Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[O:9][C:10]1[CH:36]=[CH:35][C:13]([CH2:14][N:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[C:17]([CH3:27])=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[CH2:28]([N:15]([CH2:14][C:13]1[CH:35]=[CH:36][C:10]([O:9][C:8]2[CH:7]=[C:6]([CH:39]=[CH:38][CH:37]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])=[CH:11][CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:17]=1[CH3:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN)c2)cc1
Solvent: ClCCl
Product: CC(=O)NCCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 70C (0.028 g, 0.0514 mmoles) in CH2Cl2 (1 mL) was treated with acetic anhydride (0.0060 mL, 0.0617 mmoles) and stirred overnight at room temperature. The reaction was concentrated under reduced pressure, and the residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (m, 10 H), 6.96 (d, 1 H), 6.89 (d, 2 H), 6.60 (m, 2 H), 6.44 (t, 1 H), 6.29 (s, 1 H), 5.85 (br.s, 1 H), 4.09 (s, 2 H), 4.06 (s, 2 H), 3.98 (t, 2 H), 3.44 (dd, 2 H), 2.91 (s, 3 H), 2.31 (s, 3 H), 1.98 (s, 3 H), 1.90-2.10 (m, 2 H); MS (ESI+) mn/z 588 (M+H)+.
Reaction SMILES: C([Cu])#N.[Li+].[Cl-].[Br:6][C:7]1[CH:8]=[C:9]([CH:38]=[C:39](I)[CH:40]=1)[CH2:10][N:11]([CH:35]1[CH2:37][CH2:36]1)[C:12]([C@H:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:27])[CH:21]=2)[CH2:18][CH2:17][N:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15]1)=[O:13].[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[C:42]([C:39]1[CH:38]=[C:9]([CH:8]=[C:7]([Br:6])[CH:40]=1)[CH2:10][N:11]([CH:35]1[CH2:37][CH2:36]1)[C:12]([C@H:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:27])[CH:21]=2)[CH2:18][CH2:17][N:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15]1)=[O:13])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cc(Br)cc(I)c2)C2CC2)cc1=O
Reactant: O=C(Cl)c1ccccc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cc(Br)cc(C(=O)c3ccccc3)c2)C2CC2)cc1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,5-bis(bromomagnesium)pentane (1.0 eq.) in THF (0.05 M) at −78° C. was added a solution of CuCN-2LiCl prepared from CuCN (1.0 eq.) and LiCl (2.0 eq.) in THF (0.9 M with respect to CuCN). The resulting mixture was stirred at −78° C. for 30 min. A solution of trans-tert-butyl 3-{[(3-bromo-5-iodobenzyl)(cyclopropyl)amino]carbonyl}-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-piperidinecarboxylate (1.0 eq.) from the previous step in THF (0.2 M) was then added and the reaction mixture was warmed to RT over 1 h. Finally, benzoyl chloride (1.5 eq.) was added and the reaction mixture was stirred for another hour. The reaction mixture was quenched with the addition of water and subsequently extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 2:98 (v/v)→15:85 (v/v) MeOH:CH2Cl2) afforded the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][C:7]=1[Br:19]
Reactant: CCOC(=O)c1cccc(-c2ccc(N)cn2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc(N)c(Br)n2)c1
Yield: 86.2 %

Procedure:
To a solution of ethyl 3-(5-aminopyridin-2-yl)benzoate (7.52 g, 31.06 mmol) in DMF (150 mL) was added N-bromosuccinimide (5.58 g, 31.37 mmol) at 0° C. for 5 min. The reaction mixture was quenched with satd. NaHCO3 solution (150 mL) at 0° C. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 85:15 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(5-amino-6-bromopyridin-2-yl)benzoate (8.6 g, 86% yield) as a reddish brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26]>N1CCCCC1.[Pd].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.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.[Cu]I>[CH3:28][Si:27]([C:25]#[C:26][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][S:18]([C:21]([F:23])([F:22])[F:24])(=[O:20])=[O:19])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: C#C[Si](C)(C)C
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(Br)cc2)c1)C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
To 4.2 g (10 mmol) Trifluoro-methanesulfonic acid 1-(4-bromo-phenyl)-1H-indol-5-yl ester in 30 ml piperidine, 580 mg (0.5 mmol) tetrakis-(triphenylphosphine)-palladium and 100 mg (0.625 mmol) CuI were added. The solution was evaporated and purged with argon three times, before 1.4 ml (10 mmol) ethynyltrimethylsilane were added. The solution was stirred at RT for 48 h. Additional 0.38 ml (3.3 mmol) ethynyltrimethylsilane were added and the mixture was stirred at 50° C. for 1 h. The solution was concentrated and the residue redissolved in 0.5M HCl and ether. The inorganic phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Purification on silica gel with hexane/EtOAc 19:1 yielded 1.7 g (38%) Trifluoro-methanesulfonic acid 1-(4-trimethylsilanylethynyl-phenyl)-1H-indol-5-yl ester as orange oil, MS: 437 (M).
