Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:27])[N:10]2[CH2:28][CH2:29][CH2:30][CH:9]2[CH:8]1[O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)=[O:6])[CH:2]=[CH2:3].CCN=C=NCCCN(C)C.Cl.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]([O:59]C)=[O:58])[N:54]([CH3:56])[CH:55]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([NH:50][C:51]3[CH:52]=[C:53]([C:57]([OH:59])=[O:58])[N:54]([CH3:56])[CH:55]=3)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:27])[N:10]2[CH2:28][CH2:29][CH2:30][C@H:9]2[C@@H:8]1[O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)O)c(OC)cc2C(=O)N2CCCC2C1OC1CCCCO1
Reactant: COC(=O)c1cc(N)cn1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1c2cc(OCCCC(=O)Nc3cc(C(=O)O)n(C)c3)c(OC)cc2C(=O)N2CCC[C@H]2[C@@H]1OC1CCCCO1
Reaction time: 6 h

Procedure:
A solution of Alloc-THP protected PBD acid 13 (1.85 g, 3.57 mmol, 1.2 equivalent) was dissolved in DMF. EDCl (1.24 g, 6.48 mmol, 2.0 eq) and DMAP (0.99 g, 8.1 mmol, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.5 g, 3.243 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hours at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (200 mL), saturated aqueous NaHCO3 (250 mL), water (250 mL), brine (250 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product (1.88 gm) was used for hydrolysis reaction to afford 14a. For hydrolysis, Lithium hydroxide (0.24 g, 5.71 mmol, 3 eq) was added to the crude product (1.88 g, 2.87 mmol) in aqueous dioxane (75 ml dioxane, 11.5 ml water) at room temperature. The reaction mixture was stirred for 3 hours at which point TLC showed completion of reaction. Dioxane was evaporated under high vacuum and the residue was diluted with water. The resulting solution was acidified with 1 M citric acid followed by extraction with ethyl acetate (2×100 mL). The organic layer combined and washed with brine (100 mL), dried over MgSO4 and finally concentrated using a rotary evaporator under reduced pressure to obtain 14a as a white solid (yield, 1.68 gm, 74.0% over 2 steps). 1H-NMR δ 9.09 (1H, s, NH), 7.39 (1H, d, J=2.0 Hz), 7.14 (1H, s, H-6), 7.12 (1H, s, H-6), 6.96 (1H, s, H-9), 6.76 (1H, d, J=2.0 Hz, Py-H), 5.86-5.75 (2H, m, H-11), 5.13-4.84 (3H, m), 4.61-4.21 (2H, m), 4.06-3.88 (3H, m, side-chain H-1, pyran H-6), 3.87 (3H, s, O/NCH3), 3.87 (3H, s, O/NCH3), 3.86 (3H, s), 3.53-3.44 (3H, m), 2.55-2.45 (2H, m), 2.13-1.88 (6H, m), 1.70-1.39 (6H). m/z (+EI) calc. for C32H40N4O10 (M)+ 640.68. found 641.57 ([M+H]+.
Reaction SMILES: Cl[C:2]1[C:6]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[N:5][S:4][N:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][OH:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][O:25][C:2]1[C:6]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[N:5][S:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nsnc1-n1ccnc1
Reactant: OCC1CCCN1Cc1ccccc1
Product: c1ccc(CN2CCCC2COc2nsnc2-n2ccnc2)cc1

Procedure:
Following the procedures of Example 1, the title compound is prepared from 3-chloro-4-(1H-imidazol-1-yl)-1,2,5-thiadiazole and 1-benzyl-2-(hydroxymethyl)pyrrolidine.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:14])=[O:13].N1C=CC=CC=1>ClCCl>[N:1]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18]3)(=[O:13])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (Aldrich), 5-chlorosulfonyl-2-oxindole and pyridine in dichloromethane was stirred at room temperature overnight. The reaction was concentrated and the residue recrystallized from methanol to vie 5-(3,4, -dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.74 (s, 1H, NH), 7.84–7.90 (d, 1H, SO2NH), 7.67–7.72 (m, 2H, 2×CH), 7.01–7.16 (m, 4H, aromatic), 6.95–6.97(d, 1H, CH), 4.28–4.29 (m, 1H), 3.58 (s, 2H, CH2), 2.59–2.65 (m, 2H), 1.75–1.77 (m, 2H), 1.53–1.61 (m, 2H). MS m/z 329 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccccc1OCc1ccccc1

