Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].S(=O)(=O)(O)O.CC(C)=O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2ccccc2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1'-bromoethyl)naphthalene, prepared as described above, wtih sodium acetate in acetic acid to afford 2-(1'-acetonyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1'-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].Cl>>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(CNc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Product: CCCc1c(CNc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 7.1 g. of the ester prepared in Example 46 in 100 ml. of hydrochloric acid was heated to reflux for one hour. The precipitate which formed on cooling was recovered by filtration and dried to give 1.3 g. of the desired title product, m.p. 202°-204° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[C:22]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=1[S:26]([CH:29]1[CH2:31][CH2:30]1)(=[O:28])=[O:27].I[CH2:38][C@H:39]1[CH2:59][CH2:58][C:41]2([O:45][C@H:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:43]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:42]2)[CH2:40]1>C1COCC1.O.CN1CCCN(C)C1=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:32]([CH2:38][C@H:39]2[CH2:59][CH2:58][C:41]3([O:45][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@@H:43]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:42]3)[CH2:40]2)[C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=1[S:26]([CH:29]1[CH2:31][CH2:30]1)(=[O:28])=[O:27]
Reactant: IC[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: COC(=O)Cc1ccc(S(=O)(=O)C2CC2)c(Br)c1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(Br)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a mixture of diisopropylamine (6.94 mL), 1,3-dimethyltetrahydropyrimidin-2(1H)-one (18 mL) and THF (60 mL) was added 2.64 M n-butyl lithium/hexane solution (18.4 mL) at an internal temperature of −50° C. or lower, followed by stirring at an internal temperature of −50° C. or lower for 1 hour. To the reaction mixture was added dropwise a solution of methyl [3-bromo-4-(cyclopropylsulfonyl)phenyl]acetate (15.0 g) in THF (20 mL)/1,3-dimethyl tetrahydropyrimidin-2(1H)-one (9 mL) at an internal temperature of −50° C. or lower, followed by stirring at the same temperature for 30 minutes, and THF (30 mL) was added thereto, followed by stirring at −20° C. for 1 hour. A solution of (2R,3R,7S)-7-(iodomethyl)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonane (21.8 g) in THF (20 mL) was added dropwise thereto at an internal temperature of −60° C. or lower, followed by stirring at the same temperature for 30 minutes and then stirring at room temperature overnight. To the reaction mixture was added water (200 mL) under ice-cooling, followed by extraction with ethyl acetate (100 mL×3). The organic layer was sequentially washed with water (200 mL) and saturated brine (200 mL), and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 19:1→1:1) to obtain methyl 2-[3-bromo-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propionate (20.4 g) as a pale yellow amorphous substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[C:34]([CH3:39])[N:35]=[C:36]([CH3:38])[CH:37]=4)[CH:27]=3)[CH2:23][C:22](=[O:40])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M305) (0.43 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (282 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18](F)[C:17]=1[N+:24]([O-])=O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:27](O)C>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:27])=[CH:18][C:17]=1[NH2:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Product: CCOC(=O)c1cc2c(Oc3ccc(C)cc3N)cccc2[nH]1
Reaction time: 2 h

