Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5](CC1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=1)[CH2:2]2.[CH3:22][C@H]1COCCN1>>[CH3:22][C@@H:4]1[N:3]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([NH2:19])=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)[CH2:2][CH2:1][O:8][CH2:5]1
Reactant: Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1
Reactant: C[C@H]1COCCN1
Product: C[C@H]1COCCN1c1nccc(-c2ccc(N)cc2)n1

Procedure:
Method as described for intermediate 26 using (S)-3-methylmorpholine. (699 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33]>O1CCCC1>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:4]1[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=[C:2]([Cl:1])[CH:3]=1)=[O:33]
Reactant: Nc1ccccc1OCc1cc(Cl)cc2c1OCOC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1OCc1cc(Cl)cc2c1OCOC2)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(6-chloro-2H,4H-benzo[e]1,3-dioxin-8-yl)methoxy]phenylamine (75 mg, 0.257 mmol) in anhydrous tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (0.090 mL, 0.514 mmol), followed by trichloroacetyl chloride (0.058 mL, 0.514 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give 2,2,2-trichloro-N-{2-[(6-chloro(2H,4H-benzo[e]1,3-dioxin-8-yl))methoxy]phenyl}acetamide, M+1=438.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)CCC.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:4][C:5]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N:19]([CH3:28])[CH3:18])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CN(C)c1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CN(C)c1ccc(CNc2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 170 °C
Yield: 28.9 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (313 mg, 1.00 mmol) and 4-dimethylaminobenzylamine (225 mg, 1.5 mmol) in 1-butanol (20 mL) was heated to 170° C. in a 50 mL sealed tube for 3 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with 2 N sodium hydroxide, water and brine and dried over sodium sulfate. The solution was concentrated, redissolved in DMF and purified by preparative reverse phase HPLC to give the desired product (124 mg, 29%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[CH3:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([NH:27][CH3:26])=[O:25])[N:21]=1)=[CH:5]2
Reactant: CN
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Yield: 87 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and methylamine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (45 mg, Yield 87%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([N:16]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:17][C:18]([OH:20])=O)=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:26]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33])([CH3:29])([CH3:28])[CH3:27].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[C:26]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:18](=[O:20])[CH2:17][N:16]([C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1CCCC1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1CCCC1
Temperature: 0 °C
Yield: 112 %

Procedure:
N-Carbobenzoxy-L-alanyl-N-cyclopentylglycine (4 g) and L-phenylalanine tert-butyl ester (2.4 g) are dissolved in 20 ml of dimethylformamide and under ice-cooling and stirring, a solution of 1.9 g of diethyl cyanophosphate in 5 ml of dimethylformamide is added, followed by addition of 1.6 ml of triethylamine. The mixture is stirred at room temperature for 3 hours. Then, 200 ml of ice water is added and the mixture is extracted twice with 50 ml portions of ethyl acetate. The extract is washed with 1N hydrochloric acid and water and dried. The solvent is then distilled off under reduced pressure to give 6.7 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycyl-L-phenylalanine tert-butyl ester as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH2:21]([O:23][C:24](=[O:39])[C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)O2)[CH:28]=[N:27][CH:26]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:39])[C:25]1[CH:30]=[C:29]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:2]=4[F:1])[C:6]=3[CH:14]=2)[CH:28]=[N:27][CH:26]=1)[CH3:22]
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CCOC(=O)c1cncc(B2OC(C)C(C)(C)O2)c1
Product: CCOC(=O)c1cncc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)c1
Yield: 29 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (350 mg) was reacted with 5-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester as in General Procedure 4A to give the title compound as a tan solid (29% yield). M.p. 169-172° C., LCMS: m/z=411.03 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42 (t, J=7.1 Hz, 3H), 3.47-3.52 (m, 2H), 3.62-3.71 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 4.51 (s, 2H), 4.99 (s, 1H), 6.75 (s, 1H), 6.91-7.02 (m, 2H), 7.03-7.11 (m, 1H), 7.74 (d, J=2.0 Hz, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11]([O-])(O)=[O:12].[Na+]>CO>[CH3:11][O:12][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccnc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccnc(Cl)n1
Yield: 100 %

Procedure:
A solution of 0.5 g (2.82 mmol) of 2-chloropyrimidine-4-carboxylic acid chloride in 10 ml of methanol was stirred for 45 minutes at room temperature. Then the reaction solution was poured on 80 ml of saturated NaHCO3 solution and extracted three times with 50 ml of ethyl acetate each. The combined organic phase was washed with 60 ml of saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation on a rotary evaporator. After drying on a high vacuum, 0.50 g of product was obtained as white solid, corresponding to a yield of 100 percent relative to the 2-chloropyrimidine-4-caboxylic acid chloride used. The melting point of the product was 93.6° to 96.6° C. Other data for the product was:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[H][H]>O1CCCC1.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CCCO)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCCO)cc2)nc1
Yield: 99 %

