Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4[C:20]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)=[CH:19][N:18]([C:24]2[N:25]([C:29]3[CH:34]=CC(F)=C[C:30]=3F)[N:26]=[CH:27][N:28]=2)[N:17]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2C3C(CCOC=2C=1)=CN(C1N(C(C)C)N=CN=1)N=3>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4[C:20]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)=[CH:19][N:18]([C:24]2[N:25]([CH:29]([CH3:30])[CH3:34])[N:26]=[CH:27][N:28]=2)[N:17]=4)[CH2:11]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1
Agent: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2

Procedure:
3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester was prepared similarly to 3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylic acid tert-butyl ester from 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene and 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS: RT=4.85 min, M+H+=451 (40%), M+H+-OtBu=395 (100%), M+H+-Boc=351 (10%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1C=CC=CC=1>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][O:10][C:5]2[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)[CH:8]=[N:7][C:6]=2[CH3:9])=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ncc(C=O)c(C)c1OCc1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2)c(C)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 4-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (23) (0.40 g, 1.5 mmol), 4-amino-4′-cyanobiphenyl (0.35 g, 1.8 mmol) and p-toluenesulfonic acid monohydrate (0.08 g, 0.45 mmol) was heated at 100° C. in benzene (15 mL) under nitrogen atmosphere with a Dean-Stark condenser for 18 hours. The solvent mixture was then evaporated and the crude product dissolved in methyl alcohol (20 mL), and to the solution was added sodium borohydride (0.56 g, 15 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate and then back washed with water. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 1:1) as eluant to give 4′-{[5-(4-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-biphenyl-4-carbonitrile (24) (266 mg, 40% overall yield for two steps).
Reaction SMILES: [Na+].[I-:2].Br[CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[C:17](=[O:29])[N:16]([CH3:30])[C:15]=2[C:14]2[CH:13]=[C:12]3[O:31][CH2:32][O:33][C:11]3=[CH:10][C:9]1=2>CC(C)=O>[I:2][CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[C:17](=[O:29])[N:16]([CH3:30])[C:15]=2[C:14]2[CH:13]=[C:12]3[O:31][CH2:32][O:33][C:11]3=[CH:10][C:9]1=2
Reactant: COc1cc2c3c(n(C)c(=O)c2cc1OC)-c1cc2c(cc1C3=CCCCBr)OCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2c3c(n(C)c(=O)c2cc1OC)-c1cc2c(cc1C3=CCCCI)OCO2
Yield: 91.6 %

Procedure:
NaI (217 mg, 1.45 mmol) was added to a suspension of bromide 19 (70 mg, 0.15 mmol) in acetone (15 mL). The reaction mixture was heated at reflux for 12 h, after which the resulting orange precipitate was collected by vacuum filtration and purified by flash chromatography (silica gel, CHCl3) to provide 24 (73.0 mg, 95%) as an orange solid: mp 173-174.5° C.; IR (KBr) 2944, 1612, 1522, 1481, 1254, 1033 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.36 (s, 1 H), 6.84 (t, J=7.22 Hz, 1H), 6.05 (s, 2H), 4.08 (s, 3H), 4.04 (s, 3H), 4.00 (s, 3H), 3.35 (t, J=6.69 Hz, 2H), 2.95 (q, J=7.32 Hz, 2H), 2.19 (m, 2H); ESIMS m/z (rel intensity) 532.1 (100, MH+). Anal. Calcd for C24H22INO5: C, 54.25; H, 4.17; N, 2.64. Found: C, 54.64; H, 4.25; N, 2.60.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of methyl 5-(N-t-butoxycarbonyl-N-methylamino)valerate (557 mg) in methanol (6 ml) and 1N sodium hydroxide solution (3.41 ml) was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo, and the residue was poured into water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified with 1N hydrochloric acid, and extracted with ethyl acetate (20 ml×3). The extract was collected and washed with water (40 ml×2) and brine (40 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 5-(N-t-butoxycarbonyl-N-methylamino)valeric acid (470 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]([NH:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]([NH:15][NH:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH2:9]/[CH:10]=[CH:11]/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)NNCC(C)C
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1cccnc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 14.7 %