Procedure:
A solution of 8.3 g (36.1 mmol) of (2S)-1-chloro-2-hydroxy-3-N-mesylisopropylaminopropane and 8.69 g (43.4 mmol) of p-benzyloxyphenol in 75 ml DMSO was treated with 10.86 ml 4 N NaOH (43.4 mmol) and the mixture was heated at 100° for 5 hours. To the cooled reaction mixture 40 ml 1 N NaOH and 60 ml H2O were added with stirring and the resulting solid was collected by filtration and was washed well with H2O. The dried crude product was recrystallized from EtOAc-hexane to yield the end product as white needles, mp 93°-94°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[N:13]([CH:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]=[S:15]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:14](=[S:15])[NH:13][CH:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])=[O:11]
Reactant: CCOC(=O)CC(C)N=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CCOC(=O)CC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and ethyl 3-isothiocyanatobutyrate by a procedure analogous to the procedure described in example 3-a (yield 93%); 1H-NMR (DMSO-d6): δ1.18 (d, 3H, CH3), 1.20 (t, 3H, CH3), 2.61 (m, 2H, CH2), 4.08 (q, 2H, CH2), 4.58 (m, 1H, CH), 6.46 (br s, 2H, NH2), 6.65 (s, 1H, H-4), 8.34 (br d, 1H, NH), 11.35 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:25][OH:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][C:20]2[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]>>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]
Reactant: Brc1cccs1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cccs1
Yield: 95 %

Procedure:
Using general procedure C, 2-bromothiophene was coupled with 2-pyrrolidinone with the reaction time of 16 h. Chromatography gave 158 mg (95%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 6.94-6.86 (m, 2H), 6.53 (br s, 1H), 3.89 (t, 2H, J=7.2 Hz), 2.63 (t, 2H, J=8.1 Hz), 2.24 (p, 2H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:22](Cl)(Cl)=[S:23]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:14]=[C:22]=[S:23])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: S=C(Cl)Cl
Reactant: COc1c(F)cc(CCCN)cc1F
Solvent: CCN(CC)CC
Product: COc1c(F)cc(CCCN=C=S)cc1F
Yield: 52.2 %

Procedure:
3-(3,5-Difluoro-4-methoxyphenyl)propylamine (0.0693 mol), triethylamine (0.152 mol) and thiophosgene (0.076 mol) were reacted substantially as described in Example 7G to obtain 8.8 g (53%) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:12])=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[F:22][C:23]([F:29])([F:28])[CH2:24][C:25](Cl)=[O:26]>ClCCl>[F:22][C:23]([F:29])([F:28])[CH2:24][C:25]([NH:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[C:8]=1[CH3:12])=[O:26]
Reactant: Cc1c(N)nc2ccc(F)cn12
Reactant: O=C(Cl)CC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NC(=O)CC(F)(F)F)nc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine (0.033 g, 0.00020 mol) was dissolved in dichloromethane (3.0 mL) and N,N-diisopropylethylamine (0.070 mL, 0.00040 mol) was added. The reaction was cooled to 0° C. and 3,3,3-trifluoropropionyl chloride (29 uL, 0.00024 mol) was added. The mixture was warmed to room temperature and was stirred for 1 hour. Solvent removed and residue was chromatographed on silica (70% ethyl acetate/hexanes) to give 3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide Rf 0.43, 70% ethyl acetate/hexanes; MS m/z 276 (M+H). SH-SY5Y_EC50 (μM): 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([CH3:14])[C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[C:8]([CH3:14])=[N:7][C:6]2[C:11]([N:10]=1)=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(C)c(=O)[nH]c2c1
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C)c(Cl)nc2c1
Temperature: 25 °C
Yield: 34 %

Procedure:
A solution of 7-methoxy-3-methyl-1H-quinoxalin-2-one (125 g, 631 mmol, 1.0 eq) in phosphorus oxychloride (800 mL) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water and the resulting mixture is neutralized with 20% sodium hydroxide aqueous solution. The resulting precipitate is collected by filtration, washed with water to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 100:1, v/v) to afford 3-chloro-6-methoxy-2-methyl-quinoxaline as a white solid (44.4 g, 34% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 3.13 mmol) (from example 101, step 1) was dissolved in methanol (10 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.000 mL) was added dropwise and continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.192 mL, 3.13 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15 mL, 90.00 mmol) and the mixture continued to stir at 80° C. for 55 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to a yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (468 mg, 45%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.46-1.77 (m, 2H), 1.80-2.13 (m, 2H), 2.28-3.23 (m, 4H), 3.38-3.80 (m, 3H), 4.04-4.34 (m, 1H), 4.50-4.80 (m, 1H), 5.65 (s, 1H), 6.99-7.12 (m, 2H), 7.12-7.30 (m, 2H). MS m/z 335 (M+H)+
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3>C(OC(=O)C)(=O)C.C(Cl)(=O)C>[C:10]([O:17][C:16]1[CH2:18][CH2:19][C@H:20]2[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[O:11][C:16](=[O:17])[CH3:15])[CH:15]=1)(=[O:11])[CH3:9]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(C)=O)CC[C@@H]34)[C@H]2CC1