Procedure:
0.38 g (1 mmol) of the thus obtained 2-(4-(4-hydroxy-1-butenyl) phenyl)-5-decyloxypyrimidine was dissolved in 20 ml of tetrahydrofuran, added with 0.05 g of 10% Pd/C and subjected to a hydrogenation reaction in a hydrogen atmosphere under normal pressure. The reaction was stopped when about 25 ml of hydrogen was consumed. Then 10% Pd/C was filtered out and the filtrate was concentrated to obtain 0.38 g of 2-(4-(4-hydroxybutyl)-phenyl)-5-decyloxypyrimidine (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.[Br:13]P(Br)Br>ClCCl>[Br:13][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1ccc(CO)c(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-chloro-4-nitrophenyl)methanol (707 mg, 3.73 mmol) was dissolved in dichloromethane (15 mL) at 0° C. under nitrogen. Tribromophosphane (0.7 mL, 7.46 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 10% NaHCO3 solution (2 mL). After 10 minutes, Na2SO4 (15 g) was added. The solvent was filtered and evaporated to provide 1-(bromomethyl)-2-chloro-4-nitrobenzene, which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([C:17]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([CH:4]=3)[CH2:2][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])[N:14]=[C:15]([C:29]([F:31])([F:32])[F:30])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70 %

Procedure:
A mixture of 1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole from step1 of Example 160 (280 mg, 0.58 mmol) and potassium phthalimide (10 mg, 0.054 mmol) in DMF was heated at 90 ° C. for 1 hour. After cooled to room temperature, the mixture was poured into water (30 mL), and extracted with ether (30 mL×2), washed with water (30 mL) and brine (30 mL), dried over MgSO4, and concentarted in vacuo to give the title compound (240 mg, 70%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4]CC1.Cl>O1CCCC1.C(OCC)(=O)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC1CCC(=O)CC1
Yield: 50.8 %

Procedure:
A solution of 1,4-Dioxa-spiro[4.5]decane-8-carbonitrile (2.0 grams, 12.8 mmole) and 2 N hydrochloric acid (21.0 grams, 42.0 mmole) in tetrahydrofuran (30 ml) at room temperature was stirred over night. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent to give an oil (0.800 g). MW 123.15.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=O)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.[OH:68][CH2:69][C@@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[NH2:71]>C(Cl)Cl>[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([NH:71][C@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[CH2:69][OH:68])=[O:60])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 30 °C
Reaction time: 2.42 h
Yield: 75.1 %

Procedure:
p-Toluenesulphonic acid (13.55 g; 71.1 mmoles) was added to a refluxing solution of 27-stearoyloxyheptacosanoic acid (53.45 g; about 77.1 mmoles) and triethylamine (100 ml) in methylene chloride (2 l; free of alcohol) under nitrogen. After refluxing for 1 hour phytosphingosine (18.6 g; purity 94%; 55 mmoles) was added and refluxing was continued for 145 minutes. After cooling the reaction mixture to 30° C. the precipitate was filtered off and washed with methylene chloride (1 l). This solid was dissolved in hot, ethanol-free ##STR10## chloroform and filtered off while warm. The filtrate was allowed to cool. The precipitate formed was filtered off, washed with chloroform (250 ml) and acetone (2×200 ml) and dried in vacuo affording 41 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:26][CH:27]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: BrCc1ccc(-n2cncn2)cc1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(-n2cncn2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 62.7 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (0.16 g, 0.52 mmol), 1-[4-(bromomethyl)phenyl]-1H-1,2,4-triazol (0.25 g, 1.03 mmol), potassium carbonate (0.72 g, 5.17 mmol) and potassium iodide (0.02 g, 0.10 mmol) in 5 ml dimethylformamide were stirred at 65° C. for 5 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate yielded 0.15 g (64%) 4-chloro-N-(2-oxo-azepan-3-yl)-N-(4-[1,2,4]triazol-1-yl-benzyl)-benzenesulfonamide as white solid, MS: m/e (%)=460.1 (MH+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[NH3:25]>O1CCCC1.CN(C)C=O>[NH2:25][C:21]([CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[C:9]2=[O:24])=[CH:18][CH:17]=1)=[O:23]
Reactant: O=C(O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Reactant: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
9.2 g of 3-(4-bromophenyl)-1-[4-(2-carboxyethyl)phenyl]-imidazolidin-2-one are mixed with 3.8 g of N,N'-carbonyldiimidazole in a mixture of 50 ml of tetrahydrofuran and 25 ml of dimethylformamide and the resulting mixture is stirred for 2.5 hours at 80° C. After cooling, it is poured onto a mixture of 20 ml of concentrated aqueous ammonia and 100 g of ice and stirred for 15 minutes. The product is suction filtered and dried.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[N+:16]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.CO.[Pd]>[NH2:16][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:12]#[N:13]
Reactant: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(NC2CCCCC2)c(N)c1
Yield: 99.2 %

