Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH:32]([CH3:34])[CH3:33])=[C:29]([SH:31])[CH:30]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:29]1[CH:30]=[C:25]([CH3:24])[CH:26]=[CH:27][C:28]=1[CH:32]([CH3:34])[CH3:33]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1ccc(C(C)C)c(S)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ 1.16 (m, 6 H), 1.87 (s, 3 H), 2.26 (m, 3 H), 2.57 (m, 1 H), 3.23 (m, 1 H), 3.43 (q, 2 H), 6.01 (bs, 1 H), 6.78 (d, 1 H), 7.03-7.27 (m, 6 H), 7.37-7.47 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]#[CH:36].O>CN(C=O)C>[CH2:36]([CH:14]([C:12](/[CH:11]=[CH:10]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=1)=[O:13])[C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:27]=[C:24]([C:22]([OH:23])=[CH:21][CH:20]=1)[O:25][CH3:26])[C:35]#[CH:34]
Reactant: C#CCBr
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C(=O)/C=C/c1ccc(O)c(OC)c1)C(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 49 h
Yield: 47 %

Procedure:
Curcumin (5 g, 13.57 mmol) and K2CO3 (1.88 g, 13.62 mmol) were dissolved in 60 mL DMF, and 1.62 g (13.61 mmol) of propargyl bromide was added. The mixture was stirred at room temperature under Ar for 49 h. H2O was added to the mixture and solvent was removed under vacuum. The product was purified on column chromatography, eluting with CH2Cl2: hexane 50:50—CH2Cl2. Yield 47%. NMR 1H (CDCl3), δ (ppm): 2.54 (s, 1H); 3.94 (d, 6H); 4.81 (d, 2H); 5.82 (s, 1H); 5.93 (s, 1H); 6.47-6.52 (t, 2H); 6.93-7.15 (m, 6H); 7.59-7.61 (dd, 2H). MS (ESI) calcd. for C24H22O6: 406.43. found: 407.2 [M+H]+, 445.2 [M++K].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]([O:15][C:16](=[O:24])[NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(O)CCC>[C:11]([O:15][C:16](=[O:24])[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:20][CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]cnc23)CC1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
To a mixture of 6-chloropurine (0.050 g, 0.323 mmol) and piperidin-4-yl carbamic acid tert-butyl ester (0.129 g, 0.646 mmol) in n-butanol (3.2 ml) was added triethylamine (0.225 ml, 1.617 mmol). After heating at 100° C. for 20 hours, solvent was removed and the resulting solid triturated with a DCM/methanol mix (3 ml/5 ml). Filtration gave the desired product as a white solid (0.080 g, 78%). LC/MS: (LCT) Rt 5.37 [M+H]+ 319.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38].Cl>CC#N.CCOC(C)=O>[CH:1]1([CH:7]2[CH2:12][N:11]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNCC1C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccccc2F)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a solution of 3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (15.0 mg, 0.036 mmol, 1.0 equiv) in MeCN (0.2 mL) at room temperature, was added NaOH (0.40 mL, 1.5 N solution, 0.60 mmol, 16.7 equiv) and 2-fluoro-benzenesulfonyl chloride (11.4 mg, 0.059 mmol, 1.64 equiv). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 3 N HCl (0.3 mL), and then diluted with EtOAc (10 mL). The mixture was washed with water (5 mL), brine (5 mL), then dried (over Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (0.1% NH4OH) to give product (5.0 mg, 24%) as white solid. MS: 543 [M−H+]. 1H-NMR (400 MHZ, CDCl3): δ 1.12 (m, 3H), 1.34 (m, 1H), 1.45-1.90 (m, 7H), 2.70-2.87 (m, 2H), 3.34 (d, 1H), 3.60-3.70 (m, 2H), 3.95 (d, 1H), 4.18 (d, 1H), 7.13 (s, 1H), 7.21 (t, 1H), 7.27 (t, 1H), 7.30-7.40 (m, 3H), 7.51-7.61 (m, 3H), 7.83 (t, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[C@:34]([OH:38])([C:36]#[CH:37])[CH3:35].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:37]#[C:36][C@@:34]([OH:38])([C:29]6[N:30]=[CH:31][CH:32]=[CH:33][N:28]=6)[CH3:35])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1ncccn1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[C@@](O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1)c1ncccn1
Yield: 40 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-10-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (2R)-2-pyrimidin-2-ylbut-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 47 mg of the titled compound (40% yield). M+1=501.2. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=4.8 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.35 (br s, 1H), 7.74 (br s, 1H), 7.50 (t, J=4.8 Hz, 1H), 7.03 (d, J=10.5 Hz, 1H), 6.21 (s, 1H), 5.04-4.80 (m, 2H), 4.63-4.54 (m, 2H), 2.13-2.04 (m, 1H), 1.89 (s, 3H), 1.03-0.95 (m, 2H), 0.93-0.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)=[C:4]([O:32]C)[CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([C:26]([F:27])([F:29])[F:28])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)=[C:4]([OH:32])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Product: CC(C)(CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F)c1ccc(Cl)cc1O

