Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[C:1]#[C:2][CH3:3])[CH:19]=[CH:20][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 L round bottom flask was charged with 1-propynylmagnesium bromide (0.5 M in THF) (available from Aldrich) (245 mL, 123 mmol) and cooled to −78° C. To the cold slurry was added a solution of 3-benzyloxybenzaldehyde (available from Aldrich) (20.0 g, 94.2 mmol) in THF (30 mL) over 15 minutes. The mixture was stirred for 30 minutes at −78° C., the cooling bath was removed, and stirring was continued for 1 hour at ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to afford 93.A (23.1 g, 97% yield) as a pale yellow oil.
Reaction SMILES: CC(C)=O.N[C:6]1([O:15]O)[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:12][CH:10]1[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6](=[O:15])[CH2:11]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC(C)=O
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 1 h

Procedure:
Acetone (11.6 g.) in ethanol (50 c.c.) was stirred at below 0°C and 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g.; 80% pure) added. After stirring for ca. 1 hour the solid had dissolved. To the solution was added magnesium sulphate and it was stored at 0° overnight. Filtration and distillation gave acetone and dihydroisophorone (probably containing some symmetrical amino-peroxide ##EQU20## and a product (2.2 g.), b.p. 75° - 78°/1.0 mm, had a peroxide equivalent 239.4 and gave N, 6.3% an elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 59.1 %

Procedure:
A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethylsulphoxide is heated at 135°-140° C. for 2.5 hours. The solvent is distilled off under a fine vacuum and the residue is suspended in about 50 ml of water. The solid is filtered off with suction, rinsed with water, dried over calcium chloride in a vacuum drying cabinet at 80° C. and recrystallized from glycol monomethyl ether. 14.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 248°-250° C. are obtained.
Reaction SMILES: [H-].[Na+].[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH:11]2[CH2:13][CH2:12]2)C=CC=CC=1.[CH:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[C:29]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49])=O>O1CCCC1>[C:11]1(=[CH:26][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:45])[F:47])[CH:39]=3)[C:29]=2[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:13][CH2:12]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Reactant: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1cccc(C(F)(F)F)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=C2CC2)c2ccccc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 128 mg, 3.20 mmol) was suspended in anhydrous tetrahydrofuran (10 mL) and cooled to 0° C. Triphenyl-cyclopropylphosphonium bromide (1.23 g, 3.20 mmol) was added as a solid all at once, and the mixture was allowed to stir at room temperature. Once gas evolution ceased, a tetrahydrofuran solution of ethyl 3-formyl-1-[3-(trifluoromethyl)benzyl]-1H-indole-2-carboxylate (Example 40, 1.0 g, 2.7 mmol) was added, the mixture was stirred for 15 hours, and the resulting mixture was partitioned between water and ethyl acetate. Layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The resulting crude oil was purified by flash chromatography on silica gel eluted with 5% ethyl acetate/hexane. The title compound was collected as a bright yellow oil (403 mg, 38%). The product had: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1 H), 7.53 (s, 1 H), 7.41-7.38 (m, 2 H), 7.29-7.20 (m, 3 H), 7.15-7.12 (m, 1 H), 7.05 (d, 1 H), 5.72 (s, 2 H), 4.27 (q, 2 H), 1.50-1.45 (m, 2 H), 1.25 (t, 3 H), 0.83-0.76 (m, 2 H); mass spectroscopy gave MH+=400.2 (calc'd exact mass for C23H20F3NO2=399.14).