Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[BH4-].[Na+]>CO.CS(C)=O>[OH:23][CH2:22][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C@:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[N:10]=[CH:2]4)[CH2:24][C:13]=3[CH:14]=2)[N:19]=1
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: OCc1ccc2cc3c(cc2n1)C[C@@]1(C=Nc2ncccc21)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (80 mg, 0.25 mmol, described in Intermediate 10) in a mixture of MeOH (5 mL) and DMSO (1 mL) was added sodium borohydride (19 mg, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 1 h, then the MeOH was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=318 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[NH:6])[NH:4][OH:5].C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17](Cl)=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:6]=[C:17]([C:16]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:15]=2[F:14])[O:5][N:4]=1
Reactant: N=C(CCl)NO
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C(F)(F)F)cc1-c1nc(CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
To a solution of 2-chloro-N-hydroxyethanimidamide (2.4 g, 22.1 mmol) and triethylamine (3.7 ml, 26.5 mmol) in dry toluene (35 mL) was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5 g, 22.1 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and then at 100° C. overnight. The resulting solid was filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-30% EtOAc-hexanes gradient) to afford the title compound (1.2 g, 19% yield): MS (ES) m/z 281 (M+1) and 283 (M+1, isotope).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[C:21]([OH:26])[C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Br:27]Br>>[Br:27][C:23]1[CH:24]=[C:19]([C:9]2[C:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[S:13][C:14]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)[CH:20]=[C:21]([OH:26])[C:22]=1[OH:25]
Reactant: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O
Reactant: BrBr
Product: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O

Procedure:
Prepared from 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-benzene-1, 2-diol (Example 43) according to the procedure of Example 58. White solid: mp 212-213° C.: MS (EI): [M+], 2 bromine isotope pattern, 498, 500, 502; Anal. Calc. for C22H12Br2O2S:C, 52.83, H, 2.42, N, 0.00. Found: C, 52.08, H, 2.55, N, 0.01.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][S:14]2(=[O:20])=[O:19])[CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[CH:57]=[C:58]([CH:82]=[CH:83][CH:84]=1)[CH2:59][N:60]([CH2:68][C@@H:69]([OH:81])[C@@H:70]([NH2:80])[CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64]>CN(C=O)C.C(OCC)(=O)C>[C:63]([O:62][C:61](=[O:67])[N:60]([CH2:68][C@@H:69]([OH:81])[C@@H:70]([NH:80][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][S:14]2(=[O:20])=[O:19])[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[CH2:59][C:58]1[CH:82]=[CH:83][CH:84]=[C:56]([O:55][CH3:54])[CH:57]=1)([CH3:66])([CH3:64])[CH3:65]
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C(=O)OC(C)(C)C)c1
Reactant: CC(=O)c1cc(C(=O)O)cc(N2CCCCS2(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(N3CCCCS3(=O)=O)c2)C(=O)OC(C)(C)C)c1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A mixture of 3-acetyl-5-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzoic acid (68.1 mg, 0.23 mmol), HATU (104.6 mg, 0.275 mmol) and Hunig's base (118.5 mg, 0.16 mL, 0.917 mmol) in DMF (1.1 mL) was stirred for 10 min and then tert-butyl 3-methoxybenzyl((2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (100 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with H2O 3 times and concentrated under vacuum to give the title compound (164 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 1.48 (9H, s), 1.93-2.00 (2H, m), 2.32-2.38 (2H, m), 2.64 (3H, s), 2.88 (1H, dd, J=10, 15 Hz), 3.08-3.15 (1H, m), 3.20-3.23 (1H, m), 3.27-3.39 (2H, m), 3.38 (1H, m), 3.74-3.82 (6H, m), 3.96-4.00 (1H, m), 4.20-4.29 (2H, m), 6.76 (1H, m), 6.91-6.92 (3H, m), 7.05-7.08 (2H, m), 7.35 (1H, m), 8.04 (1H, m), 8.07 (1H, m), 8.11 (1H, m). HPLC retention time: 2.112 min (method A). MS (ESI) (M+Na)+ 738.28.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19])(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)NC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([N+](=O)[O-])ccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8.1 g (28.1 mmol) of N-tert-butyl-2-methoxy-4-nitro-benzenesulfonamide is mixed with 350 ml of trifluoroacetic acid and stirred for 20 hours at room temperature. The trifluoroacetic acid is drawn off, and the remaining residue is then digested with ethyl acetate. 5.0 g (21.6 mmol, corresponding to 77% of theory) of the product is obtained. The ethyl acetate phase is concentrated by evaporation, and the residue that is obtained is purified by chromatography (DCM/EtOH 95:5, Flashmaster II). Another 0.84 g (3.6 mmol, corresponding to 13% of theory) of the product is obtained.
Reaction SMILES: O.O=C[C@@H:4]([C@@H:6]([C@H:8]([C@H:10]([CH3:12])[OH:11])[OH:9])[OH:7])O.C(S)C.CCSC(SCC)[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C.O=C[C@@H]([C@H]([C@H](C)O)O)O.CCS(C(S(CC)(=O)=O)[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C)(=O)=O.[C:61]1([NH:67][NH2:68])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[C:61]1([NH:67][N:68]=[CH:4][C@@H:6]([C@H:8]([C@H:10]([CH3:12])[OH:11])[OH:9])[OH:7])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: NNc1ccccc1
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: CCS(=O)(=O)C([C@H](O)[C@H](O)[C@@H](O)[C@H](C)O)S(=O)(=O)CC
Agent: CCSC(SCC)[C@H](O)[C@H](O)[C@@H](O)[C@H](C)O
Agent: C[C@H](O)[C@H](O)[C@@H](O)C=O
Solvent: O
Solvent: CCS
Product: C[C@H](O)[C@H](O)[C@@H](O)C=NNc1ccccc1

