Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:28]3[CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=1)([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClC1C=CC=CC=1Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:13]3[CH:14]=[CH:15][C:10]4[C:5]5[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:1][C:11]=4[CH:12]=3)[C:28]=2[CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(-n2c3ccccc3c3ccc(-c4ccccn4)cc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: c1ccc(-c2ccc3c4ccccc4n(-c4ccc5c(c4)[nH]c4ccccc45)c3c2)nc1
Temperature: 180 °C
Reaction time: 46 h

Procedure:
A solution of 9-(2′-nitrobiphenyl-4-yl)-2-(pyridin-2-yl)-9H-carbazole (1.00 g, 2.27 mmol, 1.0 eq) and PPh3 (2.38 g, 9.06 mmol, 4.0 eq) in 1,2-dichlorobenzene (15 mL) was stirred at refluxed temperature of 175-185° C. in an oil bath and for 46 hours under nitrogen, and cooled. The solvent was removed by distillation under high vacuum. The residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1-3:1) as an eluent to obtain the desired product, 2′-(pyridin-2-yl)-9H-2,9′-bicarbazole, as a brown solid (814 g in 88% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.27 (t, J=8.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.42 (dd, J=8.8, 1.2 Hz, 1H), 7.45-7.51 (m, 3H), 7.59 (d, J=8.8 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.84-7.88 (m, 1H), 8.04 (d, J=8.4 Hz, 2H), 8.21 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.39 (d, J=7.6 Hz, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.61 (d, J=4.8 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3ccccc23)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A solution of (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.43 g, 0.83 mmol) in methanol (8.38 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (24 mg, 0.12 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2.5-4% methanol/dichloromethane) afforded (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.32 g, 80%) as an off-white solid: HR-ES-MS m/z calculated for C26H30N4O5 [M+H]+ 479.2289, observed 479.2287; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 1.43-1.67 (m, 2H), 1.71-1.84 (m, 1H), 3.20-3.32 (m, 2H), 3.70-3.82 (m, 1H), 3.87 (dd, J=13.5, 7.5 Hz, 1H), 4.09 (dd, J=13.5, 3.8 Hz, 1H), 4.39 (d, J=18.1 Hz, 1H), 4.66-4.77 (m, 3H), 4.89 (dd, J=10.4, 5.0 Hz, 1H), 4.95 (d, J=5.4 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.48-7.66 (m, 5H), 7.91 (d, J=8.2 Hz, 1H), 7.99-8.09 (m, 2H), 10.77 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](=[S:10])[NH2:9])=[CH:6][CH:5]=1)[CH3:2].Br[CH2:16][CH:17](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:12]=[CH:11][C:7]([C:8]2[S:10][CH:16]=[CH:17][N:9]=2)=[CH:6][CH:5]=1)[CH3:14]
Reactant: COC(CBr)OC
Reactant: CCN(CC)c1ccc(C(N)=S)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCN(CC)c1ccc(-c2nccs2)cc1
Temperature: 95 °C
Yield: 54.8 %