Reaction SMILES: [C@:1]12([CH3:28])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:14](C)([CH3:16])[CH3:15])=[O:11]>CO>[C@:1]12([CH3:28])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Solvent: CO
Product: CC(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 20.3 %

Procedure:
(RS)-1-(4-Iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.07 g) was dissolved in boiling methanol (100 mL) and left at room temperature for two days. Crystals formed were filtered to yield pure single diastereomer (R or S)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.409 g, 39%). The absolute configuration of the single diastereomer camphanate is not determined. 1H NMR (400 MHz, CDCl3): δ 8.23 (d, 1H, J=2.0 Hz, Ph-H), 7.89 (dd, 2H, J=2.0 and 8.4 Hz, Ph-H), 7.30 (d, 1H, J=8.4 Hz, Ph-H), 6.56 (s, 1H, Ph-CH), 2.42 (m, 1H), 2.07 (m, 1H), 1.94 (m, 1H), 1.73 (m, 1 H), 1.11, 1.04 and 0.87 (3 s, 9H, CH3 3), 0.95 (s, 9H, (CH3)3C).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[CH:37]=[C:36]([CH2:38][C:39](=[O:41])[NH2:40])[N:35]=[CH:34]1)=[O:6])[CH:2]=[CH2:3].[CH3:42][I:43]>CC(C)=O>[I-:43].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[CH:37]=[C:36]([CH2:38][C:39](=[O:41])[NH2:40])[N:35]([CH3:42])[CH:34]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cnc(CC(N)=O)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[n+]3cc(CC(N)=O)n(C)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Reaction time: 5.5 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(4-carbamoylmethylimidazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (1.08 g) in acetone (5.4 ml) was added methyl iodide (1.15 ml) at room temperature and the solution was allowed to stand for 5.5 hours. The solvent was evaporated to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(4-carbamoylmethyl-3-methyl-1-imidazolio)ethyl}pyrrolidin-4yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (1.31 g) as a yellow solid. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[S:29][C:28]2=[N:30][C:31]([CH3:36])=[C:32]([C:33](O)=[O:34])[N:27]2[CH:26]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:27]3[C:28]([S:29][C:25]([CH3:24])=[CH:26]3)=[N:30][C:31]=2[CH3:36])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cn2c(C(=O)O)c(C)nc2s1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sc(C)cn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,6-Dimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=506.0.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[NH:17][CH:16]=[CH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[N:5]1.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].ClCCl>CN(C)C=O>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH3:3])[CH:8]=3)[CH:10]=2)[CH:15]=[CH:16]1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: Cn1cc(-c2cnc3cc[nH]c3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc2ncc(-c3cnn(C)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
