Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15](C2C=NC=CC=2)=[N:14]1.[CH3:30][Si:31](C)([CH3:42])[C:32]1C=C(C(OCC)=O)NN=1.BrCC(C1C=C(OC)C=CC=1OC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([Si:31]([CH3:42])([CH3:32])[CH3:30])=[N:14]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Agent: COc1ccc(OC)c(C(=O)CBr)c1
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1CC(=O)c1cc(OC)ccc1OC

Procedure:
This compound was prepared in a similar method to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(2,5-dimethoxyphenyl)ethanone (Purchased from Aldrich). 1H-NMR δ 7.40 (d, 1H), 7.12 (dd, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 5.72 (s, 2H), 4.40 (q, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 1.39 (t, 3H), 0.28 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C([O-])=O)[CH:18]([CH2:19][O:20][CH3:21])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:22][O:23][CH2:24][CH3:25])[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOCc1cccc2[nH]c3c(c12)C(COC)C(C(=O)[O-])(C(=O)OCC)NC3
Solvent: Cc1ccccc1C
Product: CCOCc1cccc2[nH]c3cnc(C(=O)OCC)c(COC)c3c12
Reaction time: 0.08 h
Yield: 7.7 %

Procedure:
1,2,3,4-Tetrahydro-3-ethoxycarbonyl-5-ethoxymethyl-4-methoxymethyl-β-carboline-3-carboxylate (6.8 g) in xylene (1.1 l) is boiled under reflux for 1 hour. The xylene is evaporated in vacuo and the residue is dissolved in methylene chloride (600 ml). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (4.5 g) is added in one portion to the ice-cooled solution. After 5 minutes stirring the solution is washed with 1.2 vol. % of aqueous ammonia, and the methylene chloride is removed by destillation in vacuo. The residue, after two chromatographies on silicagel, first with a mixture of methylene chloride and acetone (1:1), and then with a mixture of methylene chloride and methanol (95:5) yields 0.46 g of pure 5-ethoxymethyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethylester. M.p. 94°97° C.
Reaction SMILES: [C:1]([CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)([OH:3])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)([OH:3])=[O:2]
Reactant: Cc1c(-n2ccnc2)n(CCCCCC=CC(=O)O)c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-n2ccnc2)n(CCCCCCCC(=O)O)c2ccccc12

Procedure:
1-(7-Carboxyhept-6-enyl)-2-(1-imidazolyl)-3-methylindole (20 mg) is dissolved in 1 ml of absolute ethanol with a catalytic amount of 10% palladium on charcoal and hydrogenated at 1 atmosphere pressure. After one mole of hydrogen is consumed the catalyst is removed by filtration and washed with a few milliliters of ethanol. The combined filtrates are concentrated to yield the 1-(7-carboxyheptyl)-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:9]([CH2:12][CH2:13][CH3:14])[CH:10]=[CH2:11].CC1C=CC=CC=1[O-].[Li+].[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:28][O:27][C:26]1[CH:14]=[CH:13][C:12]([CH:9]([O:8][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]=[CH2:11])=[CH:24][CH:25]=1
Reactant: C=CC(CCC)Oc1ccccc1C
Reactant: C1CCOC1
Agent: Cc1ccccc1[O-]
Agent: [Li+]
Product: C=CC(Oc1ccccc1)c1ccc(OC)cc1
Reaction time: 20 h

