Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)/[CH:42]=[CH:43]/[C:44](O)=[O:45]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:44](=[O:45])[CH:43]=[CH:42][C:41]1[CH:47]=[CH:48][CH:49]=[C:39]([O:38][CH3:37])[CH:40]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2cccc(OC)c2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 54 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-3-methoxy-cinnamic acid (17.6 mg, 0.099 mmol) gave 31.3 mg (54%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(3-methoxy-phenyl)-N-(4-pentyl-benzyl)-acrylamide. LC-MS: tR=1.01 min; [M+H]+=644.50.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)(=O)C.CO>[NH2:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of pyridin-3-ylmethyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate (0.075 g, 0.14 mmol) in ethyl acetate (2 mL) and methanol (1 mL) was treated with 4M HCl in dioxane (3.11 mL, 12.4 mmol) and stirred at ambient temperature for 12 hours. The reaction was evaporated in vacuo and purified by flash column chromatography (0-5% methanol/methylene chloride w/0.1% ammonia) to give the title compound as an off-white solid. 1H NMR (CD3OD) δ 8.58 (s, 1H), 8.48 (m, 1H), 7.96 (d, J=8.22 Hz, 2H), 7.87 (d, J=8.22 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J=8.22 Hz, 2H), 7.42 (m, 5H), 7.22 (t, J=7.30 Hz, 1H), 5.18 (s, 2H), 4.38 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[NH:32]1[C:40]2[C:35](=[CH:36][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:39]=2)[CH:34]=[CH:33]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:36]=[C:35]4[C:40](=[CH:39][CH:38]=3)[NH:32][CH:33]=[CH:34]4)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc3[nH]ccc3c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 12.8 %

Procedure:
To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 5-indoleboronic acid pinacol ester (0.213 g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.151 g, 0.130 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.044 g, 13% yield). MP: 197-199° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.30(s,1H), 8.06(s,1H), 8.05(dd, J=7.9,1.2Hz, 1H), 7.85(m,1H), 7.77(s,1H), 7.69(d, J=8.4Hz, 1H), 7.55(m, 2H), 7.44(t, J=2.8Hz, 1H), 7.35(m, 2H), 7.09-6.94(m, 3H), 6.54(m,1H), 6.05(q, J=7.0Hz, 1H),1.91(d, J=7.0Hz, 3H). Mass: 516.91(M+).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=[O:7])(C)(C)C.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][C:38]2[N:41]=[C:42](C([O-])=O)[S:43][C:37]=2[CH2:36]1.[Li+]>C(O)C>[Cl:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@H:9]1[NH:8][C:6]([C:42]1[S:43][C:37]3[CH2:36][N:35]([CH3:34])[CH2:40][CH2:39][C:38]=3[N:41]=1)=[O:7])=[O:22])=[CH:31]2
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1R*,2R*,4S*)-N2-tert-Butoxycarbonyl-N1-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[Br-].[Al+3].[Br-].[Br-].CSC>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][N:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:41])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask, methyl 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)nicotinate (25 mg, 41.6 μmol, Eq: 1.00) was dissolved in methylene chloride (8 ml) to give a colorless solution. Aluminum bromide (66.5 mg, 249 μmol, Eq: 6) and dimethyl sulfide (25.8 mg, 30.7 μl, 416 μmol, Eq: 10) were added and the mixture was stirred at rt for overnight. The solvent was removed and the residue was suspended in 3 ml of acetonitrile, 3 ml of water was added and the mixture was extracted with ethyl acetate (3×8 ml). The extracts were combined and dried with sodium sulfate. Removal of solvent at reduced pressure gave a yellow solid, 30 mg.
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:17][CH2:16][C:15]([OH:21])([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[OH:21][C:15]1([C:18]([NH2:20])=[O:19])[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)C1(O)CCNCC1
Reaction time: 14 h

Procedure:
Pd/C (150 mg) and HOAc (2 mL) are added to a solution of 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid amide (2 g, 8.5 mmol) in MeOH. The mixture is shaken under H2 (40 psi) for 14 hours. The catalyst is removed by filtration and the solvent is removed in vacuo to give the title product. 1H NMR (CD3OD) 2.96 (m, 4H), 2.05 (m, 2H), 1.49 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[S:31](Cl)(=[O:33])=[O:32].O>CN(C=O)C>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:24]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=2[O:22][CH3:21])(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 0.33 h

Procedure:
A solution of 0.3 g of 3-amino-5-chloro-1,3-dihydro-3-phenylindol-2-one in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.037 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 20 minutes, 0.275 g of 2,4-dimethoxybenzenesulfonyl chloride is added and the reaction mixture is stirred overnight, the temperature being allowed to rise to RT. It is poured into water, extracted with AcOEt, washed with water and with a saturated solution of NaCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether/hexane mixture. m=0.31 g. M.p.=108°-110° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@@H:17](O)[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]>ClCCl>[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@H:17]([F:7])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
Add (diethylamino)sulfur trifluoride (3.9 mL, 29.8 mmol) to a −78° C. cooled solution of 4-(R)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.81 g, 15.54 mmol) in dichloromethane (50 mL). Stir 2 h, then remove cold bath and stir 40 h at room temperature. Cool in ice bath and add saturated sodium bicarbonate solution. Warm to room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25° C.) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) to give the title compound as an oil (4.01 g, 97%).
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH2:13][C:14](OCC)=O)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1CBr.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C.O.C(O)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:14][CH2:13][C:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(Br)c(CCC(=O)c2ccccc2)c1
Yield: 87 %