Procedure:
The compound 19-nortestosterone, 400 g, is refluxed under nitrogen in a mixture of 1500 ml of acetic anhydride and 1500 ml of acetyl chloride for a period of 3 hours. The volatile solvents are distilled at atmospheric pressure and the final traces of solvent removed under reduced pressure. The solid residue which remains is triturated with ice water, filtered, washed with cold aqueous sodium bicarbonate solution, rinsed with water and dried. Two recrystallizations of this residue from acetone yield 370 g of 3,17β-diacetoxyestr-3,5-diene which melts at 165°-71° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].FC(S(O[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])(=O)=O)(F)F>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 10 °C
Reaction time: 0.2 h
Yield: 949.6 %

Procedure:
To a stirred solution of 6-bromo-1H-indole (2.04 g, 1.04 mmol) in THF under nitrogen at 0° C. was added sodium hydride (60%, 1.25 g 31.2 mmol), portionwise over 0.2 h. The mixture was stirred at 0-20° C. for 1 h then was cooled in an ice-MeOH bath, whereupon triisopropylsilyl trifluoromethylsulfonate (3.83 g, 12.5 mmol) was added dropwise over 3 h. The resulting mixture was stirred at 0° C. for 1 h then at 20° C. for 72 h. The mixture was quenched (caution,) with a mixture of THF (30 mL) and water (1 mL) with external ice cooling and the resulting clear solution was partitioned between water (100 mL) and DCM (3×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (3.48 g) as a colourless oil. 1H NMR (CDCl3): 7.66-7.64 (1H, m), 7.50 (1H, d), 7.25-7.21 (2H, m), 6.61 (1H, d), 1.76-1.64 (3H, m), 1.17 (18H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCC3=O)c2)cc1
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(2-oxopyrrolidin-1-yl)biphenyl-3-carboxylic acid (53.0 mg, 0.000152 mol) in N,N-dimethylformamide (1 mL, 0.01 mol) was added (6-methylpyridin-3-yl)methanamine (45.0 mg, 0.000368 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150.0 mg, 0.0003945 mol) and N,N-diisopropylethylamine (150.0 uL, 0.0008612 mol). The reaction mixture was stirred for 16 hours at 25° C. Checked LC/MS, the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was yield a light color foam.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].Cl>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 529.3 [(M+H)+]; mp 259° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[CH:4]=1.CCOC(C)=O.[NH4+:19].[OH-]>CO>[NH2:19][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[CH:4]=1
Reactant: [NH4+]
Reactant: Cc1nc2ccc(CO)cc2[nH]1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc(CN)cc2[nH]1

