Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].CO>O1CCCC1.[C].[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])=[N:22][CH:23]=1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.5 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-{4-methoxy-3-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (4.30 g, 9.99 mmol) in tetrahydrofuran (100 mL) were added methanol (50 mL) and 10% palladium-carbon (982 mg), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere (2.5 atm). The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (4.1 g) as a brown syrup substance. The syrup substance was used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:8]=12)([O-])=O.[Sn](Cl)(Cl)(Cl)[Cl:17].[OH-].[Na+]>Cl>[ClH:17].[ClH:17].[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=12
Reactant: O=[N+]([O-])c1cccn2ncc([N+](=O)[O-])c12
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccn2ncc(N)c12

Procedure:
0.7 g of 3,4-dinitropyrazolo[1,5-a]pyridine was added to a suspension of 11.1 g of tin chloride in 80 ml of concentrated hydrochloric acid. The reaction was monitored by thin layer chromatography (TLC). The pH of the reaction mixture was adjusted to 12 using sodium hydroxide. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The organic phase was acidified with 3 ml of hydrochloric ethanol (2.5 N HCl). The precipitate was filtered off. This gave 0.55 g of pyrazolo[1,5-a]pyridine-3,4-diamine hydrochloride, whose 1H NMR analysis (DMSO-d6, 400 MHz) (δ ppm) was as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH3:26])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][Br:28])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CBr)cc1Cl
Yield: 73.9 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((5-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (2.6 g, 6.0 mmol) in dry benzene (250 mL) were added N-bromosuccinimide (1.2 g, 6.6 mmol) and benzoyl peroxide (0.15 g, 0.6 mmol). The mixture was refluxed while irradiating with a 250 Watt lamp. After 28 hours the reaction was concentrated of all volatiles in vacuo and the resulting solid triturated with benzene. Purification by flash chromatography on silica gel afforded 2.3 g (75% yield) of N-(4-chlorophenyl)-2-[((5-bromomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a white solid; NMR (DMSO-d6) 11.1 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 7.3 (s, 1), 4.9 (s, 2) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[C:10]1[CH2:14][CH2:13][O:12][N:11]=1.[Br:15]Br>S(=O)(=O)(O)O>[Br:15][C:7]1[C:2]([CH3:1])=[C:3]([C:10]2[CH2:14][CH2:13][O:12][N:11]=2)[C:4]([S:8][CH3:9])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: CSc1cccc(C)c1C1=NOCC1
Agent: O=S(=O)(O)O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 10 g (48 mmol) of 3-(2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole are added a little at a time to 120 ml of conc. sulfuric acid, and the mixture is stirred for approximately 30 minutes. 3.7 g (23 mmol) of bromine are then added dropwise, and the mixture is stirred at 0° C. for 2.5 hours. Over a period of approximately 45 minutes, the mixture is subsequently allowed to warm to room temperature. A homogeneous solution forms. For work-up, the reaction mixture is poured into ice-water and extracted three times with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. This gives 11.4 g of crude product which is employed in the next step without any further purification.
Reaction SMILES: [F:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([O:21]C)[N:15]=1)[CH3:10].[Na+].[Cl-]>CS(C)=O.C(N(CC)CC)C>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[NH:15][C:16](=[O:21])[CH:17]=[C:18]([N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][F:1])[CH2:4]2)[N:19]=1)[CH3:10]
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Reactant: FCC1CNCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Temperature: 85 °C
Yield: 50.4 %