Procedure:
To a solution of 4-(diethylamino)benzothioamide (2.29 g, 11 mmol) in EtOH (60 mL) were added 2-bromo-1,1-dimethoxyethane (1.86 g, 11 mmol) and p-toluenesulfonic acid (1.89 g, 11 mmol). The reaction mixture was heated at 95° C. overnight, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc/Et3N (V/V/V)=2:1:0.05) to give the title compound as a white solid (1.40 g, 55%).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and t-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:31][CH2:32][O:33][C@H:28]([CH3:27])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 60.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.87 g, 1.9 mmol) was reacted with (2R,3S)-2-methyl morpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34, Step D to give the title compound as a yellow solid (0.6 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:9][N:10]([CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:19]=4)[CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:9][N:10]([CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:19]=4)[CH:14]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4)ccc3c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc3cc(OCc4cccnc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[6-(3-pyridylmethoxy)-2-naphthylmethyl]-3-pyrrolyl]propionate (638 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to obtain 3-[4-phenyl-1-[6-(3-pyridylmethoxy)-2-naphthylmethyl]-3-pyrrolyl]propionic acid (508 mg, yield: 84%). This was recrystallized from ethanol. Melting point: 158–159° C.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: CC1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: O=CN1CCNCC1
Product: CC1CCc2c(N3CCN(C=O)CC3)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
In an analogous manner as in Example 1, 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid was reacted with 1-formylpiperazine to form 8-(4-formyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:31].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=5)=[C:3]([F:31])[CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: OB(O)c1cccnc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)c(F)c4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5)c(F)c4)CC3)n2CCS1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of the compound (526 mg, 1.0 mmol) obtained in Example 25-3), 3-pyridylboronic acid (244 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2.0 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (517 mg, 99%) as a yellow oily substance.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[O:41][CH3:40])(=[O:50])=[O:49])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: COc1ccccc1S(=O)(=O)NCCc1c(CCNc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The intermediate from example 143 step 12 was treated with 2-methoxy-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 85% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:27](=[O:29])=[O:28]>C1COCC1>[CH2:1]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]([C:27]([OH:29])=[O:28])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2c3ccccc3Cc3ccccc32)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2N(Cc2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of Compound 5, N-benzylacridan (10 g, 37 mmol) in 200 mL of dry THF under inert atmosphere was cooled to 78° C. and 25.0 mL of 2.5 M n-butyllithium in hexanes (37.5 mmol) was added dropwise over 15 min. The solution was stirred at −78° C. for 1 h and then warmed to room temperature over 45 min. The reaction mixture was again cooled to −78° C. and ca. 200 g of crushed dry ice was added causing a precipitate to form. The reaction was allowed to slowly warm to room temperature and stirring under argon was continued over night. The mixture was evaporated, the solid was then suspended in 300 mL of water and acidified to pH 3 with 12N HCl. The solid was collected, washed with water, dissolved in CH2Cl2, dried over sodium sulfate and concentrated to afford 11 g of N-benzyl-acridan-9-carboxylic acid. 1H NMR: (CDCl3) ∂ 4.99 (s, 1H), 5.12 (s, 2H), 6.72-6.75 (d, 2H), 6.88-6.94 (t, 2H), 7.10-7.17 (m, 4H), 7.22-7.32 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18]1([CH:24]=[CH:25][CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>>[C:18]1([CH:24]=[CH:25][CH2:26][C:27]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: O=C(Cl)CC=Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)CC=Cc3ccccc3)CC2)cc1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and 4-phenyl-3-butenoic acid chloride/triethylamine. White crystals.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C.N1CCCCC1>CCCCCC.C(OCC)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3](/[CH:2]=[CH:12]/[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: CCCCCCCC(C)=O
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCCCCC
Product: CCCCCCCC(=O)/C=C/c1ccc(O)c(OC)c1
Reaction time: 6 h
Yield: 998.7 %

Procedure:
10 g (6.5 mmol) of vanillin and 9.3 g (6.5 mmol) of 2-nonanone were dissolved by stirring in 30 ml of hexane and 20 ml of diethyl ether. Moreover, after adding 3.9 g of acetic acid, 4.6 ml (6.5 mmol) of piperidine was added followed by stirring for 6 hours. Following completion of the reaction, unreacted vanillin was removed with an aqueous sodium bicarbonate solution followed by extraction with diethyl ether. After drying with anhydrous magnesium sulfate, the solvent was distilled off to obtain 20.2 g of crude product. The crude product was purified by column chromatography (SiO2/CHCl3) to obtain (E)-1-(4′-hydroxy-3′-methoxyphenyl)dec-1-en-3-one (17.94 g, yield: 90%).
Reaction SMILES: [CH2:1]1[O:8][C:6](=[O:7])[CH2:5][O:4][C:2]1=[O:3].N(CCO)(CCO)[CH2:10][CH2:11]O>>[C:6]1(=[O:7])[O:8][CH2:1][CH2:2][CH2:11][CH2:10][CH2:5]1.[CH2:1]1[O:8][C:6](=[O:7])[CH2:5][O:4][C:2]1=[O:3]
Reactant: OCCN(CCO)CCO
Agent: O=C1COC(=O)CO1
Product: O=C1CCCCCO1
Reaction time: 8 h

