Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34]([OH:36])=O>>[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34]([N:14]([CH:13]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15])=[O:36]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-bromo-4-chlorobenzoic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a colorless oil. MS m/e: 656.0 [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].Br[CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C(=O)C>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:9][CH2:10][CH2:11][CH3:12])[CH:4]=2)=[CH:20][CH:19]=1
Reactant: CCCSc1cc(O)ccc1C
Reactant: BrCSc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCSc1cc(Oc2ccc(SC)cc2)ccc1C
Reaction time: 14 h

Procedure:
4-Methyl-3-(n-propylthio)phenol (4.0 g, 0.02 mole) and 85.5 % potassium hydroxide (1.4 g, 0.02 mole) were dissolved in N,N-dimethylacetamide (40 ml) above 90° C. 4-Bromomethylthiobenzene (4.0 g, 0.02 mole) and Cu powder (0.5 g, 0.008 mole) were added to this solution below 90° C and the mixture was stirred at 120° - 160° C for 14 hr. After cooling, the reaction mixture was poured into water (100 ml) and extracted twice with benzene. The combined organic layers were washed with 5 % sodium hydroxide solution, 5 % hydrochloric acid solution, and water, then dried over sodium sulfate. The solvent was removed, and the residue was distilled under reduced pressure. The yield of 4-methyl-3-n-propylthiophenyl 4-methylthiophenyl ether was 4.1 g (61.5 %), colorless oil, bp 188° - 190° C/2 mmHg. Anal. Found: C, 67.12; H, 6.59. Calcd. for C17H20OS2 : C, 67.06; H, 6.62 %
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:29])[CH:11]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>S(Cl)(Cl)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:29][C:19]([C:20]4[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=4)=[N:18][C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(C(=O)NC(C(=O)c2ccc3c(c2)OCO3)c2ccccn2)cc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(-c2nc(-c3ccccn3)c(-c3ccc4c(c3)OCO4)o2)cc1
Yield: 9.4 %

Procedure:
N-(2-Benzo[1,3]dioxol-5-yl-2-oxo-1-pyridin-2-yl-ethyl)4-cyano-benzamide (0.1 g, 0.26 mmol) was dissolved in neat thionyl chloride (10 ml) and heated at reflux temperature for 2 hours. The cooled solution was cautiously added dropwise to a concentrated sodium hydroxide-ice mixture. The crude product was extracted into dichloromethane and purified using hexane-ethylacetate (1:1) as eluent to give the title compound (9 mg, 9%). 1H NMR (CDCl3) δ: 6.06 (2H, s), 6.84-6.99 (2H, m), 7.27-7.31 (1H, m), 7.86 (2H, d, J=7 Hz), 8.00 (2H, d, J=7 Hz), 8.04 (1H, s), 8.23 (1H, dd, J=7 and 1 Hz), 8.42 (1H, d, J=7 Hz), 8.65 (1H, dd, J=7 and 1 Hz); m/z (API) 368 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])C(F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].[F:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1C(Cl)=O.C(O)C(N)(CO)CO>CN(C=O)C.O.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[C:36]4[C:35]([F:34])=[CH:43][CH:42]=[CH:41][C:40]=4[F:44])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Agent: NC(CO)(CO)CO
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (370 mg, 0.83 mmol) and 1M LiOH (4.97 ml, 4.97 mmol) in 10:1 THF:H2O (10 mL) was heated at 50° C. overnight. The reaction was washed with brine (25 mL), aqueous layer extracted with EtOAc (25 mL), organic layers combined, filtered through a cotton plug, and solvent removed by rotary evaporation. After high vacuum removal of residual solvent, the crude mixture was dissolved in THF (25 mL) and to this was added 2,6-difluorobenzoyl chloride (920 mg, 5.25 mmol). After stirring 3 h at rt, DMF (25 mL) was added to dissolve any suspended solids followed by the addition of excess polymer-bound trisamine resin. Upon overnight stirring, the amine resin was removed by vacuum filtration, rinsed with MeOH (50 mL), and filtrate concentrated under reduced pressure to afford the desired amide (410 mg, 79%) as an off-white solid. ESIMS (M+H)+=492.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH:20]1([CH2:25][NH:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH:20]1([CH2:25][NH:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: C1CCC(CNCCC2CCCNC2)C1
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCNCC3CCCC3)C2)c2ncccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-[(cyclopentyl)methylamino]ethyl]piperidine in a yield of 61% of theory. Colourless crystals, m.p. 148°-150° C. (acetonitrile).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[N:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:53])[N:9]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]=[N:31][N:32](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:33]=2)=[CH:19][CH:18]=1)[CH3:3]>CO>[ClH:1].[CH2:2]([C:4]1[N:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:53])[N:9]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:30][N:31]=[N:32][N:33]=2)=[CH:21][CH:22]=1)[CH3:3]
Reactant: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: Cl
Solvent: CO
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.5 ml) was added to a solution of 5,7-diethyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one (500 mg) (A) in methanol (5 ml) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was dissolved in hot ethanol. The solution was cooled, evaporated to small volume and the product collected by filtration to give 5,7-diethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one hydrochloride (230 mg), as a solid, m.p. 265°-269° C. (decomposition); NMR (d6 -DMSO): 1.15-1.4(m,6H), 2.95(q,2H), 3.35(q,2H), 5.55(s,2H), 6.9(d,1H), 7.05(d,2H), 7.2(d,2H), 7.4-7.75(m,5H), 8.45(d,1H); mass spectrum (+ve FAB, methanol/NBA): 459(M+Na)+, 437(M+H)+ ; microanalysis, found: C, 64,8; H, 5.4; N, 17.4; C26H24N6O.HCl.0.5H2O requires C, 64.8; H, 5.4; N, 17.4%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:19][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=3)[CH2:34][CH2:33]2)[CH:27]=1)=[O:24]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cn(S(=O)(=O)c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-(phenylsulfonyl)-1H-indole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 516.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[CH:4][C:3]=1[N+:27]([O-])=O.CO.Cl.C(=O)([O-])[O-].[K+].[K+]>[Fe].ClCCl.O.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[CH:4][C:3]=1[NH2:27]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(N)c(C)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
The mixture of crude 2-methyl-4-octadecyloxynitrobenzene (30 g, ca. 0.065 mol), methanol (55 mL), concentrated hydrochloric acid (40.5 mL) and dioxane (50 mL) was heated to 85° C. Iron powder (11.2 g, 0.20 mol) was added in small portions with intensive stirring. After the addition was complete the reaction mixture was stirred at 85° C. for another 3 hours and poured warm into water (800 mL), stirred for 30 minutes and the pH adjusted to 10.0 by addition of aqueous potassium carbonate solution. Dichloromethane (1.0 L) was added and mixture was stirred intensively for 1 hour. The layers were separated and the organic layer was washed with water (2×500 mL) and dried over sodium sulfate. The solvent was evaporated to give an oil (20 g, 0.053 mol, 82% yield), which solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:17][B:16](B2OC(C)(C)C(C)(C)O2)[O:15]1.ClCCl.C([O-])(=O)C.[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][N:10]([CH3:12])[C:8]([C:5]1[N:6]=[CH:7][C:2]([B:16]([OH:17])[OH:15])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(B(O)O)cn1
Temperature: 120 °C
Yield: 52.6 %