Procedure:
A solution of 0.500 g of 2(R)-[1(RS)-(tert-butoxycarbonyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 10 ml of dimethylformamide was treated with 0.465 g of 3-bromopyridine, 0.297 g of triethylamine, 0.017 g of palladium(II) acetate and 0.045 g of tri-(o-tolyl)phosphine. The mixture was heated at 100° C. for 24 hours. After cooling to room temperature the mixture was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine and then dried over anhydrous magnesium sulphate. Evaporation of the solvents and flash column chromatography of the residue on silica gel using ethyl acetate/hexane gave 0.090 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-(3-pyridyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and aniline (Aldrich) according to the method described in Example 1c. Melting Point: 125-128° C. (diethylether)
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:10]1([C:34]#[N:35])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=O)[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:12][CH2:11]1)[C:8]#[N:9])=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>>[CH2:1]([O:3][C:4]([NH:6][CH:7]([C:10]1([C:34]#[N:35])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[S:45])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:12][CH2:11]1)[C:8]#[N:9])=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)NC(C#N)C1(C#N)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Product: CCOC(=O)NC(C#N)C1(C#N)CCN(c2ccc(N3C[C@H](CNC(C)=S)OC3=O)cc2F)CC1
Yield: 58 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)—N-{3-[4-(4-(1-ethoxycarbonylamino-1-cyanomethyl)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: OCc1cc(I)c(OCC(F)(F)F)c(Cl)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
6-Chloro-5-hydroxy-4-iodo-2-pyridinemethanol (CAS Registry No. 208519-37-3) (21.5 g, 75 mmol) was dissolved in hexamethylphosphoramide (210 mL). Over a period of 30 min sodium hydride (3.0 g of 60% dispersion in oil, ˜75 mmol) was added with stirring at room temperature. The mixture was stirred for another 45 min at room temperature and 2,2,2-trifluoroethyl trifluoromethane sulfonate (12.5 mL, 90 mmol) was added drop wise with stirring and temperature control (<40° C.). The mixture was stirred for 18 h at 120° C., cooled to room temperature and poured into water (800 mL). The mixture was acidified with 2N—HCl (50 mL) and extracted with ethyl acetate (2×350 mL). Organic phases were washed with water (2×400 mL), pooled and dried with Na2SO4. Solvents were evaporated and the brown, solid residue (27.9 g) was purified by chromatography on silica with ethyl acetate/n-heptane (1:1) to give the title compound as a white solid (24.8 g, 90%), LC-MS (UV peak area/ESI) 100%, 367.916 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:3][CH:2]=1.[ClH:22].Cl.N1C=CC(C2CNCCN2CCCC(OCC)=O)=CC=1>>[ClH:22].[ClH:22].[N:1]1[CH:2]=[CH:3][C:4]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCN1CCNCC1c1ccncc1
Agent: CCOC(=O)CCCN1CCNCC1c1ccncc1
Agent: Cl
Product: O=C(O)CCCCN1CCNCC1c1ccncc1

Procedure:
Following the method of Example 195ii), but staring from ethyl 5-[(4-pyridyl)piperazine-1-yl]pentanoate, dichydrochloride salt instead of ethyl 4-[(4-pyridyl)piperazin-1-yl]butyrate, dihydrochloride salt, the title compound was isolated after recrystallisation from wet ethanol, as an off-white crystalline solid in 59% overall yield: m.p. 294°-297° C. (dec); NMR (d6DMSO+CD3CO2D) δ 1.62(2H,m, 1.80(2H,m), 2.32(2H,t), 3.18(2H,m), 3.41(4H,m), 4.05(4H,m) 7.29(2H,d, 8.34(2H,d; m/Z 264 (M+H)+ ; calculated for C14H21N3O2. 2.0 HCl: C, 50.0%; H, 6.89%; N, 12.5%; found: C, 50.5% H, 7.2%; N, 12.2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N[CH2:31]C1C=CC(C(OC)=O)=CC=1C>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]=2[CH3:31])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN)c(C)c1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)c(C)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(aminomethyl)-3-methylbenzoate: 1H-NMR (CDCl3) δ 8.36 (1H, dd, J=8.2, 3.1 Hz), 8.25–8.18 (1H, m), 8.04 (1H, d, J=3.1 Hz), 7.85–7.81 (2H, m), 7.37 (1H, d, J=7.7 Hz), 7.15–7.07 (4H, m), 4.73 (2H, d, J=5.8 Hz), 3.89 (3H, s), 2.40 (3H, s); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2
Reactant: COc1ccc(C)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1ccc(C)c2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=427.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33].B(Br)(Br)Br>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 12.6 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 2, 112 mg of imine is reacted by reaction with 0.36 ml of BBr3 (1 M in dichloromethane), and 38 mg of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:17])[C:15]#[CH:16])=[CH:4][CH:3]=1.O.[N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:20]=[N-:21].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CS(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:22]([N:19]1[CH:16]=[C:15]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:17])[N:21]=[N:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Reaction time: 8 h