Procedure:
The CT-1 copolymer was prepared by the copolymerization of c-caprolactone (0.625 mole) with glycolide (32.3 mmole) in the presence of triethanolamine (1.05 mmole) as the initiator and stannous octanoate (0.1247 mmole as 0.2M solution in toluene) as the catalyst. The polymerization was conducted in a mechanically stirred reactor under a dry nitrogen atmosphere at 150° C. for 8.0 hours. At the conclusion of the polymerization, as determined by GPC, traces of unreacted monomer were removed by distillation under reduced pressure. The composition of the purified polymer was verified by IR and NMR. The polymer was shown to melt at 61° C. as determined by DSC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:24]2[N:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: Clc1ccc(Cl)nn1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)nn2)cs1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 7 and 3,6-dichloropyridazine (4.92 g) were dissolved in N-methylpyrrolidone (25 mL), diisopropylethylamine (4.27 g) was added, and the mixture was heated at 130° C. with stirring for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (5.5 g) as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]#[N:19]>>[O:1]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH2:17][C:18]#[N:19])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: c1ccc(OCCN2CCNCC2)cc1
Product: N#CCN1CCN(CCOc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Phenoxy-ethyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=246.2: CtRet=4.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].Cl.Cl.[N:14]1([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:18]=[CH:17][N:16]=[CH:15]1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCCCCn1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCn1ccnc1)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
A solution of 1.05 g. of 3,4-dichlorobenzoyl chloride in 25 ml. of methylene chloride was added to a stirred solution of 1.06 g. of 1H-imidazole-1-butanamine dihydrochloride in 15 ml. of 1N sodium hydroxide. The mixture was stirred for 18 hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with diethyl ether, giving the desired product, m.p. 86°-88° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][C:8]1([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C>Cl>[NH:20]1[C:21]2[C:17](=[CH:16][C:15]([N:14]3[C:8]4([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:7][NH:6][CH2:5][C:4]3=[O:3])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: CCOC(=O)CNCC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Agent: Cl
Product: O=C1CNCC2(CCCCC2)N1c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A mixture of {[1-(1H-indazol-5-ylamino)-cyclohexylmethyl]-amino}-acetic acid ethyl ester (0.808 g, 2.45 mmol) in 2N HCl (11 mL) was heated at reflux for 17 hours, then cooled to room temperature and quenched by the careful addition of K2CO3 until no more effervescence was observed. The resulting mixture was extracted with DCM and the combined extracts were dried (MgSO4), filtered and concentrated in vacuo to furnish 1-(1H-indazol-5-yl)-1,4-diaza-spiro[5.5]undecan-2-one (0.350 g, 1.23 mmol, 50%) as a solid that was used directly without further purification.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][O-:14].[Na+]>O1CCOCC1.O>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:14][CH3:13])[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1OC
Temperature: 100 °C
Reaction time: 48 h
Yield: 93.6 %

Procedure:
To a solution of methyl 2,4-difluorobenzoate (50 g, 290 mmol) in dioxane (300 mL) was added sodium methoxide (18.0 g, 333.21 mmol) and the reaction was stirred for 48 hours at 100° C. in an oil bath. The reaction mixture was cooled to room temperature and diluted with H2O (200 mL). The mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 4-fluoro-2-methoxybenzoate as colorless oil (50.0 g, 92%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)s1
Yield: 33.5 %

Procedure:
A solution of 5-formylthiophene-2-carboxylic acid (350 mg, 2.24 mmol), tert-butyl 2-aminophenylcarbamate (467 mg, 2.24 mmol) and triethylamine (470 μL, 340 mg, 3.36 mmol) and BOP (1.1 g, 2.68 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash chromatography using 25% EtOAc in hexanes as an eluent, yielding 260 mg (33%) of the title compound. 1H NMR (CDCl3) 9.95 (s, 1H), 9.7 (br. s, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.74 (m, 2H), 7.15 (m, 2H), 6.72 (s, 1H), 1.56 (s, 9H). LRMS: (calc) 346.1; (found) 369.1 (M+Na)