Procedure:
(−)-1-Methyl-2-(1-propylallyloxy)benzene (Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012): The general procedure was followed with lithium 2-methylphenoxide (228 mg, 2.0 mmol) and 2-hexenyl methylcarbonate (160 mg, 1.0 mmol) in THF (2 mL). The reaction was conducted at 50° C. for 20 h. 1H NMR analysis of the mixture indicated the ratio of regioisomers to be 87/13. The residue was purified by flash chromatography on silica gel (0-1% Et2O/Hexanes) to afford 165 mg of the title compound as an oil. [86%, Rf 0.92 (5% Et2O/Hexanes)].[α]D20=−3.0 (c 0.3, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.16 (m, 2H), 6.88 (m, 2H), 5.92 (ddd, J=17.4, 10.5, 6.1 Hz, 1H), 5.28 (dt, J=17.4, 1.2 Hz, 1H), 5.22 (dt, J=10.5, 1.0 Hz, 1H), 4.67 (dt, J=6.4, 6.1 Hz, 1H), 2.31 (s, 3H), 1.89-1.83 (m, 1H), 1.76-1.69 (m, 1H), 1.60-1.47 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); 13C NMR (125.77 MHz, CDCl3) δ 156.5 (C), 138.5 (CH), 130.6 (CH), 127.4 (C), 126.4 (CH), 120.2 (CH), 115.9 (CH2), 113.1 (CH), 78.6 (CH), 37.9 (CH2), 18.5 (CH2), 16.4 (CH3), 14.0 (CH3). HPLC analysis indicated an enantiomeric excess of 90% [Chiralcel® OD-H column, eluting with 99.9:0.1 hexane/i-PrOH, 0.6 mL/min, 220 nm; major enantiomer tR, 12.2, minor enantiomer tR 13.7 min].
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5([C:30]6[O:31][C:32]7[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=7[N:34]=6)[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:39])=[C:11]3[C:10]([N:40]3[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42][CH2:41]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[O:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[C:27]1([C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:8][N:9]=[C:10]([N:40]5[CH2:41][CH2:42][CH:43]([N:46]([CH3:47])[CH3:48])[CH2:44][CH2:45]5)[C:11]=34)=[C:19]([F:39])[CH:20]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)C5(c6nc7ccccc7o6)CC5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)C5(c6nc7ccccc7o6)CC5)cc4F)c23)CC1
Temperature: 50 °C
Yield: 48.6 %

Procedure:
To a flask containing N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(benzo[d]oxazol-2-yl)cyclopropanecarboxamide (6.6 mg, 0.01 mmol) at room temperature under a drying tube was added TFA (2 mL). The reaction was warmed to 50° C. overnight. The reaction was cooled to room temperature and was concentrated. The residue was dissolved in 10 mL dichloromethane and stirred rapidly with 10 mL 10% sodium carbonate solution. The layers were separated and the organics dried (MgSO4). The crude product was concentrated and the crude material was loaded onto a Biotage 12S column with dichloromethane. The column was eluted with a step gradient of dichloromethane (150 mL) and 94.5/5/0.5 dichloromethane/MeOH, concentrated ammonium hydroxide to provide the desires product as a yellow glass (2.7 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ 12.17 (br s, 1H), 9.92 (br s, 1H), 8.24 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.48 (m, 2H), 7.38 (m, 2H), 7.30 (m, 1H), 6.21 (d, 1H), 4.11 (m, 2H), 2.91 (m, 2H), 2.40 (m, 1H), 2.34 (s, 6H), 2.08 (m, 2H), 1.96 (br m, 2H), 1.90 (m, 2H), 1.74 (br m, 2H). LCMS (APCI+): m/z 556 (M+1) detected.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[O:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[C:12]2[O:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=1
Reactant: CCOC(=O)COc1ccc(OC)c2occc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(O)c2occc12
Reaction time: 3 h

Procedure:
A solution of boron tribromide (5.50 g, 22 mmol) in dichloromethane (20 mL) was added dropwise to a solution of the above ester (2.77 g, 11.1 mmol) in dichloromethane (30 mL) at −40° C. and the mixture was stirred for 3 h without cooling while the temperature reached 0° C. Water (3 mL) was added to the mixture the organic layer was evaporated in vacuo. The obtained residue was purified by column chromatography (silica gel Fluka 60, chloroform) affording ethyl (7-hydroxybenzo[b]furan-4-yloxy)acetate.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11](Cl)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>>[NH:19]([C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)[NH2:20]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: NN
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1NN
Yield: 99 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate (1.5 g, 6 mmol) and POCl3 (9.4 g, 62 mmol) to afford 81% of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate (12 g, 46 mmol) with citraconic anhydride (10 g, 92 mmol) to afford 75% (12 g) of the title compound (m.p. 155-156° C.) in analogy to Example 21.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:3]=1[C:4]#[N:5].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:3]=1[C:4]1[NH:21][N:20]=[N:19][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCc1ccc(O)c(C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCc1ccc(O)c(-c2nnn[nH]2)c1
Reaction time: 4 h