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:5][C:6]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:7][C:8]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:5][C:6]([OH:23])([CH2:7][C:8]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:39][CH3:40])([CH3:10])[CH3:9])[C:19]([F:21])([F:22])[F:20]
Reactant: CCI
Reactant: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of the 34 mg (0.071 mmol) of 2-[3-(3-chloro-2-fluoro-5-trifluoromethylbenzyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol in 0.5 mL of anhydrous DMF was added 78 mg (0.56 mmol) of potassium carbonate followed by 0.1 mL (1.25 mmol) of iodoethane. The mixture was stirred under argon for 2 hours and was then diluted with brine (4 mL) and extracted with three 5 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in hexanes and chromatographed on silica gel eluting with hexanes and then EtOAc-hexanes (0.5:99.5) to afford 19.6 mg of the title compound as a oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:30]=[CH:29][CH:28]=[CH:27][C:16]=2[C:17](OCC2C=CC=CC=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C1C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:30]=[CH:29][CH:28]=[CH:27][C:16]=2[CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccccc1-c1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: OCc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccccc1-c1cccc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of benzyl 2-(3′-benzyloxyphenyl)benzoate from Step D (1.35 g, 3.42 mmol) in dry THF (20+10 mL) was added dropwise to a stirred suspension of LiAlH4 (0.26 g, 6.84 mmol) in THF (30 mL) at 0° C., under argon. Stirring was continued for 1 hour at 0° C., then the reaction was quenched with wet ether, followed by water, then aq. NH4Cl. The resulting mixture was extracted with EtOAc (2×100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which contained benzyl alcohol. Vacuum distillation (1 mm Hg, 80° C.) allowed removal of most of the benzyl alcohol to give the titled product as a pale solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2cccc(N)c2)c1
Yield: 29.8 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (520 mg, 1.33 mmol) and 3-aminophenylboronic acid (310 mg, 2.0 mmol) in toluene (8 mL) was added Pd(0) (50 mg) and Na2CO3 (2.5 mL of a 2 M solution), and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on a silica gel column, eluting with CHCl3 :Et2O 100:5-100:40 to afford 160 mg of the title compound. MS (CI/NH3) m/z 404 (M+H)+. 1H NMR (CDC13, 300 MHz) δ1.44 (s, 9H), 1.88 (m, 1H), 2.03 (m, 2H), 3.37 (m, 2H), 3.76 (m, 2H), 4.16 (m, 2H), 6.75 (m, 2H), 6.82 (m, 1H), 7.22 (m, 2H), 8.08 (m, 1H).
Reaction SMILES: C[O:2][CH:3]1[O:7][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4]1>CO>[OH:2][CH:3]1[O:7][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4]1
Reactant: COC(=O)[C@H]1CCC(OC)O1
Solvent: CO
Product: COC(=O)[C@H]1CCC(O)O1