Procedure:
The compound (II) can be prepared by a similar process to the process for preparing 1',2'-diacetyl-L-biopterin [Bernard Schircks, Jost H. Bieri and Max Viscontini, Helvetica Chimica Acta, 60(1), 211 (1977)]. According to the process, L-rhamnose hydrate is reacted with ethanethiol. The obtained L-rhamnose-diethylmer-captal is converted to 5-deoxy-L-arabinose through 1,1-diethylsulfonyl-L-rhamnose. 5-Deoxy-L-arabinose is reacted with phenylhydrazine to obtain 5-deoxy-L-arabinose-phenylhydrazone. 5-Deoxy-L-arabinose-phenyl-hydrazone is reacted with an acylating agent. The obtained 2,3,4-triacyl-5-deoxy-L-arabinose-phenylhyrazone is reacted with 2,4,5-triamino-6-hydroxy-pyrimidine dihydrochloride, and then oxidized with an oxidizing agent such as iodine to obtain a 1',2'-diacyl-L-biopterin. L-Biopterin can be obtained by deacylation of the 1',2'-diacyl-L-biopterin.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.FC(F)(F)S([O-])(=O)=O.[N:19]1([S:24](N2C=C[NH+](C)C2)(=[O:26])=[O:25])[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([S:24]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:26])=[O:25])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC2(CC1)OCCO2)n1ccnc1

Procedure:
8-(Imidazole-1-sulfonyl)-1,4-dioxa-8-aza-spiro[4.5]decane was prepared in accordance with step A of the general method described in example 76 from 1,4-dioxa-8-azaspiro(4,5)decan and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=274.5 (M+H+).
Reaction SMILES: C(#N)C.[CH:4]([C:7]([CH:9]([CH3:11])[CH3:10])=[O:8])([CH3:6])[CH3:5].[I-].[Na+].Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH3:5][C:4](=[C:7]([O:8][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]([CH3:11])[CH3:10])[CH3:6]
Reactant: CC(C)C(=O)C(C)C
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=C(O[Si](C)(C)C)C(C)C
Yield: 96.6 %

