Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 50 °C
Yield: 49.9 %

Procedure:
According to the procedure described in Example 138B, phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (151 mg, 0.45 mmol) from Example 153A was reacted with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (89 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours at 50° C., the reaction was concentrated to dryness. The resulting solid was triturated with 1:1 dichloromethane/hexane and the solid removed by filtration to afford the title compound (83 mg, 50% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 7.55 (m, 4H), 7.40 (m, 5H), 7.20 (s, 1H), 6.95 (m, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 1.25 (s, 9H); LCMS (ESI) m/z 555 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=O.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:1][CH:3]2[C:12]3[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=3)[O:6][CH2:5][CH2:4]2)[CH2:30][CH2:29]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc2c(c1)OCCC2C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CCN2CCN(CC3CCOc4cc(C#N)ccc43)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol) in DCM (3 mL) was added 4-methyl-5-[2-(piperazine-1-yl)ethyl]-2-benzofuran-1(3H)-one (57 mg, 0.27 mmol), sodium triacetoxyborohydride (27.0 mg, 0.267 mmol) and DIPEA (57 mg, 0.27 mmol). The reaction was stirred under nitrogen at room temperature for 16 hours when LC-MS indicated product formation. The mixture was diluted with DCM and the product was isolated by flash chromatography. LC-MS (IE, m/z): 432 [M+1]+. (0.18 μM)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:15]([CH3:18])([O-])=O.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:7][CH:6]([C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][NH2:15]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C(O)CN)cc(OC)c1OC
Temperature: 0 °C

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (10 g, 51 mmol) and nitromethane (10 mL) in ethanol at 0° C. was treated with 10% sodium hydroxide (21.4 mL, 53.5 mmol), stirred for 45 sesonds, treated with 2% acetic acid (162 mL), stirred for 1 hour in the ice bath, and filtered. The solid was washed with water and dried under vacuum to provide 9.0 g of the desired product as an off-white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]3[C:19](=O)[CH:11]([CH2:12][CH2:13]3)[CH2:10][C:9]=2[CH:8]=1)([O-:6])=[O:5].C([O-])(=O)C.[Na+].C(O)C>O>[N+:4]([C:7]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]3[C:19](=[N:2][OH:3])[CH:11]([CH2:12][CH2:13]3)[CH2:10][C:9]=2[CH:8]=1)([O-:6])=[O:5]
Reactant: O=C1C2CCC1Cc1cc([N+](=O)[O-])ccc1C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)CC1CCC(C2)C1=NO
Temperature: 25 °C

Procedure:
Hydroxylamine hydrochloride (9.72 g) was added to a stirred solution of 5-nitro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one* (10.82 g) and sodium acetate (19.08 g) in a mixture of absolute ethanol (50 rat) and water (50 mL). The reaction was warmed to reflux for 18 hours cooled to room temperature and diluted with water (200 mL). The product was filtered off, dried under high vacuum to afford the title compound as a white powder (10.73 g) m/z 247 (M+H+). *J. Org. Chem. 1982, 47, 4329–4334
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1.C(=O)([O-])[O-].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO>[CH2:36]([O:35][C:33]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:10]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CC(O)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-naphthalene-1-sulfonic acid piperidin-4-ylamide acetic acid salt 37 (290 mg, 0.74 mmol) in MeOH (10 mL) was added MP-Carbonate (1.45 g, 3.69 mmol, 2.54 mmol/g). After shaking at 25° C. for 1 h, the solution was filtered. To the resultant solution was added ethyl chloroformate (120 mg, 1.11 mmol). After stirred for another 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The crude material was purified by Flash column chromatography (CH2Cl2: MeOH) to provide 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38. LCMS showed m/z: 407 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=1)[CH3:9]>>[CH3:9][N:8]([CH2:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)[CH3:7]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)Cc1nc(CO)cs1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice cold tetrahydrofuran (100 mL) was added ethyl 2-dimethylaminomethylthiazole-4-carboxylate (8.5 g, 39.7 mmol in 40 mL of tetrahydrofuran) dropwise over 40 min maintaining an internal temperature of 5-10C. The mixture was stirred at this temperature range for 90 min. The reaction was carefully quenched with saturated aqueous ammonium chloride (30 mL). The resulting gray slurry was stirred 15 min and filtered through celite. The pad was well washed with ethyl acetate. The filtrate was washed with brine and dried over sodium sulfate. Concentration of this organic solution gave 4.2 g (62%) of 2-dimethylaminomethyl-4-hydroxymethylthiazole as an amber oil. The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH:17]([CH3:19])[CH3:18])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)I
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(F)c(F)c1
Yield: 92.3 %