Procedure:
138 (570 mg, 1.675 mmol) is dissolved in 150 ml of ethanol and, after addition of Pd—C (200 mg), the mixture is hydrogenated at room temperature for 2 hours. The mixture is filtrated over celite to remove the catalyst and evaporated.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]O>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23][CH2:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[Br:28])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: OCc1ccccc1Br
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)OCc3ccccc3Br)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 100 mg) is reacted analogously to Example I-811 with (2-bromophenyl)methanol (49.0 mg). This gives, after chromatographic purification, 2-bromobenzyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (123 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29]C(OC(C)(C)C)=O)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>>[OH:44][C:38]([C:40]([F:43])([F:42])[F:41])=[O:39].[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2NC(=O)OC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
N-(2,6-Dichlorobenzoyl)-4-[2-(tert-butoxycarbonylamino)phenyl]-L-phenylalanine methyl ester (90 mg) was treated with TFA (1 mL) for 2 h at room temperature. Excess TFA was removed in vacuo to give N-(2,6-dichlorobenzoyl)-4-(2-aminophenyl)-L-phenylalanine methyl ester TFA salt.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:20]([C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)[OH:21])[CH3:5])[CH3:2]
Reactant: C#CCOC(C)OCC
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5 g (33 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 84 ml of tetrahydrofuran was treated at -78° under argon with 24.4 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 4.6 ml (33 mmol) of 4-methylbenzaldehyde in 34 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0° , stirred at 0° for a further 1 hour and then treated with 60 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on 500 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(4-methylphenyl)-2 -butyn-1-ol.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([S:9]([C:12]2[C:13]([S:23][CH3:24])=[N:14][N:15]3[C:20](Cl)=[CH:19][C:18]([CH3:22])=[N:17][C:16]=23)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCO.CN(C=O)C>[C:3]1([S:9]([C:12]2[C:13]([S:23][CH3:24])=[N:14][N:15]3[C:20]([NH:2][CH3:1])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=23)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CNc1cc(C)nc2c(S(=O)(=O)c3ccccc3)c(SC)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
10 ml of a 33% solution of methylamine in EtOH was added to a solution of 0.3 g (0.85 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 5 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2,CH2Cl2/AcOEt 15:1) and crystallization from EtOH yielded 0.18 g (60%) of (3-benzenesulphonyl 5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl)-methyl-amine as colorless crystals, m.p. >230°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[C:6]([CH:9]=1)[C:7]#[N:8].O.O.[Sn](Cl)[Cl:23].Cl>C(O)C>[ClH:23].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:7]([NH2:8])[C:6]=2[CH:9]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(N)=Nc1ccccc1N2
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Combine 5-methyl-2-(2-nitro-phenylamino)-benzonitrile (4.03 g, 15.91 mmol), tin(II) chloride dihydrate (10.77 g, 47.74 mmol), 5N HCl (65 ml), and ethanol (40.0 ml). Stir the mixture at reflux for 7 hours then cool it to ambient temperature and chill it in the refrigerator overnight. Remove the resulting precipitate by vacuum filtration. Place the precipitate in ethanol (100.0 ml) and 5N HCl (20.0 ml) and heat at reflux for 19 hours. Cool the reaction mixture to ambient temperature then chill it in the refrigerator. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 2.59 g (63%) of an orange solid: mass spectrum (ion spray): m/z=224.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a solution of 2,4-dichloro pyrimidine (20 gm) in methanol (200 ml) was added sodium methoxide (8.7 gm) at 0 to 5° C. The resulting mixture was stirred for 14 hours at room temperature and then concentrated under reduced pressure to obtain a residual mass. The residual mass obtained was extracted with ethyl acetate and water. The combined organic layers were washed with water and sodium chloride solution, and then concentrated under vacuum to obtain a crude solid. The crude solid obtained was dissolved in hexane (40 ml) at 0 to 5° C. and stirred for 1 hour. The solid obtained was collected by filtration and then dried to obtain 9.7 gm of 2-chloro-4-methoxypyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.CCOC(C)=O.[Cl-].[Na+].O>CN(C=O)C>[N+:9]([C:3]1[CH:4]=[C:5]([O:8][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(OCCOC2CCCCO2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 6 h
Yield: 38.2 %

Procedure:
4-amino-3-nitrophenol (2.0 g, 12.977 mmol) was dissolved in DMF (20 ml) and Potassium carbonate (3.59 g, 25.953 mmol) was added. To the mixture was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.55 ml, 16.87 mmol) and the reaction mixture was stirred at 50° C. for 6 hours and then for 3 days at room temperature. The reaction mixture was poured into EtOAc/brine. The aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine three times, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 5% to 40% EtOAc/Hexane to afford title compound (1.4 g, yield: 38%). 1H-NMR (400 MHz, CDCl3) δ 1.51-1.68 (m, 4H) 1.71-1.89 (m, 2H) 3.46-3.61 (m, 1H) 3.72-3.99 (m, 2H) 4.03-4.24 (m, 3H) 4.64-4.79 (m, 1H) 6.78 (d, 1H) 7.09-7.17 (m, 1H) 7.60 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH3:26])[N:21]=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH3:26])[N:21]=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOCn1nccc1C(=O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCn1nccc1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
0.9 g of ethyl [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetate is suspended in 20 ml of ethanol, and 10 ml of an aqueous 10% sodium hydroxide solution are added thereto. The mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated to remove ethanol and adjusted to pH 1-2 with 10% hydrochloric acid. The resulting crystals are collected by filtration, washed successively with water and isopropyl ether, and dried to give 0.82 g of [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc(C)cc1Cl
Reaction time: 24 h

Procedure:
1.25 g (6.61 mmol) of 2-chloro-4-methylbenzoyl chloride in 4 ml of dichloromethane were mixed with 0.84 g (8.60 mmol) of N,O-dimethylhydroxylamine hydrochloride and 2.4 ml (17.2 mmol) of triethylamine and stirred for 24 h. Water and 1N hydrochloric acid were added to the reaction mixture, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.10 g (78% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc(Sc2ccccc2)s1
Yield: 48 %