Procedure:
A mixture of 5-bromo-N,N-dimethylpyridine-2-carboxamide (23 g, 98 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2]bi[[1,3,2]dioxaborolanyl] (27 g, 110 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4.8 g, 5.9 mmol), 1,1′-bis(diphenylphosphino)ferrocene (3.3 g, 5.9 mmol), and potassium acetate (30 g, 300 mmol) in 1,4-dioxane (600 mL) was heated at 120° C. for 16 h. The mixture was cooled to rt and diluted with EtOAc. The organic solution was washed with saturated ammonium chloride solution which was discarded and then with water (1 L). The water wash was evaporated to give the desired compound (10 g, 50%). LCMS calculated for C8H12BN2O3 (M+H)+: m/z=195.1. found: 195.1.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[S:18])[CH3:16])[NH:13][C:12]1=[O:26])[CH3:10])(C(C)(C)C)(C)C.CO.Cl[Si](C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[S:18])[CH3:16])[NH:13][C:12]1=[O:26])[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
(3S ,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (1.29 g, 3.0 mmol) is dissolved in toluene (10 ml), and thereto are added methanol (2 ml) and chlorotrimethylsilane (0.1 ml). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate (50 ml), washed several times with brine, dried over magnesium sulfate, and evaporated to remove the solvent to give (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)- 1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (627 mg).
Reaction SMILES: C([NH:8][CH2:9][CH:10]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:9][CH:10]([CH:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)C(CNCc1ccccc1)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(CN)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 70.2 g of ethyl 2-(N-benzylaminomethyl)-3-t-butyldimethylsilyloxybutanoate in methanol (100 ml) was added portionwise 10.0 g of 10% wet palladium on carbon under nitrogen atmosphere. The mixture was shaken vigorously under 3.5 atmospheric pressure of hydrogen. After 8 hours, palladium on carbon was filtered off and washed with chloroform. The filtrate was evaporated to dryness under reduced pressure to give 50.3 g of crude ethyl 2-aminomethyl-3-t-butyldimethylsilyloxybutanoate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH3:22]I.O>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:22])[CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ccc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a mixture of 1.5 g (0.038 mole) of 60% sodium hydride dispersion and 100 ml DMSO was added dropwise a solution of 5.1 g (0.02 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole in 25 ml DMSO. After the mixture was stirred one hour at room temperature, 5.6 g (0.04 mole) of methyl iodide was added dropwise. The mixture was stirred at room temperature overnight, then poured into water and extracted with ether. The ether extracts were backwashed with water three times, then dried and concentrated. The crude solid was recrystallized from hexane to give 4.3 g of product, m.p. 129°-129.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2