Procedure:
A mixture of 13.5 parts of 2-hydroxy-5-nonyl benzonitrile, 3.6 parts of sodium azide and 2.95 parts of ammonium chloride, 50 parts of dimethyl formamide and 0.5 parts of water was stirred and boiled for four hours. After cooling the mixture was diluted with water and extracted into chloroform. The chloroform solution was washed with water and with 2 × 200 mls of a 2N solution of sodium hydroxide to extract the product. The aqueous alkaline solution was neutralised with 2N sulphuric acid and re-extracted with chloroform. The extract was washed with water, dried, and evaporated to give 7.1 parts of 5-(2-hydroxy-5-nonylphenyl)tetrazole.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1.C(N(CC)CC)C.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>ClCCl.CN(C1C=CN=CC=1)C.O>[Si:30]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100 g, 0.38 mol) in dry dichloromethane (1.51) at 25° C. was added DMAP (47 g, 0.38 mol), followed by triethylamine (39 g, 0.38 mol). To the above reaction mixture was added TBDMSCl (64 g, 0.42 mol) dissolved in dry dichloromethane (200 ml) drop-wise over a period of 45 min. After stirring at RT for 20 h, the reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with 5% aq. citric acid, brine and dried over Na2SO4. The solvent was removed under vacuum to give 1-tert-butyl 2-ethyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (140 g) as a colorless liquid. Yield: 97%
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.O.NN>C(O)C>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: COc1ccnc2c1CCCC2N(CCCCN1C(=O)c2ccccc2C1=O)Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccnc2c1CCCC2N(CCCCN)Cc1nc2ccccc2[nH]1
Yield: 67.1 %

Procedure:
To a solution of 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(4-methoxy-5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.133 g, 0.22 mmol) in ethanol (4 mL) was added hydrazine monohydrate (0.20 mL, 4.12 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) provided 56 mg (68%) of the free base of the title compound as a yellow oil.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[C:9]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:8]=2[N:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[N:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[C:9]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:8]=2[N:7]=1
Reactant: CCCC1CC(=O)N(Cn2c(Cl)nc3ccc(OC)cc32)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CC(=O)N(Cn2c(Cl)nc3ccc(O)cc32)C1
Reaction time: 48 h
Yield: 35.6 %