Procedure:
Analogously to Example 38, 110 mg (0.23 mmol) of 4-(4-chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is reacted with 4.60 ml (4.60 mmol) of a 1 M boron tribromide solution. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%) as well as with ethyl acetate-methanol (0–20%), 54 mg (50% of theory) of the product is obtained.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C.O>[OH:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@H](Cc1cccnc1)NC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@@H](CO)Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
A solution, under an inert atmosphere, of 20.77 g of ethyl (2R)-2-(acetylamino)-3-(3-pyridyl)propanoate in 208 cm3 of anhydrous ethanol is cooled to a temperature in the region of 10° C., followed by portionwise addition of 8.31 g of sodium borohydride. The reaction mixture is stirred for 16 hours at room temperature. The ethanol is evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., to give 43.56 g of a pale yellow paste which is taken up and stirred in 50 cm3 of water. The solution, which has a pH in the region of 12, is cooled to a temperature in the region of 0° C. and then neutralized by dropwise addition of concentrated hydrochloric acid. The resulting mixture is stirred for 1 hour at this temperature and the white precipitate formed is then filtered off on a sinter funnel, then dried in an oven under vacuum (0.1 kPa) at a temperature in the region of 55° C. 11.15 g of N-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]acetamide are obtained in the form of a white solid melting at a temperature above 260° C. The filtrate is extracted with 3 times 100 cm3 of ethyl acetate and the organic phases are then combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 2.4 g of N-[(1R)-2-hydroxyl-1-(3-pyridylmethyl)ethyl]acetamide partially complexed with boron are obtained in the form of a white paste. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.75 (s: 3H); 2.61 (dd, J=14 and 9 Hz: 1H); 2.88 (dd, J=14 and 5.5 Hz: 1H); from 3.20 to 3.45 (mt: 2H); 3.91 (mt: 1H); 4.82 (broad t, J=5 Hz: 1H); 7.30 (dd, J=7.5 and 5 Hz: 1H); 7.62 (dt, J=7.5 and 2 Hz: 1H); 7.72 (d, J=9 Hz: 1H); from 8.35 to 8.45 (mt: 2H)].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]([NH:18][NH2:19])=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[C:22](=S)=[S:23].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[O:17][C:22]([SH:23])=[N:19][N:18]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
The compound from Example 156 (100 mg, 0.31 mmol) was suspended in ethanol (2 ml) and cooled to 0° C. Carbon disulfide (0.04 ml, 0.71 mmol) was added follow by potassium hydroxide (20 mg, 0.31 mmol). The reaction was stirred 1 hr and the cold bath removed. After 1 hr at ambient temperature, the reaction was refluxed for 3 hours then concentrated to a solid. The crude solid was triturated with chloroform (1×5 ml) and concentrated. The residue was dissolved in water (15 ml) and acidified with formic acid. The resulting precipitate was isolated by filtration, washed with water (2×15 ml), and dried in a desiccator to yield the title compound (106 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([OH:17])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[C:24]([O-])([O-])=O.[K+].[K+].IC>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:17][CH3:24])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 99 %

Procedure:
At ambient temperature, to a stirred mixture containing 2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.232 g, 4.049 mmol) and K2CO3 (0.6155 g, 4.454 mmol) in N,N-DMF (10.1 mL) was added iodomethane (0.353 mL, 5.67 mmol). After 18 h, the reaction was diluted with H2O (100 mL) and the reaction was stirred vigorously. The resulting precipitate was collected, dissolved in CH2Cl2, dried (K2CO3) and concentrated to give 1.167 g, (99%) of the title compound. 1H NMR (DMSO-d6) δ 3.16 (s, 3H), 3.87 (s, 3H), 7.41-7.53 (m, 6H), 7.58-7.60 (m, 4H), 7.89 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:13][O:12][CH:11]([CH2:14][NH:15][CH2:16][CH2:17][CH3:18])[O:10][C:9]=2[CH:19]=1)(=[O:4])=[O:3].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:20]([N:15]([CH2:14][CH:11]1[O:10][C:9]2[CH:19]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[CH2:13][O:12]1)[CH2:16][CH2:17][CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 76.1 %

