Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C1([SiH3])C=CC=CC=1.C([OH:38])(C)C.C(Cl)Cl>[Co]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([OH:38])([CH3:26])[CH3:25])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Agent: [Co]
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (23 mg, 0.054 mmol) in 2:1 i-Propanol/CH2Cl2 (2 mL) was added the cobalt catalyst A, prepared as described below, (c.a. 1 mg, cat. amount) and phenylsilane (250 μL, excess). The mixture was stirred vigorously in open air for 1 h. LC-MS found the reaction completed. The mixture was quenched with 1% aq HCl, concentrated and purified by prep HPLC to afford the title compound (9.1 mg, 38%). LC-MS Method 1 tR=2.12 min., m/z 445, 447(M+1); 1H NMR (CDCl3) δ 7.48 (d, 2H), 7.37-7.22 (m, 5H), 6.97 (d, 2H), 5.52 (q, 1H), 2.84 (td, 1H), 2.65 (dt, 1H), 2.28-2.07 (m, 3H), 1.89 (d, 1H), 1.45 (d, 3H), 1.21 (s, 3H), 1.07 (m, 1H), 0.62 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:9]([OH:11])=O)[CH2:7][OH:8])=[O:4].S(Cl)(Cl)=O>CO>[OH:8][CH2:7][C@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:9]1=[O:11]
Reactant: NCC(=O)N[C@H](CO)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: O=C1CNC(=O)[C@@H](CO)N1

Procedure:
A mixture of glycyl-D-serine I (4 g) in methanol (12 ml) was treated with thionyl chloride (4 ml) dropwise over a 15 min period maintaining the temperature below 30°. The mixture was heated at 40°-50° for 3 h, and the solvent was evaporated in vacuo. The residue was triturated under diethyl ether and then dissolved in methanol (80 ml). Aqueous ammonia (8 ml) was added and the resulting solid was filtered off, to give the title compound as a solid (1.95 g) m.p. 218°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)COc1ccccc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=488.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:19]#[N:20])(O[Si](C)(C)C)[CH2:6]1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH2:19][NH2:20])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(C#N)(O[Si](C)(C)C)c2ccccc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1CC(CN)c2ccccc21
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a solution of 5.79 g of 3-cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester (20.0 mmol, 1.0 equivalent) in 25 mL of methanol was added 5.71 g of p-toluenesulfonic acid monohydrate (30.0 mmol, 1.5 equivalent). The solution was stirred for 15 minutes and then 4.21 g of 20% palladium hydroxide on carbon, 50% wet by weight, (3.00 mmol, 0.15 equivalent) was added. The reaction mixture was subjected to hydrogenolysis at 50 psi of hydrogen over 24 hours. After this time, the reaction mixture was filtered through Celite and typically used filtrate in the next step (Example 60D). The isolation of the title compound was conducted as follows: the filtrate was concentrated in vacuo; the residue was partitioned between 30 mL of methylene chloride and 20 mL of a saturated aqueous solution of sodium carbonate; the aqueous layer was extracted with 15 mL of methylene chloride; the combined aqueous layers were washed with 40mL of a saturated aqueous solution of sodium chloride; the organic solution was dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil (3.65 g, 89%) with approximately a 10:1 ratio of diastereomers; (major diastereomer) 1H NMR (400 MHz, CDCl3): δ 7.43 (dd, J=6.9, 1.6 Hz, 1H), 7.29-7.25 (m, 3H), 4.09 (t, J=8.1 Hz, 1H), 3.80 (s, 3H), 3.31-3.24 (m, 1H), 3.14 (dd, J=12.8, 4.7 Hz, 1H), 2.98 (dd, J=12.8, 7.3 Hz, 1H), 2.62-2.52 (m, 1H), 2,31-2.42 (m, 1H), 1.3 (bs, 2H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:13]([C:15]1[S:19][CH:18]=[N:17][CH:16]=1)=[O:14]>>[S:19]1[C:15]([C:13]([N:1]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:2]2[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:14])=[CH:16][N:17]=[CH:18]1
Reactant: O=C(Cl)c1cncs1
Reactant: CCOC(=O)C1CCCCN1
Product: CCOC(=O)C1CCCCN1C(=O)c1cncs1

