Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[F:6][CH:7]([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[F:6][CH:7]([F:14])[C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CCCCC(=O)C(F)F
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(CCCC)C(F)F

Procedure:
To a stirred suspension of 3.6 g. of magnesium and 30 mg. of mercuric chloride in 0.33 ml. of ether is added 1.5 ml. of propargyl bromide. The mixture is stirred vigorously for several minutes to initiate reaction, then a solution of 15.5 g. of 1,1-difluoro-2-hexanone and 12.1 ml. of propargyl bromide in 33 ml. of ether is added slowly (dropwise) over a 1.5 hour period, so that the mixture remains gently refluxing (25°-30° C.). After addition, the mixture is stirred at room temperature for 30 minutes, then cooled in an ice bath to 0°-5° C. and quenched by adding 35 ml. of saturated ammonium chloride solution dropwise and then stirred for 30 minutes. The mixture is filtered through Celite and washed with ether. The filtrate is concentrated in vacuo giving a yellow oil. This oil is vacuum distilled at 71° C., 12 mm giving the product as 10.54 g. of colorless oil which becomes pale yellow on standing at room temperature.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.O.[I-:13].[Na+].CNCCNC>O1CCOCC1.O.N.[Cu]I>[I:13][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Brc1cccc2[nH]cnc12
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: Ic1cccc2[nH]cnc12
Yield: 155.9 %

Procedure:
Two reactions were set up as follows: A mixture of 4-bromo-1H-benzimidazole (725 mg, 3.68 mmol), sodium iodide dihydrate (1.37 g, 7.36 mmol), copper(I) iodide (70 mg, 0.37 mmol) and N,N′-dimethylethylenediamine (78 μL, 65 mg, 0.74 mmol) in dioxane (8 mL) was irradiated at 150° C. in a microwave reactor for 2.5 hours. The two reaction mixtures were combined, diluted with water (90 mL) and conc. ammonia (20 mL), then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (20 mL), then with saturated sodium chloride solution (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with ethyl acetate, yielding the product as a yellow-white solid (1.40 g, 78%). 1H NMR (400 MHz, d6-DMSO): δ 12.72 (1H, s), 8.28 (1H, s), 7.61-7.53 (2H, m), 7.01 (1H, t, J=7.8 Hz); m/z (ES+) 245 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N-:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17]Cl)[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:19])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1[N-]C(=O)CCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N1CCCCC1=O

Procedure:
77 g (0.27 mol) of N-(3-nitro-4,6-dimethylphenyl)-δ-chlorovaleroylamide are stirred vigorously in a mixture of 50 ml of tetrahydrofurane and 500 ml of 22% strength aqueous sodium hydroxide solution for 5 hours at 60°-65°. The reaction mixture is diluted with water, cooled and acidified with hydrochloric acid. The product which has precipitated is washed until neutral and dried in a desiccator at 70°. This gives 62.8 g (93%); melting point 134°-135°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)[NH:12][C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 39.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-cyano-1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.32 g, 0.62 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.2 g, 1.1 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.14 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6]
Reactant: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reaction time: 2 h

Procedure:
2-Nitro-2-(4-octylphenethyl)propane-1,3-diol (25 g), absolute ethanol (250 mL) and 10% Pd on carbon (5 g, 50% wet) are charged into a 500 mL steel hydrogenation flask under a N2 atmosphere and the flask is equipped with a para shaker hydrogen operator. The mixture is hydrogenated with a H2 pressure of 60 psi (415 kPa) at room temperature for 2 hours and filtered through a Celite bed and washed with ethylacetate (200 mL). The filtrate is concentrated under reduced pressure at 50° C. to give the title compound as a white solid. Yield: 16 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=1)=[O:6]
Reactant: CCOC(=O)c1ccc(N)cn1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cn1
Yield: 87.3 %