Procedure:
Methyl (2R)-Tetrahydro-5-hydroxy-2- furoate was prepared as for the S-isomer from methyl (2R)-tetrahydro-5-methoxy-2-furoate in similar yield: α!D25 -9.2° (c=1.8, CH3OH); IR (neat, cm-1) 3543 (br), 2956, 1741, 1068, 1010; 1H NMR (CDCL3) for diastereomer A (58%) a 5.62 (m, 1H), 4.67 (dd, J=6.5, 8.1 Hz, 1H), 3.78 (s, 3H), 2.46-1.93 (m, 4H); for diastereomer B (42%) δ 5.75 (m, 1H), 4.73 (dd, J=3.8, 8.5 Hz, 1H), 3.76 (s, 3H), 2.46-1.93 (m, 4H); HRMS calculated for C6H10O4 (M+), 146.0579, found 46.0577.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C=CC(=O)C)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCC(=O)C=Cc1cccc(OC)c1
Agent: COc1cccc(C=CC(C)=O)c1
Product: CCCCCC(=O)CCc1cccc(OC)c1

Procedure:
Following the procedure of Example 15 and substituting an equivalent quantity of 1-(3-methoxyphenyl)-1-octen-3-one for 4-(3-methoxyphenyl)-3-buten-2-one there was obtained as the product 1-(3-methoxyphenyl)octan-3-one as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1ccc2ncccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3ncccc3c2)C1=O
Yield: 43.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.13 mmol) was reacted with 6-bromo-quinoline (233.9 mg, 1.13 mmol), 1,4-dioxane (15 mL), copper iodide (16.53 mg, 0.113 mmol), trans-1,2-diamino cyclohexane (0.04 mL, 0.339 mmol) and potassium carbonate (312 mg, 2.26 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% MeOH in CHCl3) afforded 150 mg of the product (43.668% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.O>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(OCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(N)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65 mg (0.12 mmol) of the compound from Example 101A are dissolved in 6 ml of acetic acid, and 3 ml of water are added. The mixture is stirred at RT for 30 min. The mixture is then heated to 70° C. and stirred at this temperature for a further 30 min. A clear solution is formed. The mixture is then freed from the solvent on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16](CC(O)=O)=[CH:15]2)=[O:13])=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:15]2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)c(CC(=O)O)cn2C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)Cl)cn2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Oxalyl chloride (30 μL, 0.35 mmol) was added dropwise to a solution of 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetic acid (100 mg, 0.29 mmol) in 2 mL of dry CH2Cl2 under argon. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude product was washed with dry hexane (3×1 mL) and dried in vacuo to give the title compound in 95% yield (100 mg). C18H13Cl2NO3, Mr=362.21; 1H NMR (400 MHz, DMSO-d6) d: 3.90 (s, 3H), 4.21 (s, 2H), 6.95 (d, J=2.4 Hz, 1H), 7.04 (dd, J=2.4/9.0 Hz, 1H), 7.29 (s, 1H), 7.52-7.55 (m, 2H), 7.67-7.71 (m, 2H), 8.29 (d, J=9.2 Hz, 1H); LCMS (ESI) tR: 2.72 min (>99%, UV254), m/z: 358.2 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[CH:2]([CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23])=[O:1]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(CO)C(C)(C)C2=O)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(C=O)C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3-(4-hydroxymethyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (174 mg) in acetonitrile (5.0 mL) was added Dess-Martin periodinane (348 mg). The reaction mixture was stirred at room temperature for 3 hr, and diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was used for the next step without purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:27][CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Br:29]Br.S([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:29][C:10]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH2:3][CH:2]([CH3:1])[CH2:27][CH3:28]
Reactant: BrBr
Reactant: CCC(C)COc1ccc(-c2ccc(S(=O)(=O)c3ccc(C)cc3)cc2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)COc1ccc(-c2ccc(S(=O)(=O)c3ccc(C)cc3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 113.2 %

Procedure:
4'-(2-methylbutyloxy)-4-p-toluenesulfonylbiphenyl (41 g) prepared in the above step (ii) was dissolved in CCl4 (400 ml). To the resulting solution was dropwise added bromine (25 g) dissolved in CCl4 (100 ml), at room temperature over one hour, followed by stirring at room temperature for 5 hours, adding an aqueous solution of sodium hydrogen sulfite till the color of bromine disappeared, separating the organic layer, washing with 6N hydrochloric acid, washing with an aqueous solution of 2N NaOH, washing with water to make the solution neutral, drying and distilling off CCl4 to obtain oily 3'-bromo-4'-(2-methylbutyloxy)-4-p-toluenesulfonylbiphenyl (55.7 g).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@H:10]([NH:26]C(=O)OC(C)(C)C)[C:11](=[O:25])[N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][C:15]=3[CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:26][C@H:10]1[CH2:9][O:8][C:7]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]=2[CH3:24])[C:11]1=[O:25]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c(Br)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)COc2c(Br)cccc21
Reaction time: 0.75 h

Procedure:
In a similar manner to that described for Example 89 Step 2 except the reaction was stirred 45 min., (S)-tert-butyl 9-bromo-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (40 mg, 78.2 μmol) in DCM (2 mL) was cooled to 0° C. and treated with TFA (300 μl). After 45 min, the mixture was concentrated to dryness and the residue azeotroped with MeCN to afford (S)-3-amino-9-bromo-5-((2-methylnaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4 (5H)-one trifluoroacetate (41 mg), which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](/[N+:11]([O-:13])=[O:12])\[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH:8]([C:7]3[C:2]([CH3:1])=[C:3]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[CH:5][CH:6]=3)[CH:9]([N+:11]([O-:13])=[O:12])[CH3:10])=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: C/C(=C\c1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Reactant: Brc1ccc2cc[nH]c2c1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)[N+](=O)[O-]
Temperature: 140 °C
Yield: 31.3 %