Procedure:
Under argon, BBr3 (1 M in CH2Cl2) (1.86 ml, 1.8645 mmol, 2 eq) is added drop wise to a solution of 1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 305 (0.3 g, 0.9322 mmol, 1 eq) in dry CH2Cl2 (20 ml). After 48 hours at room temperature, saturated aqueous solution of NaHCO3 (20 ml) is added. The aqueous layer is extracted with CH2Cl2 (3×20 ml) then the combined organic layers are dried on anhydrous MgSO4, filtered off and evaporated under reduced pressure. The remaining pale yellow solid is recrystallized in MeCN/H2O (9/1) to yield 102 mg of 1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 320 as a white solid.
Reaction SMILES: C(O[C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)C1C=CC=CC=1.C([Li])CCC.[C:24]([O:29][CH2:30][C@@H:31]1[O:33]C1)(=[O:28])CCC>C1COCC1>[F:17][C:13]1[CH:12]=[C:11]([N:10]2[CH2:9][CH:30]([CH2:31][OH:33])[O:29][C:24]2=[O:28])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OC(CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of amine 102 (39.2 g, 160.0 mmol) in anhydrous THF (300 mL) was cooled to −78° C. in a dry-ice/acetone bath before a solution of n-butyl lithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv) was dropwise added under N2. The resulting reaction mixture was subsequently stirred at −78° C. for 1 h before a solution of (R)-(−)-glycidyl butyrate (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF (100 mL) was dropwise added into the reaction mixture at −78° C. under N2. The resulting reaction mixture was stirred at −78° C. for 30 min before being gradually warmed to room temperature for 12 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (200 mL), and the resulting mixture was stirred at room temperature for 1 h before EtOAc (200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. White crystals precipitated from the concentrated solution when most of the solvent was evaporated. The residue was then treated with 20% EtOAc/hexane (100 mL) and the resulting slurry was stirred at room temperature for 30 min. The solids were collected by filtration and washed with 20% EtOAc/hexane (2×50 mL) to afford the desired (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one 103 (24.4 g, 72.3% yield) as white crystals. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.34-3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 1H, J=12.0 Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H), 7.32-7.56 (m, 3H). C10H10FNO3, LCMS (EI) m/e 212 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:27][C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:39]4[CH:38]=[CH:37][C:36]([CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[CH:41][CH:40]=4)=[CH:30][CH:29]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
4-{2-(4-Bromo-benzyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester (2.7 g, 5 mmol) was coupled with 4-cyclohexyl-phenylboronic acid (1.25 g, 6.0 mmol) according to general procedure G to give 4-{2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[CH:9]2)([O-])=O>[Pd].C(O)C>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=2)[N:12]=1
Reactant: Cc1ccc2cccc([N+](=O)[O-])c2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cccc(N)c2n1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a Pressure reaction bottle was added 5.0 g of 8-nitroquinaldine, 0.5 g 5% palladium on carbon, and 150 ml ethanol. The mixture was purged with hydrogen and then hydrogenated under 40 psi hydrogen for 16 hours. The catalyst was filtered off on a bed of celite. The solvent was removed, resulting in 4.2 g of a dark oil.
Reaction SMILES: Cl[C:2]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[N:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)=[CH:14][C:6]1=2.[C:33]([Cu])#[N:34]>CN(C=O)C>[F:32][C:27]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][C:7]3[N:11]=[CH:12][C:13]([C:15]4[CH:16]=[N:17][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:19][CH:20]=4)=[CH:14][C:6]2=3)=[C:2]([C:30]([F:31])=[CH:29][CH:28]=1)[C:33]#[N:34]
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)c1Cl
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc(F)c1CN1CCNc2ncc(-c3ccc(N4CCOCC4)nc3)cc21
Temperature: 150 °C
Yield: 37 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous DMF. CuCN (5.0 eq) was added and the resulting mixture was heated to 150° C. in a microwave for 30 minutes. The reaction mixture was concentrated, taken up in CH2Cl2, washed three (3) times with an aqueous solution of NH4OH (10%), and the organic phase was dried, filtered, and concentrated. The residue was purified via silica gel chromatography (0-100% ethyl acetate in hexanes followed by 5% methanol in ethyl acetate) to give the title compound (37% yield). M.p 188-190° C., LCMS: m/z=449.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.24-3.31 (m, 2H), 3.48-3.56 (m, 6H), 3.80-3.88 (m, 4H), 4.51 (s, 2H), 4.86 (bs, 1H), 6.65-6.73 (m, 1H), 6.98-7.06 (m, 2H), 7.09-7.19 (m, 2H), 7.59-7.64 (m, 2H), 8.36 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(COC(C)=O)cc(-n2cccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (4.0 g) in pyridine (40 ml) was added acetic anhydride (4.9 ml) under ice cooling. After being stirred for 3 hours under ice cooling, the reaction mixture was poured into ice-water and the product was extracted with diethyl ether. The diethyl ether extracts were washed with water, 1N-hydrochloric acid and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-acetoxymethyl-5-(pyrrol-1-yl)benzoate (4.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C1CCNC1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CC1(C)CN(CC(=O)N2CCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 82 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and pyrrolidine in 82% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](NC)=[O:16])(=[O:13])=[O:12]>ClC1C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Yield: 105.5 %

Procedure:
5.9 g of N-[2-(3,3,3-trifluoro-1propen-1-yl)phenylsulfonyl]-N'-methylurea are suspended in 100 ml of chlorobenzene. The solution is dried by refluxing it in a water separator. Then 6 g of phosgene are introduced into the reaction mixture over 20 minutes at 120°-130° C. The solvent is removed by evaporation, affording 5.6 g of 2-(3,3,3-trifluoro-1propen-1-yl)phenylsulfonyl isocyanate as a yellowish oil.