Procedure:
To a solution of 3,4-difluoro-phenol (5 g, 38.4 mmol) in acetone (50 mL) was added potassium carbonate (54 g, 38.4 mmol) and 2-iodo-propane. The reaction mixture was heated at refluxing for 24 h. The crude was cooled down and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:9) to give 1,2-difluoro-4-isopropoxy-benzene as colorless oil (Yield 6.12 g, 92.3%).
Reaction SMILES: [NH:1]([C:26]([CH3:28])=[O:27])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23](O)=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.[NH2:36][C@H:37]([C:49]([NH:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:50])[CH2:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.CN(C=O)C>[NH:1]([C:26]([CH3:28])=[O:27])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([NH:36][C@H:37]([C:49]([NH:51][CH2:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:50])[CH2:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1)C(C)C
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
The ketoamide (8) (227 mg, 0.5 mmol) was dissolved in ethyl acetate (10 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure to give 22. To a solution of Ac—Tyr—Val—Ala—OH (197 mg, 0.5 mmol) in dry THF (10 mL) and DMF (2 mL) cooled to −15° C. was added N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) followed by iso-butyl chlorofornate (68 mg, 65 μL, 0.5 mmol) and the solution stirred at −15° C. for 5 min. A previously prepared solution of 22 and N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) in dry THF (5 mL) was added, the solution stirred at −15° C. for 15-30 min and then at r.t. for 16 h. The solution was filtered and the solvent removed under reduced pressure to yield the product which was recrystallized from methanol/ether to give 340 mg (93%) of Ac—Tyr—Val—Ala—Asp(Bzl)—CONH—CH2CH2Ph: mp 192-194° C.; 1H NMR (DMSO) δ0.77 (m, 6H, Val CH3's), 1.19 (m, 3H, Ala CH3), 1.74 (s, 3H, Ac CH3), 1.93 (m, 1H, Val β-CH), 2.62 (obs, 2H, CH2Ph), 2.77 & 3.18 (m, 4H, Tyr & Asp β-CH2's), 3.37 (m, 2H, NH-CH2), 3.75, 4.09, 4.19 & 4.53 (m, 4H, α-CH's), 5.06 (s, 2H, benzyl CH2), 6.62 & 7.01 (2xd, 4H, Tyr aromatic CH's), 7.20 (m, 5H, phenethyl aromatic CH's), 7.35 (s, 5H, benzyl aromatic CH's), 7.83 (m, 1H, NH), 8.04 (m, 4H, NH's), 9.15 (s, 1H, Tyr OH); FABMS m/e 730 (M++1).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[O:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[Co+3].[Co+3].[Zn+2].[Zn+2].[Zn+2].[Cl-].[Zn+2].[Cl-].C(COC)OC.O>[C:9]1(=[O:5])[O:4][CH2:2][CH2:1][CH2:6][CH2:7][CH2:8]1.[CH2:1]1[O:4][CH:2]1[CH3:3]
Reactant: C1CCOC1
Agent: [Co+3]
Agent: CC1CO1
Agent: [C-]#N
Solvent: COCCOC
Solvent: O
Product: O=C1CCCCCO1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
The one-liter reactor previously described was charged with a 480 molecular weight poly(propylene oxide) triol (78.9 g), zinc hexacyanocobaltate/zinc chloride/glyme/water catalyst (0.575 g, 980 ppm), and tetrahydrofuran (60 mL). The load-cell reservoir was charged with propylene oxide (341 g). The reactor was purged several times with nitrogen, then pressurized to about 5 psi. The reactor contents were stirred and heated to 90° C. over a 1.5 hour period. An initial charge of 37 g of PO was added to the reactor. A pressure drop was observed about 1 hour after addition of the initial charge, indicating that initiation of the catalyst had occurred. The remaining PO was added over about a 10-hour period. The product was heated for an additional 8 hours at 90° C. following addition of the propylene oxide. ε-Caprolactone (165 g was charged to the load-cell reservoir, and was added to the reactor at 90° C. at a rate of about 40 g/hour. The product was heated for an additional 8 hours at 90° C. following addition of the ε-caprolactone. The product was cooled, drained from the reactor, and filtered through diatomaceous earth. Tetrahydrofuran was removed using a rotary evaporator. Residual ε-caprolactone was removed by passing the polymer product through a wiped-film evaporator under vacuum at 150° C. The ε-caprolactone-capped poly(PO) triol product had a hydroxyl number of 60.5 mg KOH/g and a GPC number average molecular weight of 2410.
Reaction SMILES: [Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C@:4]([OH:13])(C(O)=O)[CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].O>C(O)(=O)C>[Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C:4](=[O:13])[CH:3]=1
Reactant: O=C(O)[C@]1(O)C=C(Cl)[C@@H](O)C1(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(Cl)[C@@H](O)C1(Cl)Cl
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
The (1R,4R)-acid (4) (200 mg, 0.8 mmol) was added portionwise over 10 min to lead tetraacetate (500 mg, 1.13 mmol) in acetic acid (5 ml) containing water (0.05 ml) at 80°. After a further 5 min, water (25 ml) was added and the cooled mixture extracted with ether (3×25 ml). The combined ether solutions were extracted with 5% aqueous sodium bicarbonate until the washings were alkaline (pH 7.5-8), then washed with water (10 ml), dried (MgSO4), and evaporated under reduced pressure. Short path distillation (bath temp. 60°/0.1 mmHg) gave the (4R)-enone (6) (160 mg, 98%) as a colourless oil, [α]35725 +1547° (c 5.66×10-2, EtOH) [α]25225 -11,280° (c 2.26×10-3, EtOH), [θ]33325 +8407° (c. 5.66×10-2,EtOH), [θ]24025 -45,025° (c 2.26×10-3, EtOH) (Found : C, 29.8; H, 1,65; Cl, 51.3; C5H3Cl3O2 requires C, 29.8; H, 1.5; Cl, 52.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17]CC)=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([OH:17])=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(C(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
117 mg (purity 81%, 0.26 mmol) of ethyl 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 79 mg (purity 86%, 78% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:12][C:13](=[O:25])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:16][CH2:15]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=1[O:46][C:47]([F:48])([F:49])[F:50])(=[O:44])=[O:43])[C:6](=[O:11])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:12][C:13](=[O:25])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3nccs3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4nccs4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 89.3 %