Procedure:
A solution of 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (80.48 mg, 0.31 mmol), ethyl 5-aminopyridine-2-carboxylate (57.0 mg, 0.34 mmol), HATU (130.4 mg, 0.34 mmol) and N-methylmorpholine (68.57 μL, 0.62 mmol) in DMF (1 mL) was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water, brine, dried over Na2SO4, filtered and evaporated to give ethyl 5-[[2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]pyridine-2-carboxylate (110 mg, 87%) as an orange waxy solid. ESI-MS m/z calc. 406.07. found 407.3 (M+1)+; Retention time: 1.64 minutes (3 minutes run).
Reaction SMILES: C[C:2]12[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2.C([OH:13])C>[Pd]>[CH2:8]1[CH:7]2[CH:2]([CH:3]([OH:13])[CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:9]1
Reactant: CC12CCCCC1CCC2
Reactant: CCO
Agent: [Pd]
Product: OC1CCCC2CCCC12
Reaction time: 12 h
Yield: 100 %

Procedure:
Typically, the compound of formula VI, (1R,3aR,4S,7aR)-4-Hydroxy-1-[(S)-3-[2-(carboxylic acid ethyl ester)-phenyl-1-methyl-propynyl]-7a-methyl-octahydro-indene (218 mg; 0.615 mmol) was dissolved in dry ethanol (12 ml). Palladium on carbon (10%; 55 mg) was added and the reaction was put under hydrogen at one atmosphere for 12 hours at room temperature. The catalyst was filtered off and the solvent was evaporated. The compound of formula VI of the above Example 1E, the [1R,3aR,4S,7aR]-7a-Methyl-1-[(S)-1-methyl-3-[2-(carboxylic acid ethyl ester)-phenyl-propenyl]-octahydro-inden-4-ol (226 mg; yield: 100%) was obtained as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[C:21](=O)[CH3:22]>C(O)C>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][C:20]1[S:17][C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:18][C:21]=1[CH3:22]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(=O)C(Cl)Cc1cccc(Cl)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3cccc(Cl)c3)s2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A suspension of 78.7 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and of 71.6 mg (0.33 mmol) of 3-chloro-4-(3-chlorophenyl)-2-butanone in ethanol (3 ml) was heated over night to reflux to yield a yellow solution. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel with methylene chloride/methanol 19/1 yielding 55 mg (43%) [5-(3-chloro-benzyl)-4-methyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 425.1/427.2 (100/43) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.16 (s, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 7.35-7.19 (m, 6H), 7.01 (s, 1H), 4.01 (s, 2H), 3.78 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[CH:6]=2.Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1.C(OC(O)C)C>CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.O>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([CH3:12])=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([C:23]([N:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]4)=[O:24])=[CH:30][CH:29]=3)[C:3](=[O:14])[O:4]2)=[CH:9][CH:8]=1
Reactant: Cc1c(Br)c(=O)oc2cc(O)ccc12
Reactant: CN1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOC(C)O
Solvent: O
Product: Cc1c(-c2ccc(C(=O)N3CCN(C)CC3)cc2)c(=O)oc2cc(O)ccc12
Temperature: 150 °C
Yield: 163.1 %