Procedure:
A suspension of 2-bromo-1,3-thiazole-5-carboxylic acid ethyl ester (1.5 g, 6.15 mmol, 1 eq) and K2CO3 (1.7 g, 12.3 mmol, 2 eq) in EtOH (60 mL) is cooled in an ice bath, and thiophenol (0.631 mL, 6.15 mmol, 1 eq) is added. The reaction is monitored by HPLC until the starting material is consumed. The reaction mixture is filtered (to remove a solid by-product), and the solvent is removed in vacuo. The crude mixture is purified by silica gel chromatography using a Biotage Flash 40S column using 2% EtOAc in hexanes to afford the product as an oil (0.784 g, 46%). MS (ESI) for C2H11NO2S2 m/z 266.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)=[CH2:15].[OH-].[Na+]>C1C=CC=CC=1.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH:10]1[C:11]2[N:12]([CH2:20][C:19]3[CH:22]=[CH:23][C:16]([CH:14]=[CH2:15])=[CH:17][CH:18]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C=Cc1ccc(Cn2c3ccccc3c3ccccc32)cc1
Yield: 80 %

Procedure:
Carbazole was reacted with 1.5-fold excess of 4-vinylbenzyl chloride in benzene/water using NaOH as a base, and benzyltriethylammonium chloride as phase catalyst to afford 4-(9-carbazolyl)methylstyrene (CMS) at 80° C. for 5 h. The reaction mixture was extracted with chloroform and the organic layer washed with water, evaporated, and washed with hexane several times. The solid was dissolved in and recrystallized from diethyl ether at −20° C. Yield: 80%. The solid monomer was dried over P205 at 10-6 mmHg for 1 week and then dissolved in anhydrous THF and stored at −30° C. in glass ampoules under high vacuum. This reaction scheme is schematically shown in FIG. 2. The monomer is characterized by using 1H-NMR, 13C-NMR and FT-IR. Undesirable side-reaction of the monomer prepared is seen in FIG. 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C(Cl)CCl.C1C=C[C:25]2N(O)N=[N:28][C:26]=2[CH:27]=1.CCN(C(C)C)C(C)C.CC(N)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:28][CH:26]([CH3:27])[CH3:25])=[O:16])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 103.1 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (400 mg, 1.590 mmol) (prepared as in Ex. 2, Part A) in DMF (6 mL) cooled to 0° C. was added EDC (457 mg, 2.384 mmol) and HOBT (487 mg, 3.18 mmol) and the mixture was stirred for 5 min. To the resultant solution DIPEA (0.83 mL, 4.77 mmol) followed by propan-2-amine (470 mg, 7.95 mmol) were added and the mixture was stirred at room temperature for 12 h. The reaction mixture was treated with ice and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N-isopropylnicotinamide (480 mg, 1.64 mmol, 100%) as an off-white solid. LC/MS (ESI) m/e 293.2 [(M+H)+, calcd for C15H15ClFN2O 293.1]; LC/MS retention time (method C): tR=1.84 min.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6](=[O:27])[CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22](OC)=[O:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO>[NH:2]([C:22](=[O:23])[C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][C:6]([O:5][CH3:4])=[O:27])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:26])[NH2:3]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (0.361 mL) was added to a stirred solution of methyl ({4-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl]phenyl}amino)(oxo)acetate (2260 mg) in EtOH (50 mL). The mixture was stirred for 1 hour. The precipitate was filtered off, washed with Et2O, and dried under vacuum overnight to give the title compound (Intermediate 43, 1845 mg) as a solid; 1H NMR δ 10.44 (1H, s), 10.20 (1H, s), 7.70 (2H, d), 7.21 (2H, d), 4.60 (2H, s), 3.60 (3H, s), 2.42 (1H, m), 1.79 (5H, m), 1.45 (2H, m), 1.11 (2H, m); MS m/e MH+ 334.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.C(OC(=O)CN1CCCC(NC(C2C=NC(OCC3C(C4C=CC=CC=4)=NOC=3C)=CC=2)=O)C1)C>>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)O)cn1
Yield: 91.4 %

Procedure:
As described for example 41a, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (3.3 g, 10 mmol), instead of (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid ethyl ester, was converted, to the title compound (3.0 g, 95%) which was obtained as an off white solid. MS: m/e=327.4 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[N:8]2[CH2:11][CH2:12][CH2:13][S:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>ClCCl>[CH:15]1([S:14][CH2:13][CH2:12][CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:10]=3)[C:6]([CH3:20])([CH3:19])[C:7]2=[O:18])[CH2:17][CH2:16]1
Reactant: CC1(C)C(=O)N(CCCSC2CC2)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C(=O)N(CCCSC2CC2)c2cc(NC(=O)c3ccncc3)ccc21

Procedure:
A solution of 6-amino-1-(3-(cyclopropylthio)propyl)-3,3-dimethylindolin-2-one (160 mg, 496 μmol), isonicotinoyl chloride (84.2 mg, 595 μmol) and DIPEA (192 mg, 260 μl, 1.49 mmol) in dichloromethane (3 ml) was stirred at room temperature for 3 hours. The crude material was purified by flash chromatography on silica gel using EtOAc/heptane as eluent. The title compound was obtained as yellow viscous oil (131 mg).