Procedure:
Following the procedure for 109, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-amino-2-methylpropan-1-ol gave 137. MS: (ESI+)=481.1. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.73-7.65 (m, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.51-7.42 (m, 1H), 7.39 (s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 4.96 (t, J=6.0 Hz, 1H), 4.49 (d, J=6.1 Hz, 4H), 3.52 (d, J=5.8 Hz, 2H), 1.35 (s, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([O:53]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:51]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:48][CH2:49][C@@H:50]2[CH2:51][O:53]2)[C@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:32][CH:33]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@@H](CO)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccccc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@@H]2CO2)cc1

Procedure:
In analogy to the procedure described in example 1 (j) the (3S,4R,5R)-3-[(2R)-3-hydroxy-2-(toluene-4-sulfonyloxy)-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1) (i)] was treated with sodium hydroxide in dimethylsulfoxide to yield the (3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2S)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 714.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[I:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([N:24]3[CH:25]=[C:21]([I:20])[N:22]=[CH:23]3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.7) (1.97 g, 6.0 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.67 g, 92%). MS (ISP) 485.1 [(M+H)+]; mp 223° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].N1C=CC=CC=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:32]([O-])=[O:33])C=1>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]2[O:15][C:32](=[O:33])[NH:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)c(O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc([N+](=O)[O-])c2oc(=O)[nH]c2c1
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 2-amino-4-tert-butyl-6-nitrophenol (300 mg, 1.43 mmol) and pyridine (0.30 mL) in methylene chloride (30 mL) was added 4-nitrophenylchloroformate (280 mg, 1.39 mmol). The mixture was stirred for 24 h. The resulting solution was washed with aqueous sodium bicarbonate (2×20 mL), dried over solid magnesium sulfate and concentrated to an orange solid. Column chromatography (silica gel, eluant=40% EtOAc/petroleum ether) afforded 5-tert-butyl-7-nitro-3H-benzoxazol-2-one (70%).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1.B(F)(F)F.CCOCC.ClC1C=CC(O)=CC=1C(OC)=C1C2CC3CC(CC1C3)C2>>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Agent: COC(=C1C2CC3CC(C2)CC1C3)c1cc(O)ccc1Cl
Agent: FB(F)F
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OC)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 86.8 %

Procedure:
Triethyl phosphite (0.98 ml, 5.7 mmol) was added dropwise to a solution of dimethyl acetal 27 (1.08 g, 4.7 mmol), boron trifluoride etherate (1.2 ml, 9.8 mmol) and CH2Cl2 (10) at 0° C. After warming the reaction to room temperature overnight, the solution was partitioned with 3N HCl and the aqueous layer was washed with CH2Cl2 twice. The organic layers were washed with dilute NaHCO3, dried over Na2SO4, decanted and evaporated. The crude residue was purified on a silica gel column, eluting with 0-80% EtOAc/hexanes, to give 1.36 g (86%) phosphonate 28 as a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:23])[C@@H:20]([OH:22])[CH3:21])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:38]=2)[CH:33]=[CH:32]1>>[OH:22][C@@H:20]([CH3:21])[C:19]([NH:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3][C:2]([C:36]4[CH:35]=[C:34]5[CH:33]=[CH:32][NH:31][C:39]5=[N:38][CH:37]=4)=[N:7][C:6]=3[C:8]=2[CH3:24])[CH:12]=1)=[O:23]
Reactant: Cc1c(-c2cccc(CNC(=O)[C@H](C)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1c(-c2cccc(CNC(=O)[C@H](C)O)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
Crude (2S)-N-(3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methyl-2-hydroxypropanamide (65 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 48.4 mg of 421. MS (Q1) 529.2 (M)+
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[CH:24]=[N:23][C:22]([NH2:29])=[CH:21]2>ClCCl>[N:29]([C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([CH3:17])=[CH:27][C:26]=2[CH3:28])=[C:1]=[S:2]
Reactant: Cc1cc(C)c2cnc(N)cc2c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1cc(C)c2cnc(N=C=S)cc2c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 7.5 %

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.35 g, 5.8 mmol) in dichloromethane (19 mL) at ambient temperature was added 6,8-dimethylisoquinolin-3-amine (1 g, 5.8 mmol). The reaction mixture was placed into a preheated oil-bath and stirred at 40° C. for 18 h, then cooled, concentrated, and the crude material was purified by silica gel chromatography (10-35% ethyl acetate in hexanes) to afford 3-isothiocyanato-6,8-dimethylisoquinoline (93.7 mg, 0.437 mmol, 8%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.20 (s, 1H), 7.36-7.44 (m, 2H), 7.23 (s, 1H), 2.75 (s, 3H), 2.51 (s, 3H). MS (LC/MS) R.T.=2.03; [M+H]+=215.1.