Procedure:
To sodium ethoxide (5.72 g, 84 mmol) in 50 ml of anhydrous ethanol was added 14.8 g (77 mmol) of ethyl benzoylacetate with stirring. The reaction mixture was then brought to a gentle reflux and 19.6 g (70 mmol) of 1-Bromo-2-bromomethyl-4-methoxy-benzene in 20 ml of ethanol was added over 20 min. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled, filtered and concentrated. The concentrated mixture was subjected to acid hydrolysis and decarboxylation by refluxing for overnight in a solution containing 40 ml of glacial acetic acid, 5 ml of concentrated sulfuric acid, and 10 ml of water. The reaction mixture was then neutralized with 10% NaOH and extracted with methylene chloride. The extracts were concentrated to give a weight of 19.43 g crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one (yield: 87%). This compound was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfinyl-6-phenyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:10]=1[C:27]([CH3:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O:34]CC)[O:31][CH2:32][CH3:33].[H-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][C:10]=1[C:27]([CH2:29][C:30]([O:31][CH2:32][CH3:33])=[O:34])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
There were mixed 4.11 g of methyl 2-benzyloxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 20.6 ml of diethyl carbonate, 20.6 ml of N,N-dimethylformide and 1.6 g of sodium hydride (purity: 60%). The mixture was stirred for 30 minutes at 90°-100° C. The reaction mixture was introduced into 200 ml of ice water. The resulting mixture was washed with 50 ml of diethyl ether. The aqueous layer was separated, adjusted to pH 5 with 4N hydrochloric acid, and extracted with two 100-ml portions of ethyl acetate. The extracts were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 3 : 1 mixture of toluene and ethyl acetate) to obtain 4.35 g (yield: 90%) of ethyl 2-(2-benzyloxy-4-methylsulfonylamino-5-phenoxybenzoyl)acetate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.O>ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)N3CCOCC3)cc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.19 mmol) in dichloromethane (1 mL) was treated with triethylamine (0.39 mmol) and 4-morpholinecarbonyl chloride (0.39 mmol). The reaction mixture was stirred for 18 h at 50° C. and poured into water (1 mL), followed by extraction with (3×3 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a yellow powder (50%). ESMS [M+H]+: 417.4
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)cnc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (185 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (257 mg, 1.0 mmol, Amine-3) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]#N)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:46]>ClCCl.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH:32]=[O:46])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C=O)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-cyanopyrrole (2.44 g) in dichloromethane (25 ml) was added diisobutylaluminum hydride (1.5 M solution in toluene, 4.9 ml) under nitrogen atmosphere in water bath, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was cooled in ice water bath, and to the mixture were added dropwise methanol (1 ml) and water (1 ml). The mixture was stirred for 1 hour, quenched with 1N sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (20:1, V/V) to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-formylpyrrole (1.9 g) as an oil.
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][CH2:11][OH:12])[O:9][CH2:8][CH2:7][CH2:6][O:5]1)CC.[CH3:13][O:14]CC(=O)CC(OC)=O>>[CH3:13][O:14][CH2:1][C:4]1([CH2:10][CH2:11][OH:12])[O:5][CH2:6][CH2:7][CH2:8][O:9]1
Reactant: COCC(=O)CC(=O)OC
Reactant: CCCC1(CCO)OCCCO1
Product: COCC1(CCO)OCCCO1
Yield: 34 %

Procedure:
The same procedure as in the steps (8a) and (8b) of Example 8 was repeated using methyl 4-methoxyacetoacetate to obtain the title compound (4.5 g, total yield: 34%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]1[CH2:8][CH2:7][C:6]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)([C:9]2[CH:14]=[CH:13][C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[NH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N:35]1([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=4)[CH2:7][CH2:8][CH:3]([C:2]([F:34])([F:1])[F:33])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CCC(C(F)(F)F)CC2)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2(c3ccc(N4CCCc5ccccc54)cc3)CCC(C(F)(F)F)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of the title compound of Example 3, Step A (50 mg, 0.1 mmol), 1,2,3,4-tetrahydroquinoline (0.019 mL, 0.15 mmol), 2-(di-tert-butylphosphino)biphenyl (1 mg, 0.003 mmol), palladium (II) acetate (0.5 mg, 0.002 mmol) and sodium tert-butoxide (13 mg, 0.14 mmol) was added 0.30 mL of toluene. The reaction was stirred at 90° C. for 16 h, then partitioned between EtOAc/brine acidified with a few drops of 2 N HCl. The aqueous layer was washed with EtOAc then DCM. The combined organic layers were concentrated under reduced pressure to provide the product as a mixture of the title methyl ester and the hydrolyzed carboxylic acid. LC-MS (ESI): m/z=494.3 [M+1]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[CH2:57]([NH2:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:64][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-]2'-(3"-methoxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone from Example 20 (79.7 mg) in dry isopropyl alcohol (3 ml) is added benzyl amine (86.5 mg). The mixture is stirred at r.t. for 30 min., and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@@H:11]([CH3:26])[CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([O:17][Si](CC)(CC)CC)[CH3:16])(C)(C)C.F.O>C(Cl)Cl>[CH3:26][C@@H:11]([CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([OH:17])[CH3:16])/[CH:10]=[CH:9]\[CH2:8][CH2:7][OH:6]
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@H](C)/C=C\CCO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: ClCCl
Solvent: O
Product: C[C@H](/C=C\CCO)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.3 %

Procedure:
To a stirred solution of compound 12 (201 mg, 0.4 mmol) in anhydrous CH2Cl2 (10 mL) was added hydrofluoric acid (48%, 6 mL). After 40 minutes of stirring at room temperature, water was added, and the organic layer was separated, washed with water and NaHCO3, dried over MgSO4, and evaporated. The residue was chromatographed on silica Sep-Pak cartridge using hexane/EtOAc (6:4) as an eluent to give an oily diol 13 (76.4 mg, 92%).