In a N2 charged round bottom flask, Sodium Hydride, 60%, (41 mg, 1.01 mmol) was suspended in dimethylformamide (2.5 mL). The solution was maintained under N2 and cooled to 0° C. for 10 minutes. Next, 6-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) was dissolved in dimethylformamide (2.5 mL) and added to the cooled solution dropwise. The solution was allowed to stir at 0° C. for an additional 10 minutes. Finally, Bromo-acetic acid ethyl ester (123 uL, 1.11 mmol) was slowly added to the reaction vessel. The reaction was allowed to equilibrate back to room temperature, while stirring for 2 hours. Finally, the solution was transferred to a separatory funnel with dichloromethane (75 mL) and washed with water (2×75 mL). The organic layer was dried over Na2SO4, concentrated down and purified by flash chromatography (0-10% Methanol/dichloromethane step gradient) to afford the title compound (122 mg, 43% yield). MS m/z=285 [M+H+]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Yield: 94 %

Procedure:
To a mixture of 3,4,5-trifluoronitrobenzene (3.894 g, 0.022 mol) and 4-piperidone hydrochloride monohydrate (3.072 g, 0.020 mol) in chloroform (24 ml), was added triethylamine (8.3 ml, 0.06 mol) under stirring. The resulting mixture was heated and stirred at 70° C. for 7 h. After completion of the reaction (TLC), the solvent was evaporated under reduced pressure and the residue diluted with water (10 ml). The separated solid was filtered, washed with water (8 ml) followed by hexane (5 ml) to obtain yellow crystalline solid as a product, 4.8 g, 94% yield M.P.: 130-132° C.; MS: M+1=257 (MH+ 100%) for M.F.: C11H10F2N2O3
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(O)(C(F)(F)F)=O>>[NH2:27][CH2:26][CH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:2]([Br:1])[C:3]1=[O:28]
Reactant: N#CCc1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1

Procedure:
The title compound was prepared from compound of Example 97 by a procedure similar to the one described for Example 99, as the TFA salt (0.13 g, 33%): mp 70-74° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.21 (br s, 1H), 6.60-6.50 (m, 1H), 7.52 (d, J=6 Hz, 1H), 7.30-7.10 (m, 3H), 7.01 (d, J=9 Hz, 1H), 6.94-6.85 (m, 2H), 6.20 (d, J=6 Hz, 1H), 5.20 (s, 2H), 5.05 (s, 2H), 3.23 (br s, 2H), 2.97 (t, J=8 Hz, 2H), 2.05 (br s, 2H). ES HRMS m/z 449.0698 (M+H C21H20BrF2N2O2 requires 449.0671).
Reaction SMILES: C(OC([C:6]1[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]([C:14]2[C:19]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:17]([Cl:34])=[CH:16][N:15]=2)=[N:8][N:7]=1)=O)C.[CH3:35][Mg]Br.[CH2:38]1[CH2:42][O:41]CC1>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:19]2[C:14]([C:9]3[N:10]([CH:11]([CH3:13])[CH3:12])[C:6]([C:42]([OH:41])([CH3:38])[CH3:35])=[N:7][N:8]=3)=[N:15][CH:16]=[C:17]([Cl:34])[CH:18]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C1CCOC1
Reactant: C[Mg]Br
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C(C)C
Product: CC(C)n1c(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nnc1C(C)(C)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 25 mL scintillation vial was charged with 5-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (prepared according to general procedure B, 11 mg, 0.02 mmol), methylmagnesium bromide in THF (0.2 mL, 3.0 M), and tetrahydrofuran (3 mL). The vial was sealed and stirred at 0° C. for 2 h. The volatiles were then evacuated in vacuo and the residue was purified via preparatory HPLC to afford 4-tert-butyl-N-{5-chloro-2-[5-(1-hydroxy-1-methyl-ethyl)-4-isopropyl-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-benzenesulfonamide as a white powder: MS (ES) M+H expected 492.2, found 492.5.