Procedure:
Ethyl N-(5-thiazolylcarbonyl)pipecolinate is prepared as in Example 1, from 4.4 g of ethyl pipecolinate and 5.25 g of 5-chloroformylthiazole. 7.7 g of ethyl N8(5-thiazolylcarbonyl)pipecolinate are thus obtained in the form of brown oil. (Rf=0.51; thin layer chromatography on silica gel; eluent: 55/45 dichloromethane/ethyl acetate).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([O:23][CH3:24])[CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C1COCC1.CO.O.[Cl-].[Na+].O>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[C:17]([O:23][CH3:24])[CH:16]=1)([C:6]([CH3:8])([CH3:7])[CH3:9])([CH3:4])[CH3:5]
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.3 %

Procedure:
Sodium borohydride (1.24 g) was added to a solution of the product from step (i) (21.3 g) in THF (100 mL), methanol (15 mL) and stirred at RT for 2.5 h. The mixture was diluted with water and brine, and extracted with EtOAc. And the combined organic solutions were dried and concentrated. The residue was purified by silica gel chromatography eluting with hexane/EtOAc to give the subtitle compound (18.5 g) as a colourless oil; 1H NMR: 7.14 (1H, d), 6.42-6.48 (2H, m), 4.61 (2H, d), 4.06 (2H, t), 3.84 (3H, s), 3.80 (2H, t), 2.15 (1H, t), 1.94-2.02 (2H, m), 0.89 (9H, s), 0.04 (6H, s).
Reaction SMILES: N(C[CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]=[C:13]=[O:14])[CH2:6]1)=C=O.[N-:15]=[C:16]=[O:17].[N-]=[C:19]=O.O=C1CC(C)(C)CC(C)=C1>>[N:12]([CH2:11][CH:7]1[CH2:6][CH2:5][CH:10]([CH2:19][N:15]=[C:16]=[O:17])[CH2:9][CH2:8]1)=[C:13]=[O:14]
Reactant: [N-]=C=O
Reactant: O=C=NCC1CCCC(CN=C=O)C1
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: O=C=NCC1CCC(CN=C=O)CC1

Procedure:
1,3-bis-(isocyanato-methyl)-cyclohexane (H6XDI) isophorone-di-isocyanate
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.C1([CH:23](C2CC2)[CH2:24][OH:25])CC1.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][C:24](=[O:25])[CH2:23][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:1](=[O:19])[C:2]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:3]2[C:4]1=[O:14])[CH3:30]
Reactant: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: CCO
Reactant: OCC(C1CC1)C1CC1
Product: CCOC(=O)CC(=O)CCCCCN1C(=O)c2ccccc2C1=O

Procedure:
This ester is synthesized according to the process described in stage A of Example 4, but replacing the 8-phthalimido-3,6-dioxaoctanoic acid with 6-phthalimidohexanoic acid and the 2,2-dicyclopropylethanol with ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K6) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (254 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C@H:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=2)=[O:26])[CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C@H:21]([NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:29][CH:28]=2)[CH2:20][CH2:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCc2cccc(N3CCNCC3)c2C1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 69 %

Procedure:
To an ice-cooled solution of (R)-N-[8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinophenylcarboxamide (1.0 g, 2 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at ambient temperature for 7 h. The solvent was evaporated in vacuo and the residue was dissolved in water (20 mL), alkalized with a 2 M aqueous sodium hydroxide solution and extracted, twice, with methylene chloride. The phases were separated, the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent gave 580 mg (70% yield) of the title compound as white crystals: mp 202-203° C.; [α]21D −56° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 420 (5, M+).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:12].CC(=[CH:39][CH3:40])C>O.C(O)(C)(C)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:11]([O:6][CH2:39][CH3:40])=[O:12])=[C:14]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1c(C(=O)OCC)n(Cc2ccc(Cl)c(Cl)c2)c2ccccc12
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of sodium chlorite (3.39 g) and sodium dihydrogen orthophosphate (4.54 g) in water (50 ml) was added dropwise to a stirred solution of ethyl 3-formyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate (1.56 g) and 2-methylbut-2-ene (50 ml) in tert-butyl alcohol (100 ml) at ambient temperature and reaction stirred vigorously overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane (100 ml), washed with water (100 ml), dried (MgSO4) and concentrated in vacuo to give the product as a yellow solid (1.50 g, 92%); NMR d (CD3SOCD3) 1.20 (t, 3H), 4.30 (q, 2H), 5.50 (s, 2H), 7.00 (m, 1H), 7.25 (m, 2H), 7.42 (m, 1H), 7.58 (m, 2H), 8.00 (m, 1H), 12.68 (s, 1H); M/z (−) 390.4 (M−H+).
Reaction SMILES: [OH:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]([CH3:11])[CH:10]=1)=[N:6][CH:5]=[N:4]2.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:9]([CH3:11])=[N:8][C:7]2[N:3]([N:4]=[CH:5][N:6]=2)[C:2]=1[OH:1]
Reactant: BrBr
Reactant: Cc1cc(O)n2ncnc2n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2ncnn2c(O)c1Br
Reaction time: 2 h
Yield: 83 %

