.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18].C1(C)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)[CH3:18]
Reactant: O=C1c2ccccc2CSc2ccccc21
Reactant: CCNCCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCNCCCN=C1c2ccccc2CSc2ccccc21

Procedure:
9.1 g. of dibenzo[b,e]thiepin-11(6H)-one are mixed, while stirring, with 40 g. of N-ethyl-1,3-propanediamine and 250 ml. of absolute toluene and treated dropwise at 0° C. with 8.8 ml. of titanium tetrachloride. The reaction mixture is stirred at room temperature for 18 hours, then cooled and hydrolyzed with 250 ml. of water. The resulting suspension is filtered through diatomaceous earth and the aqueous phase is extracted with toluene. The combined toluene extracts are dried over sodium sulfate and evaporated under reduced pressure. Raw N-ethyl-N'-{dibenzo[b,e]thiepin-11(6H)-ylidene}-1,3-propanediamine is obtained which can be used directly in the above reaction.