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OCCCN1CCC[C@H]1C(N)=O>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2([O:4][CH3:3])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][NH:20]2)=[C:16]([F:34])[CH:15]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: NC(=O)[C@@H]1CCCN1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(Nc2ccc(Cl)cc2F)NC=Nc2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol), (prepared as described for the starting material in Example 50), in methylene chloride (4 ml). The mixture was stirred for 2 hours at ambient temperature, and further triphenylphosphine (105 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (49 mg, 0.28 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 1 hour at ambient temperature, and was purified by pouring directly onto a silica column eluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by 60/25/15). The purified oil was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 2M ethereal hydrogen chloride (0.5 ml) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give (S)-743-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-4-methoxyquinazoline hydrochloride (70 mg, 32%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].Cl[C:13]([C:15]1[C:16]([Cl:26])=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([O:20][CH3:21])=[O:19])=[O:14]>ClCCl>[Cl:26][C:16]1[C:15]([C:13]([NH:11][O:10][CH3:9])=[O:14])=[C:24]([Cl:25])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
20 4.60 g (0.045 mol) of triethylamine and 3.75 g (0.045 mol) of methoxyamine hydrochloride were added to a solution of 5.35 g (0.02 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate and in 100 ml of dichloromethane. After the reaction solution had been stirred for 12 hours at room temperature, it was washed with dilute phosphoric acid, dried and concentrated. The resulting residue was extracted by stirring with diethyl ether. This gave 4.80 g of methyl 2,4-dichloro-3-(N-methoxy)aminocarbonylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19][NH:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:7][C:6]([CH2:26][C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.[OH-].[Na+].Cl>C(Cl)Cl>[C:30]([N:20]([CH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:17])([F:18])[F:16])[CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:26][C:27]([OH:29])=[O:28])[CH:7]=1)[CH2:21][C:22]([OH:24])=[O:23])(=[O:32])[CH3:31]
Reactant: COC(=O)CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(=O)O)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{6-Methoxy-2′[(methoxycarbonylmethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.094 g, 0.23 mmol), acetyl chloride (0.03 mL, 0.46 mmol), and triethylamine (0.08 mL, 0.57 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, aqueous 1N NaOH was added. After stirring at room temperature for 45 minutes, analytical LCMS indicated that both acids had been hydrolyzed to the free acid, and so the mixture was neutralized with aqueous 1N HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 440.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]#[CH:14])[CH2:9]1)=O)(C)(C)C.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]([O-:21])=[O:16].[C:13]([CH:10]1[CH2:11][CH2:12][NH2+:8][CH2:9]1)#[CH:14]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC1CC[NH2+]C1
Product: O=C([O-])C(F)(F)F
Reaction time: 3 h

Procedure:
To 0.85 g (4.35 mmol) 3-Ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 mL DCM was added 2 mL (26.0 mmol) TFA and stirring was continued at room temperature for 3 h. The solvents were evaporated and the residue was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[Br:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH2:27][N-:28][CH3:29])=[CH:20]2.C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH2:27][N:28]([CH3:29])[C:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=1)=[O:12])=[CH:20]2
Reactant: C[N-]Cc1ccc2c(Br)c(OC)ccc2c1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(CN(C)C(=O)c3cn(C)c4ccccc34)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A solution of 1-methyl-1H-indole-3-carbonyl chloride (27 mmol), prepared in the previous step, in 50 mL of methylene chloride was added dropwise under nitrogen over 1.5 h to a solution of (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (7.56 g, 27 mmol), prepared in step 7 of Example 36, and triethylamine (3.76 mL, 27 mmol) in 200 mL of methylene chloride at room temperature. The solution was stirred at room temperature for 22 h (overnight). The reaction was extracted with 1N HCl. The aqueous layer was separated and extracted two additional times with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 11.52 g of an off white solid. The solid was recrystallized from methylene chloride-isopropanol. Off-white crystals were collected by filtration and dried under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (9.3389 g, 79%) as an off white solid, mp 168-169° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](O)([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5].[F:15]C(F)=C>>[F:1][C:2]([F:14])([F:13])[C:3]([F:15])([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5]
Reactant: C=C(F)F
Reactant: OC(CC(F)F)(C(F)(F)F)C(F)(F)F
Product: FC(F)CC(F)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,4,4-pentafluoro-2-butanol may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be dehydrohalogenated and then reacted with sulfuric acid and then water to form 2-trifluoromethyl-1,1,1,4,4-pentafluoro-2-butanol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.O>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]([O:13][CH3:14])=[O:12])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: COC(=O)C(O)c1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(OS(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
Methanesulfonyl chloride (9.3 g) was added at 0° C. to a solution of methyl 3,5-dichloromandelate (19.0 g) and triethylamine (8.2 g) in dichloromethane (150 ml). After the addition, the mixture was stirred at room temperature for 3 hours, after which water (150 ml) was carefully added. The organic phase was separated, dried and concentrated to dryness, giving methyl 2-(3,5-dichlorophenyl)-2-mesyloxy-acetate (23.6 g) as an oil.