Procedure:
In a 50 ml round-bottomed flask, 680 mg of 2-fluoromethylmorpholine (Yoshikazu Jinho et al.; J. Med. Chem., 37(17), 2791-2796; 1994) and 0.63 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester (example 8b, step 2b) are placed in 15 ml of DMSO and 1,013 ml of triethylamine. The reaction medium is heated for 18 h at 85° C. The reaction medium is poured into a saturated NaCl solution and the mixture is extracted with 3 times 25 ml of ethyl acetate. The organic extracts are combined and washed with a saturated NaCl solution, dried over magnesium sulfate and evaporated. The compound obtained is chromatographed on silica gel (15-40 μm, Merck), elution being carried out with a gradient of dichloromethane and methanol (98/2 to 95/5 v/v). The fractions containing the expected compound are combined and evaporated, so as to give (±)-[4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid ethyl ester (412 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH3:13])([O-:12])=[O:11].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:22]=[N:23]/[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:13][N+:10]([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
263 μl (1.51 mmol) of N,N-diisopropylethylamine were added to 10.1 ml (186 mmol) of nitromethane, and the yellow solution was stirred at RT for 1 h. 1.38 g (5.03 mmol) of the compound of Example 22A were then added, and the mixture was stirred at RT overnight. All volatile components were removed on a rotary evaporator. The residue was purified by preparative HPLC [Method 12]. This gave 865 mg (51% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]1[C:18](=[O:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].CC(C[C@@H]1C(=O)C[C@@H]2N(CCC3C2=CC(OC)=C(OC)C=3)C1)C>>[CH3:3][CH:2]([CH2:4][CH:5]1[C:18](=[O:19])[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:1]
Reactant: COc1cc2c(cc1OC)[C@H]1CC(=O)[C@H](CC(C)C)CN1CC2
Agent: COc1cc2c(cc1OC)[C@@H]1CC(=O)[C@@H](CC(C)C)CN1CC2
Product: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2

Procedure:
To a round bottom flask was added 6,7-dimethoxy-3,4-dihydroisoquinoline (13 g, 67.8 mmol), 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide 1b (26 g, 81.4 mmol) and EtOH (130 mL). The suspension was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature and H2O (200 mL) was added forming a precipitate. The EtOH was removed in vacuo and CH2Cl2 (400 mL) was added. A 10% NaOH solution was added to the mixture until basic. The aqueous layer was then extracted 3× with CH2Cl2 (250 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude reaction mixture was purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2) and further recrystallized from EtOAc and Hexanes to give 16.1 g (51 mmol) of a racemic mix of (3S,11bS) and (3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one 1c (tetrabenazine, TBZ) in a 75% yield. The enantiomers of tetrabenazine were separated by SFC utilizing a Chiralpak AD-H column with 15% CAN/MeOH plus 0.5% DMEA at 2.5 mL/min at 100 bar and 35° C. to yield 4.3 g of (3R,11bR)-tetrabenazine 1c.1 and 4.3 g of (3S,11bS)-tetrabenazine 1c.2. (3R,11bR)-tetrabenazine 1c.1: MS calcd: (317). Found 318.7 (M+H). (3S,11bS)-tetrabenazine 1c.2: MS calcd: (317). Found 318.7 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=1)[CH:5]=2.CO.C(OCC)(=O)C.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[CH3:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH2:5][C:6]=2[CH:7]=1
Reactant: CC1=CC=C2C(=Cc3cc(C)ccc32)C1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2c(c1)Cc1cc(C)ccc1-2
Yield: 89.5 %

Procedure:
A mixture of 2,7-dimethylfluorenone (7.0 g, 32.8 mmol), methanol (100 mL), ethyl acetate (50 mL), acetic acid (20 mL) and palladium hydroxide (20% on carbon, water content 44.43%, 0.5g) was hydrogenated in a shaker at 26 psi of hydrogen for 4 hr. The reaction was monitored by TLC (silica, 10% ethyl acetate/hexane). The catalyst was filtered out and the solvents were removed in vacuum. Treatment of the residue with methanol afforded 5.7 g (89.3%) of 2,7-dimethylfluorene.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:6]
Reactant: CC(C)(C)N
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc(Cl)ccc1N
Yield: 76.8 %