Procedure:
N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}propan-1-amine (1.2 g, 4.2 mmol), benzylbromide (0.53 ml, 4.4 mmol), potassium carbonate (0.70 g, 5.0 mmol) and ACN (50 ml) were heated at 60° C. for 2.5 h. EtOAc (100 ml) was added and the mixture was filtered and evaporated to dryness. Purification by flash chromatography (isooctane/EtOAc 1:1) and evaporation of pure fractions afforded the title compound (1.2 g). 1H-NMR (400 MHz, MeOH): δ 7.48 (1H, dd, J1 8.0 Hz, J2 2.0 Hz), δ 7.38-7.21 (7H, m), δ 5.18 (1H, t, J 5.6 Hz), δ 4.97 (2H, dd, J1 41.6 Hz, J2 15.6 Hz), δ 3.77 (2H, q, J 13.6 Hz), δ 3.10 (3H, s), δ 2.94-2.84 (2H, m), δ 2.58 (2H, dt, J1 7.2 Hz, J2 1.6 Hz), δ 1.56 (2H, m), δ 0.90 (2H, t, J 7.2 Hz).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([OH:25])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#CC(C)(C)O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To a precooled −78° C. solution of 2-methylbut-3-yn-2-ol (4.71 g, 0.05 mol) in THF (250 mL), n-BuLi (51.2 mL, 0.08 mol) was added under an inert atmosphere, and the mixture stirred for 30 min. Then, 4-(benzyloxy)benzaldehyde (8.0 g, 0.037 mol) in THF was added and the mixture was stirred for an additional 3 h at RT, quenched with a saturated NH4Cl solution and concentrated in vacuo. The residue was acidified with HCl (1 N) and extracted with DCM (3×200 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-(4-(benzyloxy)phenyl)-4-methylpent-2-yne-1,4-diol (6 g, 54%) as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[P:6]([O:13]CC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].BrCC>>[Br:1][CH2:2][CH2:3][CH2:4][P:6]([O:10][CH2:11][CH3:12])(=[O:13])[O:7][CH2:8][CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: BrCCCBr
Solvent: CCBr
Product: CCOP(=O)(CCCBr)OCC
Temperature: 130 °C

Procedure:
A mixture of 605 g (3.0 mol) of 1,3-dibromopropane and 250 g (1.5 mol) of triethyl phosphite was heated at an oil bath temperature of 130° C., while stirring and passing in nitrogen, for approximately 5 hours until approximately 154 g (1.5 mol) of bromoethane distilled over into a strongly ice-cooled receiver. The reaction mixture was distilled first in a bulb tube and then fractionally.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:36][C:37]#[N:38]>C1COCC1>[C:37]([CH2:36][N:10]1[C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:29]([CH3:32])(=[O:31])=[O:30])[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:11]1=[O:28])#[N:38]
Reactant: N#CCBr
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC#N)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 68.1 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (115 mg, 250 μmol) was initially charged in THF (1 ml) at 0° C., sodium hydride (14 mg, 350 μmol; 1.4 eq.) was added and the mixture was stirred for 20 min. After addition of bromoacetonitrile (50 mg, 376 μmol; 1.5 eq.), the mixture was stirred at RT for 120 min. The reaction mixture was then purified directly by preparative HPLC (column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). This gave the title compound as a colorless solid (85 mg, 68% of theory).
Reaction SMILES: [C:1]1([Li])C=CC=CC=1.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=O)[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[CH2:1])[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=C(CCCCC(C)(C)C(=O)OCC)CCCCC(C)(C)C(=O)OCC
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
Under nitrogen atmosphere, a solution of phenyllithium (in diethyl ether: cyclohexane=30:70, 7.06 mL, 1.8 M, 12.7 mmol) was added dropwise over 10 min to a solution of methyltriphenylphosphonium iodide (5.52 g, 13.3 mmol) in anhydrous THF (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, before 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (4.5 g, 12.2 mmol) was added and the reaction mixture was stirred for 5 h at 50° C. The resulting light-orange mixture was quenched by adding methanol (0.3 mL), and most of the solvent was removed on a rotary evaporator. The residue was purified by chromatography on silica (hexanes:ethyl acetate=95:5) to furnish the product (2.1 g, 47%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.67 (s, 2H), 4.10 (q, 4H, J=7.3 Hz), 1.97 (t, 4H, J=7.6 Hz), 1.6-1.3 (m, 8H), 1.30-1.15 (m, 10H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 149.6, 108.6, 60.1, 42.1, 40.6, 35.8, 28.2, 25.1, 24.7, 14.2. HRMS (LSIMS, nba): Calcd. for C22H41O4 (MH+): 369.3004. found 369.3009.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[O:24])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 46.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-methylpiperazine (54 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 5a (80 mg, yield 49%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[Pd]>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cn1c(C)nc2c(OCc3ccccc3)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)nc2c(O)cccc21
Yield: 93.2 %

Procedure:
To a solution of ethyl [4-(benzyloxy)-2-methyl-1H-benzimidazol-1-yl]acetate (2.57 g) in a mixture of EtOH (25.7 mL) and THF (12.9 mL) was added 10% palladium on carbon (50% wet, 0.78 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 2 hours. The catalyst was removed by filtration and evaporated in vacuo to give crude solid. The crude solid was recrystallized from solvent (EtOAc:n-hexane) to give ethyl (4-hydroxy-2-methyl-1H-benzimidazol-1-yl)acetate (1.73 g) as a white solid.