Procedure:
A mixture of 3-bromo-7-hydroxy-4-methyl-2H-chromen-2-one (i) (7.66 g, 30 mmol), 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid hydrochloride (2) (10.24 g, 36 mmol), Na3PO4 (22.14 g, 135 mmol), ethoxyethanol (140 g) and water (14 g) was purged with Argon for five minutes in a 250 ml, pressure vessel. Ligand Sphos (obtained from Aldrich, Cat No. 638072) (739 mg, 1.8 mmol) and Pd(OAc)2 (202 mg, 0.90 mmol) were added under an Argon atmosphere then the vessel was sealed and heated for 60 min in a 150° C. oil bath with strong stirring. This process was repeated once. Upon cooling, the reaction mixtures were filtered through a silica plug using CH2Cl2 and MeOH wash. The unified solutions were evaporated to 100 mL slowly diluted with water (100 mL) and crystallized at 0° C. The product was filtered, washed with 50% MeOH (2×30 mL) and dried to afford 18.52 g (81%) of the title compound. MS (ESI): 379 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.57 (s, br, 1H), 7.69 (d, 1H), 7.44 (d, 2H), 7.36 (d, 2H), 6.84 (dd, 1H), 6.76 (d, 1H), 3.65-3.30 (m, 8H), 2.23 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]([C:15]#[N:16])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl>[CH2:1]([N:4]([CH:5]1[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)[CH2:14]1)[C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCNC1CCc2ccc(C#N)cc2C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(Allylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (300 mg, 1.4 mmol) in 20 mL of DCM was added TEA (430 mg, 4.26 mmol) and BOC2O (460 mg, 2.1 mmol), and the mixture was stirred at room temperature overnight. The reaction was completed, and DCM was added. Then the mixture was washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound. MS m/z: 313 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2cccc(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3-chlorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C@H:36]2[CH2:41][CH2:40][C@H:39]([C:42]([O:44]C)=[O:43])[CH2:38][CH2:37]2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C@H:36]2[CH2:37][CH2:38][C@H:39]([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 8.0 ml methanol solution of 330 mg of methyl trans-4-({[(3R,4S)-3-({(tert-butoxycarbonyl) [(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)cyclohexane-carboxylate was mixed with 1.5 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred overnight at room temperature. The solvent was evaporated under a reduced pressure, and the residue was mixed with 1 M hydrochloric acid, extracted with chloroform and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 176 mg of trans-4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)cyclohexane carboxylic acid as a colorless amorphous substance.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:30]=[C:29](C(C)C)[CH:28]=[C:27]([CH:34]([CH3:36])[CH3:35])[C:5]=1[O:6][CH2:7][C:8]([C:10]1[C:11]([CH:24]([CH3:26])[CH3:25])=[C:12]([O:19][S:20](=[O:23])(=[O:22])[NH2:21])[C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1)=[O:9])[CH3:3].C(C1C=C(C(C)C)C=C(C(C)C)C=1O)(C)C.C(C1C=CC=C(C(C)C)C=1O)(C)C>>[CH3:36][CH:34]([C:27]1[CH:28]=[CH:29][CH:30]=[C:4]([CH:2]([CH3:3])[CH3:1])[C:5]=1[O:6][CH2:7][C:8]([C:10]1[C:11]([CH:24]([CH3:25])[CH3:26])=[C:12]([O:19][S:20](=[O:22])(=[O:23])[NH2:21])[C:13]([CH:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=1)=[O:9])[CH3:35]
Reactant: CC(C)c1cc(C(C)C)c(OCC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1
Agent: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Agent: CC(C)c1cccc(C(C)C)c1O
Product: CC(C)c1cccc(C(C)C)c1OCC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 46, except that 2,4,6 - triisopropylphenol was replaced with 2,6-diisopropylphenol, mp 108°-110° C.
Reaction SMILES: [C:1]([S:5][C@@H:6]([CH3:10])[C:7](O)=[O:8])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([S:5][C@@H:6]([CH3:10])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(C)(C)C)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: C[C@@H](CO)SC(C)(C)C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of 1.47 g of the (2S)-2-(t-butylthio)propanoic acid in 22 mL of THF at 0° C. was added dropwise 22 mL of 1M borane/THF over a period of 15 min. Stirring was continued at room temperature for 3 h. The reaction was quenched by dropwise addition of cold water. The mixture was extracted with ether. The organic layer was washed with saturated NaHCO3, saturated NaCl solution and dried over Na2SO4. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (10% EtOAc in hexane) to give 1.10 g of (2S)-2-(tert-butylthio)-1-propanol as an oil at 82% yield. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ3.61 (ddd, J=5, 9, 11 Hz, 1H), 3.33 (ddd, J=4, 8, 11 Hz, 1H), 2.89 (m, 1H), 2.31 (dd, J= 4, 9 Hz, 1H, OH), 1.36 (s, 9H), 1.30 (d, J=7 Hz, 3H); [α]D25 -10.3° (c=2.04, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[C@H:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29]C(OCC1C=CC=CC=1)=O)=[N:18]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:40]>[Pd].CO.C(OCC)(=O)C>[ClH:40].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[C@H:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:29])=[NH:18])=[O:4]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 84 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5mL) solution of compound 9 (313 mg, 0.58 mmol) and 1N HCl (0.58 mL) was stirred under a hydrogen atmosphere with 10% palladium on carbon catalyst. When the starting material had disappeared as determined by TLC, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated to afford 150 mg (84%) of the title product as a yellow foam.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:27]([N:34]1[CH2:38][C@H:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[C@@H:36]([CH:47]=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:35][C@H:36]([CH:47]=[CH2:2])[C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of methyltriphenylphosphonium iodide (5.53 g, 0.0136 mol) in THF (50 mL) was added n-BuLi (1.6N in heptane, 6.5 mL, 0.0104 mol) dropwise at 0° C. and stirred for one hour. To this reaction mixture was added a solution of (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbaldehyde 2.68 g (0.008 mol) in THF (15 mL) dropwise at 0° C. and stirred for another one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (4:1) yielding 2.12 g (80%) of the title compound as a light yellow oil. ES-MS m/e: 332.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[CH:10]=2)[CH:6]=[N:5]1.[Br:20][C:21]1[C:22]([N:28]2[CH2:34][CH:33]([OH:35])[CH2:32][N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30][CH2:29]2)=[N:23][C:24](I)=[CH:25][CH:26]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[Br:20][C:21]1[C:22]([N:28]2[CH2:34][CH:33]([OH:35])[CH2:32][N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30][CH2:29]2)=[N:23][C:24]([N:17]2[C:11]3[CH:10]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:1])([F:18])[F:19])[CH:8]=4)[N:14]=[CH:13][C:12]=3[CH:15]=[N:16]2)=[CH:25][CH:26]=1
Reactant: FC(F)(F)Cn1cc(-c2cc3[nH]ncc3cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(I)ccc2Br)CC(O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)ccc2Br)CC(O)C1
Temperature: 100 °C
Yield: 18.9 %