Procedure:
The title compound was prepared from 5-(hydroxymethyl)-2-methylbenzimidazole: Rf (8:1:1 EtOAc:MeOH:NH4OH)=0.15. 1H NMR (300 MHz, CD3OD): δ7.45 (m, 2H), 7.20 (d, J=8.1 Hz, 1H), 3.90 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:40])[C@H:15]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@@H:16]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[C@@H:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])C1C=CC=CC=1.[BH4-].[Li+]>C1COCC1>[CH2:20]([O:19][C@@H:17]([CH3:18])[C@H:16]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[C@@H:15]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)[CH2:14][OH:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=C(C)CO[C@@H]([C@H](C)OCc1ccccc1)[C@@H](Cc1ccc(C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CO[C@H]([C@H](CO)Cc1ccc(C)cc1)[C@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of (R)-4-benzyl-3-((2R,3R,4S)-4-(benzyloxy)-3-((2-methylallyl)oxy)-2-(4-methylbenzyl)pentanoyl)oxazolidin-2-one (9.36 g, 17.3 mmol) in aqueous THF (4:1 THF/H2O; 86 mL) was added lithium borohydride (34.6 mL of 2.0 M in THF, 69.1 mmol) dropwise at −5° C., and the resulting yellow solution was vigorously stirred. After 1 h the yellow color (dba) had dissipated and the reaction was allowed to slowly warm to room temperature. The reaction was stirred for an additional 5 h and then poured into ice cold saturated aqueous NH4Cl (250 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (3×100 mL). The combined organics phases were dried over Na2SO4, filtered, and concentrated to a light yellow oil (10.11 g), which was purified by both reverse phase (RP; C18, 0→100% CH3CN/H2O) and normal phase (NP: SiO2, 0→30% EtOAc/CH2Cl2) to give (2S,3R,4S)-4-(benzyloxy)-3-((2-methylallyl)oxy)-2-(4-methylbenzyl)pentan-1-ol (4.04 g, 48% from Ex. 2, Step 1) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 5H), 7.06 (m, 4H), 4.98 (m, 1H), 4.87 (m, 1H), 4.64 (d, J=11.6 Hz, 1H), 4.44 (d, J=11.6 Hz, 1H), 4.08 (d, J=11.6 Hz, 1H), 3.97 (d, J=12.1 Hz, 1H), 3.78 (p, J=6.2 Hz, 1H), 3.56 (m, 3H), 2.88 (dd, J=13.8, 4.7 Hz, 1H), 2.53 (dd, J=13.8, 10.1 Hz, 1H), 2.30 (s, 3H), 2.18 (ddd, J=14.4, 7.7, 4.3 Hz, 1H), 2.01 (dd, J=6.2, 4.9 Hz, 1H), 1.76 (s, 3H), 1.33 (d, J=6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.41, 138.50, 137.87, 135.28, 129.00, 128.37, 127.75, 127.57, 111.86, 83.08, 75.92, 75.73, 70.79, 62.83, 44.60, 32.63, 21.05, 20.99, 19.84, 16.33; ESIMS m/z 391 ([M+Na]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H][H]>CCO.CCOC(C)=O.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2cccnc2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(-c2cccnc2)c1
Yield: 100 %

Procedure:
A suspension of 3-(2-fluoro-5-nitrophenyl)pyridine (26 g, 119 mmol) in EtOH (200 ml) and EtOAc (200 ml) was treated with PtO2 (1.35 g, 6 mmol) then exposed to 50 psi hydrogen until uptake ceased (circa 3 hours). The reaction was filtered through glass-microfibre filter paper and concentrated to gave 3-(2-fluoro-5-aminophenyl)pyridine (22.4 g) as a dark oil which solidified on standing: δH (360 MHz, CDCl3) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4), 8.76 (1H, m).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[C:7]2[CH:13]=[N:14][NH:15][C:6]=12)[CH:2]=[CH2:3]>C(O)C.Cl.[Pd]>[NH2:12][CH2:11][C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[C:6]2[NH:15][N:14]=[CH:13][C:7]2=[N:8][CH:9]=1
Reactant: C=CCNc1c(C#N)cnc2cn[nH]c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCNc1c(CN)cnc2cn[nH]c12
Temperature: 4 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
A solution of 7-allylamino-6-cyano-1H-pyrazolo[4,3-b]pyridine (E2, 487 mg, 2.4 mmol) in ethanol (100 ml) and ethanolic hydrogen chloride (2 ml) was hydrogenated over 10% palladium on charcoal (200 mg) at 40° C. and atmospheric pressure for 48 h. The catalyst was filtered off and the solution was evaporated in vacuo. The resulting solid was dissolved in water (15 ml) and the solution was adjusted to pH 8 with 10% sodium carbonate solution. After washing with ethyl acetate, the aqueous solution was cooled at 4° C. for 2 days. A white solid separated and was filtered off and dried to give the title compound (185 mg, 37%), m.p. 97°-100° C.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])C.[K+]>CN(C)C=O.O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 22 h

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (0.36 g; 1.25 mmol), potassium acetate (0.15 g; 1.5 mmol) and N,N-dimethylformamide:water (6:4 v/v) (3.5 ml) is heated at 95° C. under stirring for 22 h. Usual work up gives 2-(4-methoxyphenyl)-propionic acid. 2-(1-Bromoethyl)-2-(4-methoxyphenyl)-1,3-dioxolane (0.36 g; 1.25 mmol) and 2-chloro-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (0.30 g; 1.25 mmol), when reacted, separately, under the reaction conditions above described give similar results.