Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:4][CH:3]=1.[CH2:46]=O.[BH4-].[Na+]>CO>[CH3:21][C@@H:17]1[N:18]([CH3:46])[CH2:19][CH2:20][N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([F:1])=[CH:3][CH:4]=[C:5]([CH2:22][NH:23][C:24]([C:26]4[CH:27]=[C:28]([CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][CH2:38]5)[CH:29]=[CH:30][CH:31]=4)=[O:25])[CH:6]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16]1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[3-({[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]amino}carbonyl)phenyl]methyl}-1-piperidinecarboxylate (130 mg, 0.21 mmol) in MeOH (5 mL) was added formaldehyde (37% in water, 69 mg, 0.85 mmol). After 30 minutes stirring at rt, sodium borohydride (16 mg, 0.42 mmol) was added. After stirring at rt for a further 3 hours, the solvent was removed to give a residue which was purified by loading onto a 2 g aminopropyl SPE cartridge and eluting sequentially with DCM (3×5 mL), EtOAc (3×5 mL), and MeOH (3×5 mL). The dichloromethane and ethyl acetate fractions were combined and evaporated to give the title compound (130 mg, 99%). LC/MS: m/z, 629 (M+H), 1.97 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[C:4]([CH2:11][O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:10])=[C:4]([CH2:11][OH:12])[CH:3]=1
Reactant: CC(C)[Si](OCc1cc(F)ccc1B(O)O)(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1cc(F)ccc1B(O)O
Temperature: 23 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of 2.60 g (7.97 mmol) (4-fluoro-2-{[(triisopropylsilyl)oxy]methyl}phenyl)boronic acid which was prepared according to intermediate example 299b in 10 mL dichloromethane were added 6.14 mL trifluoroacetic acid and the mixture was stirred for 16 hours at 23° C. The solvent was removed and the residue crystallized from n-hexane to give 682 mg (50%) of the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1.C(N(CC)C(C)C)(C)C.[C:22]([OH:26])([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+]>O.C(OCC)(=O)C>[C:22]([O:26][C:1](=[O:2])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)(C)O
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
87 mL of ethyl acetate were added to a reaction system and cooled to −15° C. followed by blowing in 14.3 g (144.5 millimoles) of phosgene. A mixed solution containing 10.0 g (57.8 millimoles) of 2-amino-6-bromopyridine, 14.9 g (115.6 millimoles) of N,N-diisopropylethylamine, 8.57 g (115.6 millimoles) of t-butanol and 58 mL of ethyl acetate were dropped into this phosgene solution over the course of 1.8 hours while holding the internal temperature at −15° C. to −5° C. Following completion of dropping, the solution was stirred for 1 hour at the same temperature range. Next, 60 mL of water and 39.6 g of 28% sodium hydroxide were sequentially added while holding the internal temperature at 0° C. or lower. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and concentrated under reduced pressure. The resulting crude crystals were subjected to quantitative analysis by HPLC. The target (6-bromo-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at a yield of 81%. There was hardly any urea compound formed.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:25]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=O)[CH3:26]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][N:1]2[C:31](=[O:32])[C:30]3[C:29](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:28]=[C:25]2[CH3:26])=[CH:11][C:12]=1[F:17]
Reactant: CC(=O)Nc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: Cc1nc2ccccc2c(=O)n1C[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Product: Cl