Procedure:
A mixture of 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (539 mg, 2.02 mmol), tert-butyl 4-(3-bromo-6-iodopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (1.00 g, 2.02 mmol), N1,N2-dimethylethane-1,2-diamine (535 mg, 6.06 mmol), CuI (768 mg, 4.04 mmol), and K2CO3 (1.12 g, 8.08 mmol) in 1,4-dioxane (10 mL) under N2 was heated at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/petroleum Ether (20%40%) as eluting solvents to afford tert-butyl 4-(3-bromo-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a white solid (244 mg, 19%). MS (ESI) m/z: 637 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:23]2[CH:30]=[N:29][CH:28]=[C:27]([N:31]3[CH2:43][CH2:42][N:34]4[C:35]5[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=5[CH:41]=[C:33]4[C:32]3=[O:44])[C:24]=2[CH:25]=[O:26])=[CH:3]1.[BH4-].[Na+]>CO>[OH:26][CH2:25][C:24]1[C:23]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:30][N:29]=[CH:28][C:27]=1[N:31]1[CH2:43][CH2:42][N:34]2[C:35]3[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=3[CH:41]=[C:33]2[C:32]1=[O:44]
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)nc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
A mixture of 3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)isonicotinaldehyde 102b (135 mg, 0.22 mmol) and NaBH4 (20 mg, 0.5 mmol) in MeOH (5 mL) was stirred at 0° C. for 0.5 h. The mixture was quenched with water and the residue was extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 102 (18 mg, 20%). LCMS: [M+H]+ 595. 1H NMR (500 MHz, DMSO) δ 8.59 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 7.87 (s, 1H), 7.37-7.38 (m, 2H), 7.23-7.25 (m, 1H), 6.54 (s, 1H), 5.16 (t, J=3.0, 1H), 4.40 (s, 2H), 4.14-4.18 (m, 3H), 3.93-3.95 (m, 1H), 3.60 (s, 3H), 3.09 (s, 4H), 2.60-2.61 (m, 6H), 2.48-2.34 (m, 5H), 1.78-1.79 (m, 2H), 1.69-1.70 (m, 2H)