Procedure:
Stir and cool to 0° C. a solution of 2-amino-5-chlorobenzoic acid (1.21 g, 10 mmol) and N-hydroxysuccinimide (1.38 g, 12 mmol) in dichloromethane (12 mL). Add, dropwise, a 1M solution of dicyclohexylcarbodiimide in dichloromethane (12 mL, 12 mmol), and stir at 0° C. for 1 h. Add tert-butyl amine (1.74 g, 23.79 mmol) by syringe and stir at ambient temperature overnight. Filter the reaction mixture and wash the filtrate with aqueous sodium bicarbonate. Dry the organic phase with MgSO4 and chromatograph over silica gel eluting with 4% ethyl acetate/dichloromethane to afford 1.74 g of the title compound: MS 227(M+H), m.p. 126–127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:21]3[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncccc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncccc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=399.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Cl.FC(F)(F)C(O)=O>C(O)C.C(OCC)(=O)C.[Pd].[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 4′-Benzyloxy-biphenyl-3-carboxylic acid ethyl ester (2.3 g) in ethanol/ethyl acetate (3:1) (200 mL) is added 5% palladium on carbon (300 mg). The reaction mixture is placed under an atmosphere of hydrogen (55 psi) and is shaken on a Parr apparatus for 2 h. Concentrated hydrochloric acid (0.3 mL) is added to the reaction mixture. The reaction mixture is allowed to proceed for an additional 10 h. Trifluoroacetic acid (1 mL) and 20% palladium hydroxide on carbon (300 mg) are added to the reaction mixture and the reaction is allowed to stir under an atmosphere of hydrogen (60 psi). After an additional 80 h, the reaction mixture is degassed with nitrogen and is filtered though a plug of silica gel, eluting with 500 mL ethyl acetate and 500 mL ethanol. The filtrate is concentrated under reduced pressure and the residue is diluted with 400 mL saturated sodium bicarbonate solution. The product is extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1.6 g, 95%) as a white solid.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[H-].[Na+].CSC.[O:13]1[CH:19]2[CH:14]1[C:15]([CH2:33][F:34])([CH2:31][F:32])[O:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=[CH:20][C:18]=12.S(=O)(=O)(O)O>O1CCCC1.[Cu]Br.O>[F:30][C:24]([F:29])([C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([CH2:33][F:34])([CH2:31][F:32])[C@@H:14]([OH:13])[C@H:19]([O:6][C:3]3[CH2:4][CH2:5][C:1](=[O:7])[CH:2]=3)[C:18]=2[CH:20]=1)[C:25]([F:28])([F:27])[F:26]
Reactant: O=C1CCC(=O)C1
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C(O[C@@H]2c3cc(C(F)(F)C(F)(F)F)ccc3OC(CF)(CF)[C@H]2O)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 3.4 %