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-(acetylamino)benzoic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:25]([CH2:33][CH3:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[NH4+].[Cl-:36]>CN(C=O)C>[Cl:36][C:3]1[CH:4]=[C:5]([C@H:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]([C@@H:25]([CH2:33][CH3:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:13]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: O=C1CC[C@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: [Cl-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 13.5 g (42.2 mmol) of (5R,6S)-5,6-bis(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 140 mL of DMF was added 4.22 g (105 mmol) of a dispersion of 60% sodium hydride in mineral oil at 0° C. After being stirred for 20 min, tert-butyl 2-bromobutanoate (28.2 g, 126 mmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 1.5 h until completion of the reaction. Then sat. aq. NH4Cl solution was added and the mixture was extracted with ethylacetate. The combined organic layers were washed with water and sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 50% EtOAc/hexanes, gradient elution) provided tert-butyl (2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate as the faster eluting minor isomer:
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (278 mg) in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN/IPE to give the title compound (195.4 mg) as colorless crystals.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3ccc(Cl)cc3)cc2O)c1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(4-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[C:21]3[C:16](=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[C:21]3[C:16](=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([CH2:26][NH2:27])=[N:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(Nc2cnc(CN)c3c(OC)cc(OC)cc23)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
2-[1-(tert-Butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinolin-4-ylamino]thiazole-4-carboxylic acid ethyl ester (22 mg, 0.045 mmol) in CH2Cl2 (1.0 mL) was added a 4.0 M HCl solution in dioxane (0.67 mL) at room temp. After the reaction mixture was stirred at room temperature for 4.5 h, the suspension was filtered. The yellow solid was dried in vacuo to give 2-(1-aminomethyl-6,8-dimethoxy-isoquinolin-4-ylamino)thiazole-4-carboxylic acid ethyl ester hydrochloride salt (14.0 mg; 73% yield). 1H-NMR (D2O): δ, 8.84 (d, 1H, J=6.3 Hz), 7.70 (s, 1H), 6.92 (s, 1H), 6.77 (s, 1H), 4.66 (s, 2H), 4.20 (q, 2H, J=7.1 Hz), 3.92 (s, 3H), 3.84 (s, 3H), 1.20 (t, 3H, J=7.3 Hz); MS: calculated for C18H21N4O4S (M−Cl) 389.0; found: 389.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
4-Benzyloxy-phenol (500 mg, 2.50 mmol) was dissolved in 7 mL of DMF. K2CO3 (414 mg 3.00 mmol) was added and the resulting mixture was stirred at room temperature for 10 mins. 4-Fluorobenzaldehyde (371 mg, 3.00 mmol) was added and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was then heated to 80° C. for 3 hours. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 710 mg of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 3/97 EtOAc:Hexane as the eluent) afforded 550 mg (72% yield) of 4-(4-Benzyloxy-phenoxy)-benzaldehyde. LC-MS purity: 99.5%
Reaction SMILES: [F:1][CH:2]([F:17])[C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([OH:10])[CH2:6][N:5](C(=O)CCCC)[CH2:4]1.C([Cl:24])(=O)CCCC>>[ClH:24].[F:17][CH:2]([F:1])[C@H:3]1[CH2:4][NH:5][CH2:6][C@@H:7]([OH:10])[C@@H:8]1[OH:9]
Reactant: CCCCC(=O)N1C[C@@H](O)[C@H](O)[C@@H](C(F)F)C1
Reactant: CCCCC(=O)Cl
Product: Cl
Product: O[C@H]1[C@H](O)CNC[C@@H]1C(F)F

Procedure:
1-((3S,4R,5R)-3-(Difluoromethyl)-4,5-dihydroxypiperidine-1-yl)pentane-1-one (8a; Z=CO; R5=butyl). Following General Procedure D, except that the reaction was run at room temperature and using pentanoyl chloride (0.17 g, 1.4 mmol), the title compound was obtained as a white solid (0.26 g, 71%). MH+=252. 1H NMR (DMSO-d6) 5.9-6.5 (dt, 1H), 5.35 (m, 1H, ex), 5.25 (m, 1H), ex), 4.2 (dd, 1H), 3.75 (dd, 1H), 3.35 (m, 2H), 3.1 (m, 1H), 2.85 (m, 1H), 2.3 (t, 2H), 1.9 br m, 1H), 1.4 (m, 2H), 1.25 (m, 2H), 0.85 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].O.[NH2:19][NH2:20]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([NH:19][NH2:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: NN