Procedure:
A suspension of 4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene (15.0 g, 0.1 mol) in acetic acid (100 ml) was treated dropwise at 20° C. with a solution of bromine (16.172 g, 0.102 mol) in acetic acid (20 ml). As the reaction progressed, the suspended crystals dissolved and new crystals of brominated product were formed. After about 2 hours, the reaction mixture was poured into water (250 ml) and crystals were collected by filtration. The crude product was purified by first converting into its sodium salt by dissolving 22 g in one liter of hot aqueous 0.2N sodium carbonate and then slowly acidifying with dilute hydrochloric acid. The unchanged starting material was converted into a soluble salt by addition of excess of triethylamine. Crystals were then collected and recrystallized from hot water to give 19 g (82%) of Compound TAI-4 as white needles, m.p.=269° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:34]4[CH:35]=[C:36]([N+:39]([O-:41])=[O:40])[CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:43])=[O:44])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc([N+](=O)[O-])ccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-methyl-5-nitro-benzenesulfonyl chloride. Purity (ELSD, based on MW=620.7)=88%.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH2:1]([S:4]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: CCCS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 63 %

Procedure:
Propylsulfonyl chloride (70 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (60 mg, 0.153 mmol, 63% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 3.63 (m, 1H), 3.52 (d, J=12.4 Hz, 2H), 3.08 (m, 4H), 1.90 (d, J=9.6, 2H), 1.70 (m, 1H), 1.43 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:37]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:8]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=[CH:10][N:9]3[C:13]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:24]=2)=[CH:21][CH:20]=1)[CH:36]=[CH2:35]
Reactant: Oc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
To a solution of 4-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}phenol (110 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (27 μL, 0.31 mmol) and cesium carbonate (160 mg, 0.48 mmol). The mixture was heated at 80° C. for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-8-amine (40 mg, 34%) as a yellow foam. 1H NMR (CDCl3): δ 8.87 (d, 1H), 8.04 (d, 1H), 7.57 (d, 2H), 6.95 (d, 2H), 6.75 (t, 1H), 6.40 (d, 1H), 6.26 (d, 1H), 6.1 (m, 1H), 5.43 (d, 1H), 5.30 (m, 3H), 4.58 (d, 2H), 4.35 (m, 1H), 3.92 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1).
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([O:27][CH3:28])[O:25][CH3:26])=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)CCN(C)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH:42]=[O:43]>CCCCCC.O1CCCC1.O>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([O:25][CH3:26])[O:27][CH3:28])=[C:16]2[CH:42]([OH:43])[C:41]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:39]([O:38][CH3:37])[CH:40]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(OC)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: COc1ccc(C=O)cc1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2c(C(OC)OC)c3ccccc3n2S(=O)(=O)c2ccccc2)cc1OC
Yield: 61 %

Procedure:
40 ml of 1.55M n-butyl lithium in hexane are added under stirring with cooling to a tetrahydrofuran solution of 19 g of 1-phenylsulfonyl-3-dimethoxymethylindole and 6.5 g of N,N,N',N'-tetramethylethylenediamine. The mixture is stirred at room temperature, and then a solution of 9.3 g of 3,4-dimethoxybenzaldehyde in tetrahydrofuran is added thereto under cooling. The mixture is further stirred at room temperature, poured into water, and then extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove the solvent. The residue is purified by using silica gel column. 17 g of 1-phenylsulfonyl-2-(α-hydroxy-3,4-dimethoxybenzyl)-3-dimethoxymethylindole are obtained as syrup.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](=O)[CH3:21])=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:21])=[CH:15][CH:14]=1)[CH3:12]
Reactant: NCC(O)c1ccccc1
Reactant: CCc1ccc(CC(C)=O)cc1
Product: CCc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 using 2-hydroxy-2-phenylethanamine and 4-ethylphenyl acetone. Recrystallization of the chromatographed material from hexane gave the title compound m.p. 76-82 as a 19:81 mixture of diastereoisomers (analysed as the hemi-hydrate). τ(CDCl3), 8.9 (3H, d, J=6 Hz), 8.8 (3H, t, J=6 Hz), 7.5 (2H, disappears with D2O), 7.0-7.5 (7H, m), 5.35 (1H, dd), 2.9 (4H, s), 2.7 (5H, s).
Reaction SMILES: [C:1](=[O:4])([O-])N.[SiH3]O[SiH3].[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:15]1[C:20]([O:22]C)=[O:21])=[O:13])[CH:9]=[CH2:10]>C(Cl)(Cl)Cl>[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@:15]1([CH2:1][OH:4])[C:20]([OH:22])=[O:21])=[O:13])[C:9]1[CH:10]=[CH:17][CH:16]=[CH:15][CH:20]=1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Reactant: NC(=O)[O-]
Agent: [SiH3]O[SiH3]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@]1(CO)C(=O)O