Procedure:
A solution of compound 3 (1.23 g, 5.01 mmol) in ethyl acetate (30 mL) and methanol (10 mL) was hydrogenated over 10% palladium on carbon (0.11 g) at 20 psi for 1 h. The reaction mixture was filtered and concentrated on a rotary evaporator to give compound 4 (1.07 g, 99%) as a red-brown solid. ESI-MS m/e 216.3 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:24]=[CH:23][C:9]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([I:25])[CH:7]=1)(=[O:3])[CH3:2]>O(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:24]=[C:23]2[C:9](=[C:8]([I:25])[CH:7]=1)[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]2[OH:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(COC(C)=O)cc1I)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(I)cc(COC(C)=O)cc2c1O
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of diethyl 2-({4-[(acetyloxy)methyl]-2-iodoanilino}methylene)malonate (1.75 g) in Ph2O (20 mL) is heated at 250° C. for 40 min. The reaction is cooled to room temperature and diluted with hexanes. The resulting solid is collected and dried. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2CI2 to 2% MeOH/CH2Cl2). Product containing fractions are combined and concentrated to yield 0.98 g (62%) of ethyl 6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate, m.p. 119-123° C.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([C:34]#[N:35])[C:19]3[C:24]([C:25]=2[OH:26])=[CH:23][CH:22]=[C:21]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=3)=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:34]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([S:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:20]=2)[C:25]([OH:26])=[C:16]([C:14]([NH:13][CH2:12][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11]2)=[O:15])[N:17]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Sc4ccccc4)ccc3c2O)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(Sc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 1-{[(1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-methyl}-cyclobutanecarboxylic acid tert-butyl ester (58 mg), TFA (2 mL) and DCM (6 mL) was stirred at rt for 1 h; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (50 mg). LC MS ESI+: 434 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][O:17][C:13]=3[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)Cl.C1C(=O)N(Br)C(=[O:27])C1.OP([O-])([O-])=O.[K+].[K+]>CC(N=NC(C#N)(C)C)(C#N)C.CC#N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][O:17][C:13]=3[C:12]([CH:18]=[O:27])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2ccc(C)c3occc23)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(-c2ccc(C=O)c3occc23)cc1
Yield: 78.7 %

Procedure:
To a 250 ml round bottom flask was added 4-(4-methoxyphenyl)-7-methylbenzofuran (600 mg, 2.52 mmol), CCl4 (70 ml), NBS (490 mg, 2.77 mmol), and a catalytic amount of AIBN (25 mg). The reaction was brought to reflux for 2 h after which the reaction was allowed to cool, the solids were filtered off, and the solution concentrated. CH3CN (30 ml), K2HPO4 (440 mg, 2.53 mmol), and potassium benzeneselenite (630 mg, 2.77 mmol) were added and the reaction was brought to reflux for 2 h after. The reaction was cooled, passed through a silica plug (washed with 30% EtOAc/hex.), and concentrated to 810 mg of an orange solid. Further purification by chromatography (100% CH2Cl2) afforded 500 mg (78%) of product as a tan colored solid: mp 104–105° C.; 1H NMR (500 MHz, DMSO-d6): δ 3.85 (3H, s), 7.14 (2H, d, J=8.8 Hz), 7.20 (1H, d, J=2.2 Hz), 7.56 (1H, d, J=8.0 Hz), 7.69 (2H, d, J=8.8 Hz), 7.91 (1H, d, J=7.7 Hz), 8.26 (1H, d, J=2.2 Hz), 10.36 (1H, s); HRMS (ESI+) m/z 253.08622 ([M+H]+).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][C:2]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(-c2nc(N)sc2C)cc1
Yield: 77.5 %

Procedure:
A mixture of 2-bromo-1-(4-methoxyphenyl)propan-1-one (10.4 g, 36.1 mmol) and thiourea (2.76 g, 36.2 mmol) in 95% EtOH (70 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-methoxyphenyl)-5-methylthiazol-2-amine (6.16 g) as yellow solids in 78% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 2 H), 7.46-7.44 (m, 2 H), 7.09-7.07 (m, 2 H), 3.81 (s, 3 H), 2.47 (s, 3 H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].O>CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[CH2:16][CH2:15]3)[OH:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CCN2CCC(C(=O)c3ccc(-n4ccnc4)cc3)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CCN2CCC(C(O)c3ccc(-n4ccnc4)cc3)CC2)cc1OC
Yield: 48.8 %

Procedure:
To a stirred solution of [4-(1H-imidazol-1-yl)phenyl][1-[2-(3,4-dimethoxyphenyl)ethyl]-4-piperidinyl]methanone (5.90 g, 14.1 mmol) in methanol (100 ml) at 0° C. was added sodium borohydride (1.80 g, 47.6 g mmol) in three equal portions over a 24 hour period. Water was added and the solution was concentrated to a white suspension. This aqueous suspension was extracted twice with dichloromethane. The combined organic layers were dried (MgSO4), and filtered through a pad of silica gel (eluting with acetone). The eluent was concentrated and the resulting solid was recrystallized from tetrahydrofuran to afford α-[4-(1H-imidazol-1-yl)phenyl]-1-[2-(3,4-dimethoxyphenyl)ethyl]-4-piperidine methanol (2.9 g, 49%): m.p. 59°-60° C.