Procedure:
In 40 ml of tetrahydrofuran was dissolved 0.36 g of cyclopentan-1,3-dione and 0.13 g of sodium hydride (60%) was added thereto under nitrogen stream with cooling at -20° C. After the mixture was stirred at room temperature for 15 minutes, 0.72 g of a complex of copper (I) bromide and dimethyl sulfide was added. To the reaction mixture was added 0.92 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran dissolved in 10 ml of tetrahydrofuran. The mixture was stirred for 6 days. To the mixture were added water and a small amount of concentrated sulfuric acid. The mixture was extracted with methylene chloride and the organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) and another silica gel column chromatography (developing solution, AcOEt:hexane=1:1) to obtain 0.04 g of trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-(3-oxo-cyclopent-1-enyloxy)-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[F-].[Cs+].Br[C:58]1[CH:63]=[C:62]([F:64])[C:61]([F:65])=[C:60]([F:66])[C:59]=1[F:67]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Pd].C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:58]1[CH:63]=[C:62]([F:64])[C:61]([F:65])=[C:60]([F:66])[C:59]=1[F:67])[CH:7]=[CH:6]2
Reactant: Fc1cc(Br)c(F)c(F)c1F
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CC#N
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)c(F)c(F)c3F)ccc2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (259 mg, 0.49 mmol), bis(pinacolato)diboron (151 mg, 0.59 mmol), bis(tricyclohexylphosphine)palladium (0) (75 mg, 0.11 mmol) and cesium fluoride (764 mg, 5.03 mmol) in 20 mL degassed acetonitrile and heat at 100° C. under nitrogen in a sealed vial. The reaction is complete in 10 minutes. Cool and add 1-bromo-2,3,4,5-tetrafluorobenzene (224 mg, 0.99 mmol) along with 10 mL acetonitrile, seal the vial, purge with nitrogen and heat at 80° C. for 2 hours. Cool, filter and purify on an SCX column eluting with 2N ammonia/methanol. Evaporate the solvent and purify the resulting oil on a silica column eluting with 3% methanol/methylene chloride to give 188 mg of the title compound (73%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -15 °C
Yield: 91.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 mL) at -20 to -30° C. was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20° C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ˜600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.27 (m, 1 H), 3.44-3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1H), 2.15 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [BH4-].[Na+].Cl.[CH2:4]1[CH2:8]O[CH2:6][CH2:5]1.CO>>[CH3:6][C:5]1[CH2:8][C:4]2[C:8]([CH:4]=1)=[C:4]([C:5]1[C:6]3[C:5](=[CH:6][CH:8]=[CH:4][CH:5]=3)[CH:4]=[CH:8][CH:6]=1)[CH:8]=[CH:6][CH:5]=2
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=Cc2c(cccc2-c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.3 g (33 mmol) of sodium borohydride were added at 0° C. to a solution of 12 g (44 mmol) of (16) in 100 ml of THF/methanol 2:1 and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto 100 g of ice, concentrated hydrochloric acid was added until the pH was 1 and the mixture was extracted a number of times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The crude product was taken up in 200 ml of toluene, admixed with 0.5 g of p-toluenesulfonic acid and refluxed for 2 hours on a water separator. The reaction mixture was washed 3 times with 509 ml each time of saturated sodium hydrogen carbonate solution and the solvent was removed under reduced pressure. The solid residue was washed with a little pentane and dried under reduced pressure. This gave 10.3 g of (37) in the form of colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=3[O:25][CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].B(F)(F)F.C1C[O:36]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=3[O:25][CH3:26])[CH:13]([OH:36])[CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CC=C(c3c(OC)cc(OC)cc3OC)CC2)cc1
Reactant: C1CCOC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(N2CCC(c3c(OC)cc(OC)cc3OC)C(O)C2)cc1
Temperature: 52.5 °C
Reaction time: 1 h

Procedure:
Compound of example 118 (15 g, 42 mmol) was subjected to hydroboration using NaBH4 (2.7 g, 71.4 mmol) and BF3-etherate (12.6 g, 88.8 mmol) in THF (50 mL). Excess diborane was destroyed by the addition of water. Conc. HCl (15 mL) was added and the reaction mixture was stirred at 50-55° C. for 1 h. It was cooled to room temperature The resulting mixture was made basic (pH 12-14) using an aqueous 50% NaOH solution. 30% H2O2 (9 mL) was added and the reaction mixture was stirred at 50-55° C. for 1 h. The reaction mixture was processed as described in example 2 to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](OC(C)(C)C)(N(C)C)[N:26]([CH3:28])[CH3:27]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:24])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][N:26]([CH3:28])[CH3:27])[CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C(Cc1ccccc1)c1c[nH]c(C(=O)NCc2ccccc2)c1
Solvent: C1CCOC1
Product: CN(C)C=C(C(=O)c1c[nH]c(C(=O)NCc2ccccc2)c1)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of compound 4 (1 equivalent) in THF, at ambient temperature, was added (Me2N)2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product 7 was used without purification. 1H NMR (CDCl3) δ 4.4 (s, 2H), 4.8 (s, NH), 6.8–7.4 (m, 13H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH2:18]1[C:20]2([CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]2)[CH2:19]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][CH:23]2[CH2:24][CH2:25][C:20]3([CH2:18][CH2:19]3)[CH2:21][CH2:22]2)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)nc1Cl
Reactant: OCC1CCC2(CC1)CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of a 2,4-dichloroprimidine-5-carboxylic acid (440 mg) in THF (4.0 mL) are added t-BuOK (potassium tert-butoxide) (5.7 mmol) and spiro[2.5]oct-6-ylmethanol (2.3 mmol) in THF (1.0 mL) at 0° C. After stirring at 0° C. for 1.5 h, the reaction is quenched by the addition of sat. aq. NaHCO3. The mixture is washed with ether. The aqueous layer is acidified to pH 2 with sat. aq. KHSO4, then extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude title compound.