Procedure:
With 300 mg of the compound obtained in Step 46-1 and 200 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 409 mg of the title compound (yellow amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])=[CH:9][N:10]=2)[N:7]=1.[NH2:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=C1CCCN1c1cnc2ccc(Cl)nn12
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(N3CCCC3=O)n2n1
Yield: 73 %

Procedure:
The 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)pyrrolidin-2-one was reacted with (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate using the amine displacement conditions described in example 5.6.42, Part A to afford the desired product in 73% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38-1.46 (m, 10H) 1.71 (br. s., 1H) 1.80-1.91 (m, 2H) 1.95-2.08 (m, 1H) 2.22 (quin, J=7.55 Hz, 2H) 2.50-2.58 (m, 2H) 3.22-3.41 (m, 4H) 3.90 (q, J=6.69 Hz, 2H) 4.16 (br. s., 1H) 6.40 (d, J=9.70 Hz, 1H) 7.44 (s, 1H) 7.54 (d, J=9.70 Hz, 1H); LRMS (ESI) m/401.0 [(M+H)+, calcd for C20H28N6O3 400.0].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1([F:19])[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: OC1CCC(F)(F)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
The inside of a reactor was sufficiently dried by vacuum heating, and the atmosphere inside the reactor was replaced with dry nitrogen. The reactor was charged with 2000 ml of dichloromethane and 128.4 ml (1.5 mol) of oxalyl chloride at −78° C. After the dropwise addition of 233 ml (3.0 mol) of DMSO, the mixture was stirred at −78° C. After 10 minutes had elapsed, a dichloromethane (300 ml) solution of 136.1 g (1.0 mol) of 4,4-difluorocyclohexanol was added dropwise to the mixture using a syringe over 10 minutes. After stirring the reaction mixture at −78° C. for 40 minutes and at −45° C. for 40 minutes, N,N-diisopropylethylamine (500 ml) was added to the reaction mixture. After stirring the mixture at 0° C. for 20 minutes, a saturated ammonium chloride aqueous solution (1000 ml) was added to the mixture to terminate the reaction. The mixture was then extracted three times with dichloromethane (3000 ml). The organic layer was washed with 1N hydrochloric acid and a saturated salt solution, and dried over magnesium sulfate. After removing anhydrous magnesium sulfate using a Buchner funnel, the solvent was evaporated. The residue was distilled under reduced pressure (30 mmHg) to obtain 4,4-difluorocyclohexanone (118.9 g (yield: 85%)).
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[F:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1.[H-].[Na+]>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]([NH:21][C:3](=[O:13])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)Nc2cccc(F)c2)cc1