Procedure:
A mixture of (E)-benzyl (2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate (5.16 g, 15.8 mmol) and 6-bromo-1H-indole (6.20 g, 31.6 mmol) was heated neat at 140° C. overnight. The crude reaction mixture was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%) to give benzyl (3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate (2.58 g, 4.94 mmol, 31% yield) as a burgundy oil/solid and as a 1:1 mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)(=[O:16])=[O:15])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[Sn](Cl)Cl>Cl>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:15])=[O:16]
Reactant: COc1cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: COc1cc(NS(=O)(=O)c2ccccc2N)c2ncccc2c1
Yield: 67.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(6-methoxyquinolin-8-yl)-2-nitrobenzenesulfonamide (Intermediate 152) (460 mg, 1.17 mmol), tin (II) chloride (886 mg, 4.68 mmol) and 6 N HCl (3 drops) gave the title compound (260 mg, 68%). The structure was confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)[C:5]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:4][N:3]=1.Br[C:31]1[N:32]=[CH:33][C:34]([C:37]#[N:38])=[N:35][CH:36]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:5]2[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:7][C:2]([NH:1][C:31]3[N:32]=[CH:33][C:34]([C:37]#[N:38])=[N:35][CH:36]=3)=[N:3][CH:4]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2cnc(N)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1cnc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC2CCN(C)CC2)cc1
Temperature: 100 °C
Yield: 19.9 %

Procedure:
Dry DME (402 μL) was added to a mixture of tert-butyl 4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (16 mg, 0.040 mmol), 5-bromopyrazine-2-carbonitrile (7.39 mg, 0.040 mmol), xantphos (1.859 mg, 3.21 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.471 mg, 1.606 μmol), and cesium carbonate (26.2 mg, 0.080 mmol) in a nitrogen purged, sealed microwave vial. Nitrogen gas was bubbled through the mixture for 5 min. The reaction mixture was heated for 1 hr at 100° C. by microwave irradiation. Upon cooling the mixture was diluted with MeOH and purified by ion exchange on Isolute SCX II acidic resin (5 g), eluting with MeOH. The eluent was concentrated and further purified by preparative thin layer chromatography, eluting with 7% MeOH, 1% NH3, 92% DCM, to give 5-(5-(4-methoxyphenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (4 mg, 7.97 μmol, 20% yield) as a light yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.S(O)(O)(=O)=O.CS[C:19](=[NH:21])[NH2:20]>[OH-].[Na+]>[C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)(=[NH:20])[NH2:21]
Reactant: CSC(=N)N
Reactant: O=C(O)CCC1CCNCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)N1CCC(CCC(=O)O)CC1
Reaction time: 8 h
Yield: 102.5 %

Procedure:
500 mg of 4-piperidinepropionic acid are added at 2° C. to a solution of 553 mg of S-methyl-isothiourea sulphate in 3.2 ml of 2N sodium hydroxide solution. After leaving to stand at room temperature overnight the separated crystals are filtered off, washed with water, acetone and ether and dried. There are obtained 600 mg of 1-amidino-4-piperidinepropionic acid, m.p. above 275° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][F:18])=[CH:11][C:10]=1[O:19][CH3:20])(C)(C)C.[ClH:22]>C(O)(=O)C>[ClH:22].[F:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[C:10]([O:19][CH3:20])[CH:11]=1
Reactant: COc1cc(OCCF)ccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(OCCF)ccc1CN

Procedure:
The above [4-(2-fluoro-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester (9.9 mg, 0.33 mmol) is treated with 37% aq. HCl (0.1 mL) and acetic acid (1 mL) for 1.5 h at rt. The solvents are removed by lyophilisation to give 4-(2-fluoro-ethoxy)-2-methoxy-benzylamine hydrochloride (7.8 mg) as a beige resin. LC-MS: tR=0.73 min, [M+1]+=200.04.