Procedure:
Acetonitrile (300 mL) was mixed with 20.3 g of diisopropyl ketone, 32 g of sodium iodide, and 21.6 g of triethylamine, to which was gradually added 23.1 g of chlorotrimethylsilane. The mixed solution was reacted at 50° C. for 4 hours and then allowed to stand for cooling. The reaction mixture was poured into ice and extracted with hexane. An organic phase was rinsed with a sodium hydrogencarbonate solution, dried, and then concentrated. The resultant was purified by distillation in vacuo to obtain 32 g of 2,4-dimethyl-3-trimethylsilyloxy-2-pentene (silylenol ether of diisopropyl ketone). The resulting silylenol ether (15 g) and 8.8 g of tetramethylene sulfoxide were dissolved in 150 mL of chloroform under a nitrogen gas stream. The solution was cooled to −30° C. or lower, and 17.7 g of trifluoroacetic anhydride was added dropwise thereto over 30 minutes. The mixture was reacted at room temperature for 1 hour, and a solution of potassium nonafluorobutanesulfonate in acetonitrile/water was added to the reaction mixture. The mixture was extracted with chloroform, and an organic phase was subjected to alkali rinsing with a 5% by weight tetramethylammonium hydroxide aqueous solution, followed by rinsing with distilled water until aqueous phases had become neutral. An organic phase was concentrated, and diisopropyl ether was added to the resulting crude product to deposit a powder. The powder was collected by filtration to obtain 17 g of Compound (I-1).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:19]([F:22])([F:21])[F:20])(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([F:31])[C:29]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[C:28]([F:31])=[CH:27][C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:25][C:24]=3[F:23])=[C:8]([C:19]([F:22])([F:21])[F:20])[S:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate (636 mg, 1.72 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (514 mg, 2.23 mmol, 1.30 equiv), potassium carbonate (712 mg, 5.15 mmol, 3.00 equiv), N,N-dimethylformamide (10.0 mL). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:6). The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 4×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.865 g (100%) of ethyl 3-(4-[[4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C23H18C1F5O3S, 505.1 (M+H). found 505.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Agent: BrB(Br)Br
Product: O=Cc1ccc(O)c(Cl)c1Cl

Procedure:
The title compound was prepared by reacting 2,3-dichloro-4-methoxybenzaldehyde (10 g, 49 mmol) with boron tribromide (147 ml of 1N solution in CH2Cl2, 147 mmol) according to method D to yield 11.3 g dark grey solid which is mainly the designed product indicated by 1H-NMR. It was triturated with 30% CHCl3 in hexane to give 3.6 g of grey solid as pure product. An analytical sample was afforded as white solid by reverse-phase preparative HPLC: mp 176-178° C.; 1H NMR (DMSO-d6): δ 7.10 (1H, d, J=8.68 Hz), 7.74 (1H, d, J=8.67 Hz), 10.16 (1H, s), 11.95 (1H, s); MS (ESI) m/z 189/191/193 (M−H)−, 193/191/195 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Br[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][C@H:4]1[CH2:3][C@@H:2]([NH:1][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]1[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Reactant: Cc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 120 °C
Yield: 13 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (80 mg, 0.203 mmol), 2-bromo-5-methylpyridine (69.8 mg, 0.406 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium tert-butoxide (39.0 mg, 0.406 mmol) were combined in 1,4-dioxane (2 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 30 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3×50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) to give 1-((2S,4R)-2-methyl-4-((5-methylpyridin-2-yl)amino)-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (13 mg, 0.027 mmol, 13% yield) as an off-white solid. LCMS: (Formate, 2 min), Rt=0.58 mins, MH+=486.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:29][CH2:30][CH3:31])=[CH:7][CH:6]=1)[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([CH:21]([OH:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:29][CH2:30][CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCc1nc2ccc(C(=O)c3ccccc3)cc2n1Cc1ccc(C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCc1nc2ccc(C(O)c3ccccc3)cc2n1Cc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of 4-(6-benzoyl-2-propyl-benzoimidazol-1-ylmethyl)-benzoic acid ethyl ester (1.5 g; 3.5 mmol) in ethanol (50 mL) was added sodium borohydride (1.0 g; 29.4 mmol). After stirring at ambient temperature for 4 hours, acetone (20 mL) was added. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was evaporated to give the title compound (0.9 g, 60% yield) as a white solid which was used without further purification in step 2.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:10][C:11]=2[CH2:12][OH:13])=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:10][C:11]=2[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of [4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol (0.33g, 0.78mmoles, 1eq) in dry 1,2-dimethoxyethane (5ml, 0.16M) was added tetrakis(triphenylphosphino) palladium I (0.45g, 0.39mmoles, 0.5eq) and stirred for 5minutes at room temperature. Phenylboronic acid (0.143g, 1.2mmoles, 1.5eq) was then added followed by the addition of sodium carbonate (2M aqueous solution, 2.3ml, 4.68mmoles, 6eq). The reaction mixture was heated at 100degrees centigrade for 13hours at which point, after cooling to room temperature, the reaction was partitioned between EtOAc and water. After separation of the phases the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to yield after purification by silica gel chromatography (CH2Cl2to 2% MeOH/CH2Cl2) 268mg (80%) of product.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[NH2:5][C:6]1[CH:13]=[C:12](F)[C:9]([C:10]#[N:11])=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:5][C:6]1[CH:13]=[C:12]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]([C:10]#[N:11])=[CH:8][N:7]=1
Reactant: CC(C)N
Reactant: N#Cc1cnc(N)cc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(N)ncc1C#N
Temperature: 50 °C