Procedure:
Lithium borohydride (1.57 g, 73 mmol) was added portionwise to a solution of (2S,4R)—N-(benzoxycarbonyl)-2-methyoxycarbonyl-4-hydroxyproline (46) (20.17 g, 73 mmol) in THF (350 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stir overnight. The resulting suspension was cooled to 0° C. and quenched with water (2-3 mL) until effervescence ceased, at which point 2 M HCl (15 mL) was added to dissolve the precipitate. The product was extracted with ethyl acetate (3×150 mL) and the combined organic phases washed with brine (1×100 mL) and then dried (MgSO4). Concentration in vacuo afforded a white gum (18.25 g, 100%). [α]22.3D=−404° (C=0.043, CHCl3). 1H NMR (CDCl3): δ 1.24-1.26 (m, 1H, H1), 1.73-2.08 (m, 1H, H1), 3.40-4.30 (m, 6H, H2, H3, H11, H11a), 5.06 (bs, 1H, OH), 5.09 (s, 2H, H6) 7.25-7.31 (m, 5H, H arom). 13C NMR (CDCl3): δ 36.7 (C1), 55.2 (C3), 58.7 (C2), 65.0 (C11), 67.0 (C6), 68.7 (C11a), 127.0, 127.5 (C arom), 127.8 (C arom), 128.2 (C arom). IR (thin film): ν=3390 (OH), 3065, 3033, 2953 (OH), 1681 (C═O carbamate), 1586, 1538, 1498, 1454, 1192, 1122, 978, 914, 862, 770, 698, 673 cm−1. MS (FAB)′ m/z (relative intensity): 252 (M+., 58), 208 (33), 176 (5), 144 (6), 118 (8), 116 (7), 92 (13), 91 (100). HRMS calcd. for C13H17NO4=251.1158 found 251.1230.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][C:14]=2[CH:20]=1)[CH3:2].[OH2:22].[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1>C(O)C>[CH2:23]([O:19][C:17](=[O:22])[CH2:16][CH2:15][C:14]1[CH:20]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH:11]=[CH:12][C:13]=1[OH:18])[CH3:24]
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCC(=O)O2
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(O)c(CCC(=O)OCC)c1
Yield: 61.4 %

Procedure:
A mixture of 1.5 g (9.15 mmol) of 6-hydroxy-3,4-dihydrocoumarin, 2.1 g (10 mmol) of ethyl 5-bromovalerate, 4.16 g (30 mmol) of anhydrous, granular potassium carbonate, and 15 mL of N,N-dimethylformamide was stirred at room temperature, for 23 hr. The resulting dark-brown slurry was diluted with ether and washed with water and brine. Completion of the usual work-up gave 2.32 of a red-orange oil which was chromatographed on 50 g of silica gel. Elution with 1:1 hexane-ether gave 2.03 g of a yellow oil which was a mixture of the desired 5-[(3,4-dihydro-2-oxo-2H-1-benzopyran-6-yl)oxy]pentanoic acid ethyl ester and an impurity. This material was dissolved in 25 mL of ethanol and 52 mg of p-toluenesulfonic acid monohydrate was added. The resulting solution was stirred and refluxed for 22.5 hr and then concentrated in vacuo. The residue was dissolved in ether and the ether solution was processed in the usual manner giving an amber oil. This material was chromatographed on 50 g of silica gel. Elution with 1:1 hexane-ether afforded 1.90 g (61.4%) of 5-(5-ethoxy-5-oxopentyloxy)-2-hydroxybenzenepropanoic acid ethyl ester as a pale-yellow oil.