Reactant: Cc1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(NN)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-methylpyridine (121 mg, 0.363 mmol) in DMSO (1 mL) was added hydrazine hydrate (177 μL, 3.63 mmol) and the mixture was heated at 100° C. for 18 hours. The mixture was then purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound. LRMS (M+1)=329.8.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1.[CH2:36]([N:38]([CH2:41][CH2:42]Cl)[CH2:39][CH3:40])[CH3:37]>CN(C)C=O.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:37][CH2:36][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In one portion 2.1 g (6.4 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.8 g (7.0 mmol) of potassium t-butoxide in 35 ml of dimethyl formamide which was cooled to 0°. After stirring for 15 min 2.5 ml (7.5 mmol) of a 3 M toluene solution of diethylaminoethyl chloride was added. The mixture was warmed to room temperature and stirred for 3 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. Purification of the residue by column chromatography (25 g, silica gel; eluent 4:1 methylene chloride:ether) gave an off-white solid, mp 130°-131°.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[OH-:11].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([OH:2])=[O:11])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: O=C1OCc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1C(=O)O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
Phthalide (134 g, 1 mole) is dissolved in 20% NaOH (715 ml, 3.58 mole) by heating the mixture to about 60° C. The obtained solution is diluted with water (750 ml) and ice (5 kg). Benzoyl chloride (151 ml, 1.3 mole) is added in 10 minutes with vigorous stirring and about 1 hour later the pH of the reaction mixture is brought to 2.5 by the addition of 10% HCl (750 ml). The solid which is collected under vacuum filtration is washed carefully with warm water (4×1500 ml) and crystallized from ethanol/water 7/3 (800 ml), yielding 98.2 g of 2-benzoyloxymethylbenzoic acid. M.p. 118°-124° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8](=[O:11])([O-])[O-].[K+].[K+].[I-].[K+].[C:16](#[N:18])[CH3:17].O.[C:20](#[N:22])C>>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:18]1[CH:16]=[C:17]([CH:8]=[O:11])[N:22]=[CH:20]1)[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CBr
Reactant: CC#N
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cn1cnc(C=O)c1
Yield: 44 %

Procedure:
To a solution of 1H-imidazole-4(5)-carbaldehyde (5.5 g) in acetonitrile (100 ml) were added ethyl bromoacetate (7.65 ml), potassium carbonate (15.8 g) and potassium iodide (11.4 g) with stirring. The mixture was stirred at 50° C. for 3.5 hours, and after cooling, precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified successively by silica gel chromatography using dichloromethane and methanol (10:1) as an eluent and by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/water, 15/85, v/v) to afford ethyl(4-formyl-1H-imidazol-1-yl)acetate (4.60 g, yield: 44%) as the more mobile isomer, and the title compound (1.95 g, yield: 19%) as the less mobile isomer, both as yellow oils respectively. The less mobile, title isomer: 1H NMR (500 MHz, CDCl3) δ ppm: 1.30 (3H, t, J=7.0), 4.26 (2H, q, J=7.0), 5.05 (2H, s), 7.68 (1H, s), 7.84 (1H, s), 9.75 (1H, s).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][C:34]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[N:35]4)=[CH:30][CH:29]=3)[N:19]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Cl>>[C:38]1([C:34]2[CH:33]=[CH:32][C:31]3[C:36](=[CH:37][C:28]([C:20]4[N:19]=[C:18]([CH2:17][CH:14]5[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]5)[N:22]5[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=45)=[CH:29][CH:30]=3)[N:35]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1nccn2c(CC3CCN(C(=O)OCc4ccccc4)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: Cl