Procedure:
A mixture of isopropylamine (1.83 ml, 21.3 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 972 mg, 7.09 mmol) and diisopropylethylamine (3.71 ml, 21.3 mmol) in DMA (17 ml) was heated at 50° C. in a septum sealed reaction vessel for 48 h. The reaction mixture was then cooled, evaporated and purified by normal phase chromatography using an 40 g RediSep® column, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated. The residue was partitioned between DCM and 10% aqueous citric acid solution, the aqueous layer washed 2× with DCM, basified with NaHCO3, extracted with DCM (4×), the combined organic extracts from the basic extraction dried over Na2SO4 and evaporated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 6.31 (s, br, 2H), 5.71 (d, br, 1H), 5.58 (s, 1H), 3.61-3.49 (m, 1H), 1.14 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.C[Mg]Cl>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C=O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CO

Procedure:
0.500 g (1.89 mmol) of the above prepared 2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde was dissolved in 9.4 ml of abs. THF and treated at −10° C. with 0.94 ml of 3M methyl magnesium chloride solution (in THF). After 30 Min., the reaction mixture was carefully poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.532 g of the title product, pure according to NMR.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[C:9]([Br:11])[N:10]=1>CO>[Br:11][C:9]1[N:10]=[C:5]([O:2][CH3:1])[C:6]([NH2:12])=[N:7][CH:8]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Br)cnc1N
Temperature: 25 °C

Procedure:
A 30% w/w solution of NaOMe in MeOH (8.4 mL, 44.8 mmol) was added to a stirring suspension of 3,5-dibromo-2-aminopyrazine (10 g, 39.5 mmol) in dry MeOH (40 mL). The reaction mixture was heated to reflux and maintained for 3 h. The reaction was allowed to cool to rt and concentrate to 1/3 volume. The reaction was then partitioned between DCM and saturated aqueous NaHCO3 solution. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution (3×). The combined aqueous portions were back extracted with DCM (3×). The combined organic portions were washed with brine, dried (Na2SO4), and concentrated to provide 8.1 g of 5-bromo-3-methoxypyrazin-2-amine: 1H NMR (300 MHz, CDCl3): 7.64 (s, 1H), 4.79 (br s, 2H), 4.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O.[C:42]([O-:45])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:19]4[CH2:27][CH:23]5[CH2:22][CH:21]([CH2:26][CH:25]3[CH2:24]5)[CH2:20]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30][N:12]1[CH2:13][CH2:42][O:45][CH2:10][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC3(CCN(C(=O)NC4C5CC6CC(C5)CC4C6)CC3)c3c(Br)cccc32)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(CCN1CCOCC1)c1cccc(Br)c12
Temperature: 85 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (50 mg, 0.078 mmol) and K2CO3 (21.56 mg, 0.156 mmol) in anhydrous CH3CN (3 mL) was added NaI (3 mg, 0.020 mmol) at 0° C. Then the mixture was stirred overnight at 80-90° C. The mixture was concentrated to give the crude product which was purified by preparative HPLC to afford (±)-7-bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (4 mg, 9%). LC-MS Method 5 tR=1.09 min, m/z=558; 1H NMR: (400 MHz, CDCl3): δ=1.43 (m, 2H), 1.56-1.69 (m. 3H), 1.75-1.85 (m, 9H), 1.94-2.05 (m, 3H), 2.45-2.59 (m, 4H), 2.91 (m, 2H), 3.12 (m, 5H), 3.25 (m, 2H), 3.56 (m, 3H), 3.91-4.16 (m, 6H), 4.20 (m, 2H), 7.12 (m, 2H), 7.40 (m, 1H).