Procedure:
Using the procedure for Example 22, (4-methoxy-phenyl)-acetic acid methyl ester Compound 22a was reacted with 3-fluoro-phenylamine and sodium hydride in DMSO at room temperature to provide N-(3-fluoro-phenyl)-2-(4-methoxy-phenyl)-acetamide Compound 23a. Compound 23a was reacted with borotribromide in dichloromethane to yield N-(3-fluoro-phenyl)-2-(4-hydroxy-phenyl)-acetamide Compound 23b.
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH2:33][OH:34])[CH2:9][CH:10]([C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[N:13]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([N:8]1[CH2:32][CH2:33][O:34][CH:10]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[N:13]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(O)CN(CCO)Cc2ccccc2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: Br
Product: Cc1c(C2CN(Cc3ccccc3)CCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
The suspension of 2-[benzyl-(2-hydroxy-ethyl)-amino]-1-[5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-ethanol 2A-3 (150 mg, 0.3 mmol) in 48% hydrobromic acid (0.3 ml) was heated to 100° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and partitioned with ethyl acetate and saturated NaHCO3. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 40% ethyl acetate/hexanes) to give the title compound 5A-1 (77 mg).
Reaction SMILES: [Na].[H-].COCCO[Al+2].[H-].C[O:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH:16]1[O:28][CH:17]1[C:18]1[NH:19][C:20](=[CH:24][CH2:25][CH2:26][OH:27])[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[OH:27][CH2:26][CH:25]=[CH:24][C:20]1[N:19]=[C:18]([CH:17]2[O:28][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:12][OH:11])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCC1OC1C1=CC=CC(=CCCO)N1
Agent: COCCO[Al+2]
Agent: [H-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: OCC=Cc1cccc(C2OC2CCCCO)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium (bis) 2-methoxyethoxy-aluminum hydride (0.31 ml, 1.05 mmole) is dissolved in 1 ml toluene in an oven-dried 10 ml 2-neck round bottom flask under nitrogen at 0° C. Methyl-5,6-epoxy-6-[6-(3-hydroxy-propyl-1yl)pyridine-2yl]-hexanoate (72 mg, 0.263 mmole), in 3×0.3 ml toluene, is added dropwise to the reaction mixture at 0° C. The reaction mixture is stirred 4 hours at 0° C., quenched with the careful addition of 5 ml 0.5M sodium potassium tartrate, and stirred vigorously for 1.5 hours while warming to room temperature. The mixture is poured into 15 ml saturated sodium chloride and extracted with r×10 ml ethyl acetate. The combined organics are dried over magnesium sulfate and concentrated in vacuo to an amber oil (64 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:31])[NH:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:31])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:33][CH3:32])=[CH:25][C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccccc1-c1ccc(NC(=O)[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c(F)c1

Procedure:
(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.95 g, 1.84 mmol), 2-(methylthio)benzene boronic acid (0.37 g, 2.2 mmol), and tetrabutylammonium bromide (30 mg, 0.09 mmol) were combined in 15 mL toluene, added 2 mL of a 2M aqueous Na2CO3 solution followed by tetrakistriphenylphosphine palladium(0) (0.11 g, 0.09 mmol). Heated reaction at reflux for 5 hours, cooled, dissolved in EtOAc (100 mL), washed with water (3×50 mL), brine (50 mL), dried with MgSO4, filtered, and concentrated. Purified on a silica gel column eluted using an automated system with gradient of 0-60% EtOAc in hexanes over 40 minutes. Combined and concentrated pure fractions to yield title compound as a light yellow foam. (0.77 g, 74%) APCI (AP−): 559.3 (M−H)−.