Product: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylic acid benzyl ester (1.94 g, 3.41 mmol) was mixed with 37% HCl (90.00 mL, 3.96 mol), heated to 60° C. and continued to stir for 5 mins. It was then cooled to rt, washed with ether (2×90 mL) and then with CH2Cl2 (2×90 mL). The aqueous layer was gradually basified with 5N NaOH and extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified by a 25 g Jones silica gel (eluted with 10% (7N NH3) in MeOH/EtOAc), affording the desired product; 1H NMR (400 MHz, METHANOL-d) δ 8.38 (1 H, d, J=8.68), 8.24 (1 H, d, J=0.74 Hz), 8.08 (2 H, dd, J=1.55 Hz, J=1.19), 8.00 (2 H, m), 7.80 (1 H, dd, J=1.68, J=1.70), 7.51 (1 H, d, J=5.14), 7.44 (3 H, m), 6.99 (1 H, d, J=5.10), 2.99 (2 H, d, J=12.60), 2.94 (2 H, d, J=7.20), 2.55 (2 H, t), 2.01 (1 H, m), 1.66 (2H, d, J=12.72), 1.29 (2 H, m); MS (ES+): m/z 435.12/436.10 (15/5) [MH+]; HPLC: tR=1.71 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Li+].[CH3:14][CH:15]([CH3:19])[CH:16]=[CH:17]Br.CN(C)C=[O:23]>>[CH3:14][C:15]([CH3:19])=[CH:16][CH2:17][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:23])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: CC(C)C=CBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li+]
Product: CC(C)=CCn1c2c(ccc1=O)C(=O)CCC2
Yield: 74 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-(2(1H)-quinolinone (10.0 g), lithium hydride (0.79), an dimethylformamide (400 ml) was stirred for 3 hrs at 25° C., under nitrogen. 3-Methylbutenyl bromide (10.6 ) was added and the mixture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether to afford 10.5 g (74%) of 5,6,7,8-tetrahydro-1-(3-methyl-2-butenyl)-5-oxo-2(1H)-quinolinone.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O.[C:58](OC(=O)C)(=[O:60])[CH3:59].N1C=CC=CC=1>C1COCC1>[C:58]([NH:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1)(=[O:60])[CH3:59]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to a solution of 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one (5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h at room temperature. Water (1.41 mL, 78.3 mmol) was added, and the mixture heated at 40° C. overnight. Solvent was removed under vacuum, and the oily residue dissolved in dichloromethane (50 mL). Acetic anhydride (4.62 ml, 49.0 mmol) and pyridine (7.92 ml, 97.9 mmol) were added, and the mixture stirred for 8 h at r.t. Solvent was removed under vacuum and the crude product purified by silica gel flash column chromatography (eluent: 30% ethyl acetate in hexanes) to give the product as a foam (4.98 g, 97%); MS (m/z): [M+H]+=527.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.Cl[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=3)[CH:8]=2)[S:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)S2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)S3)nc1
Temperature: 55 °C
Reaction time: 60 h

Procedure:
A solution of 232 mg (1.01 mmol) of 2,2,4,4-tetramethyl-6-ethynylthiochroman (Compound 35) and 190 mg (1.03 mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml of triethylamine was placed in a heavy-walled glass tube, degassed, placed under argon and then treated with a powdered mixture of 53 mg (0.28 mmol) of cuprous iodide and 84 mg (0.12 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was degassed again, placed under argon and the tube was sealed. The reaction mixture was heated at 55 degrees C. for 60 h and then cooled to room temperature. The mixture was treated with water and ether and the organic layer was separated. The aqueous layer was extracted with ether, the organic layers were then combined and washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the resultant residue was purified by flash chromatograhy (silica; 10% ethyl acetate in hexanes) to give the title compound as a dark yellow oil. PMR (CDCl3): & 1.32-1.43 (15H, m), 1.92 (2H, s), 4.38 (2H, q, J-7.1 Hz), 7.28 (1H, dd, J-8.3 Hz, 1.8 Hz), 7.32-7.38 (2H, m), 7.53 (1H, d, J-8.3 Hz), 8.24 (1H, dd, J-8.2 Hz, 2.2 Hz), 9.16 (1H, d, J-2.2 Hz). MS exact mass, m/e 379.1594 (calcd. for C23H25NO2S, 379.1606).