Procedure:
To a solution of 1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol (Enantiomer A) (0.530 g, 1.81 mmol) in DMSO (4 mL) and H2O (4 mL) was added azidomethyl-benzene (0.242 g, 1.81 mmol), followed by sodium ascorbate (0.036 g, 0.181 mmol) and copper(II) sulfate pentahydrate (0.005 g, 0.018 mmol), and the reaction was stirred overnight. After aqueous workup the crude material was purified by silica gel chromatography (15-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([N:51]1[CH2:54][CH:53]([CH2:55]O)[CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>O1CCCC1.[Cl-].[Na+].O>[O:24]=[C:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH2:55][CH:53]3[CH2:54][N:51]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:52]3)[CH:15]=2)[NH:20]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COc2ccc3c(c2)CCC(=O)N3)C1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Diethylazodicarboxylate (40% solution in toluene, 3.4 mL, 7.4 mmol) was added to a mixture of 6-hydroxy-3,4-dihydro-2(1H)-quinolinone 2 (1.0 g, 6.1 mmol), triphenylphosphine (1.607 g, 6.1 mmol), and 1-boc-azetidine-3-yl-methanol 18 (1.148 g, 6.1 mmol) in anhydrous tetrahydrofuran (25 mL) at 0° C. After the addition, the mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with brine (20 mL) and stirred for 30 min. The mixture was extracted with ethyl acetate (2×50 mL), and washed with brine. The combined organic extract was dried over Na2SO4, and later evaporated on a rotavap. The residue was purified by flash column chromatography on silica gel (230-400 mesh; 24 g) using dichloromethane:methanol:methanol (95:5:0.05) solvent mixture. Yield: 4.02 g (some phosphorus side products were present, used without further purification for subsequent step). 1H NMR (400 MHz, CDCl3): δ 6.70 (m, 2H), 6.63 (m, 1H), 4.02 (m, 4H), 3.96 (m, 1H), 3.75 (m, 2H), 2.91 (t, 2H), 2.58 (t, 2H), 1.41 (m, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21]C[N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.N12CC(CO)(CC1)CC2>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Agent: OCC12CCN(CC1)C2
Product: O=C(OCC12CCN(CC1)C2)c1c[nH]c2ccccc12

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethyl 1H-indole-3-carboxylate was synthesized using the procedure described for (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate using 1-Azabicyclo[2.2.1]heptan-4-ylmethanol. MS: (m/e) 270.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1>O>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][C:25]=1[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[S:2][CH3:1])=[O:6]
Reactant: CSc1ccccc1C(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CSc1ccccc1C(=O)c1cc(C)ccc1C
Yield: 46 %

Procedure:
To a mixture of 1.2 g 2-(methylthio)benzoyl chloride (B) and 1.55 g AlCl3 at 0° C. was added slowly 20 ml DCM. The mixture was stirred 5 minutes at ambient temperature before 7.8 g p-xylene was added slowly. The reaction was stirred 30 minutes at ambient temperature before water was added slowly. The mixture was extracted with DCM (2×50 ml). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash silica chromatography (hexane:ethyl acetate 85:15) afforded 0.758 g product.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[C:21](=[O:26])[CH2:20]2)=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:32]([O:36][C:37](=[O:41])CCC)[C@@H:33]1[O:35]C1>C1COCC1>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:32]([CH2:33][OH:35])[O:36][C:37]2=[O:41])[CH:13]=[CH:14][C:15]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[C:21](=[O:26])[CH2:20]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
5-Benzyloxycarbonylamino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene (4.5 g) was dissolved in dry THF (100 ml) under argon and the solution cooled to -78° C. A solution of n-butyllithium (8.67 ml, 1.6 M in hexane) was added to this whilst keeping the temperature below -60° C. The mixture was stirred for 5 minutes and (R)-glycidylbutyrate (1.86 ml) was added. Stirring was continued at -78° C. for 30 minutes and the temperature then allowed to rise to ambient over 16 hours. The mixture was evaporated to dryness and then treated with dichloromethane. The mixture was filtered to give (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (409 mg). The residual organic solution was washed twice with water, and then brine. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 6% methanol in dichloromethane. Relevant fractions were combined and evaporated to give further (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one product (535 mg).
Reaction SMILES: I[CH2:2][CH2:3][OH:4].[N:5]1([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[C:22]4[N:23]=[CH:24][CH:25]=[N:26][C:27]=4[C:28]([C:31]4[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=4[Cl:42])=[CH:29][CH:30]=3)=[O:20])=[N:16][CH:17]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1>CC#N>[OH:4][CH2:3][CH2:2][N:8]1[CH2:7][CH2:6][N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[C:22]4[N:23]=[CH:24][CH:25]=[N:26][C:27]=4[C:28]([C:31]4[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=4[Cl:42])=[CH:29][CH:30]=3)=[O:20])=[N:16][CH:17]=2)[CH2:10][CH2:9]1
Reactant: OCCI
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)cn3)c3nccnc23)c1Cl
Solvent: CC#N
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(CCO)CC4)cn3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.1 %

Procedure:
2-Iodoethanol (26 μL, 0.33 mmol, 10 equiv) was added to a mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (5-piperazin-1-ylmethyl-pyridin-2-yl)-amide (Example 105) (18 mg, 0.033 mmol) in CH3CN (1 mL), under an argon atmosphere. The reaction mixture was stirred for 14 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 15 mg of the title compound as a yellow solid. Title compound: ESI-MS: 596.6/598.4 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.30 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[K]>[Cu]Br.CN(C)C=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ncc[nH]1
Agent: [Cu]Br
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(-n2ccnc2C)cc1
Yield: 41 %

Procedure:
A mixture of 16.4 parts of 2-methyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 1 part of copper (I) bromide, 20 parts of potassium carbonated and 270 parts of N,N-dimethylformamide is stirred and refluxed for one week. The reaction mixture is cooled, poured onto water and the whole is extracted with 2,2'-oxybispropane. The extract is washed twice with a diluted hydrochloric acid solution. The acid aqueous phase is separated and alkalized with sodium hydroxide. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 4 parts (41%) of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole as a residue.