Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(OBO)O.[CH3:14][C:15]([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[CH3:8][C:7]1[C:2]([C:4]2[C:15]([CH3:14])=[CH:6][CH:7]=[CH:2][N:3]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cccnc1Br
Agent: [Pd+2]
Agent: OBOBO
Agent: [K+]
Solvent: CCO
Product: Cc1cccnc1-c1ncccc1C
Temperature: 80 °C
Reaction time: 65 h

Procedure:
Placed 172 mg(1.0 mmol) of 2-bromo-3-methylpyridine in a reaction tube together with 281 mg (1.11 mmol) of the pinacol ester of diboronic acid, 22.5 mg Pd(OAc)2 and 300 mg (3.06 mmol) of KOAc After addition of 5 ml ethanol the mixture was warmed to 80° C. After 6 h the gc of an aliquot of the reaction mixture (extracted with ether/water) indicated the formation of the 3,3′-dimethyl-2,2′-bipyridine. The reaction was left for 65 h at 80° C. after which the only peaks detected in the gc, of the ether solution of an ether/water extracted sample of the reaction solution, were 3,3′-dimethyl-2,2′-bipyridine (gc/ms, m/z 185, M+1) and the pinacol ester of diboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH2:12][NH:13][CH3:14].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cn(C)c2ccc(F)cc12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2ccc(F)cc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 39.8 %

Procedure:
According to the procedure of Example 24, except substituting 5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.14 g, 41%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:7]([F:29])[CH:6]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:7]([F:29])[CH:6]=1)#[N:2]
Reactant: NC(=O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
N-(4-Carbamoylmethyl-2-fluoro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide (0.290 g) was combined with phosphorous oxychloride (0.4 mL) neat, under nitrogen. The reaction mixture was heated to 90° C. for 2 h and then allowed to cool to ambient temperature. The reaction mixture was quenched with saturated aq. sodium carbonate (20 mL) and extracted with ethyl acetate (5×40 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate:hexanes=1:1) to yield the pure title compound (0.110 g).
Reaction SMILES: [Cl:1]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O[CH2:23][CH:24]1[C:28]2=[C:29]3[C:33](=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=[C:27]2[N:26]([C:43]([C:45]2[NH:46][C:47]4[C:52]([CH:53]=2)=[CH:51][C:50]([O:54][CH3:55])=[C:49]([O:56][CH3:57])[C:48]=4[O:58][CH3:59])=[O:44])[CH2:25]1)[NH:32][C:31]([C:39]([O:41][CH3:42])=[O:40])=[CH:30]3.O>N1C=CC=CC=1>[Cl:1][CH2:23][CH:24]1[C:28]2=[C:29]3[C:33](=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=[C:27]2[N:26]([C:43]([C:45]2[NH:46][C:47]4[C:52]([CH:53]=2)=[CH:51][C:50]([O:54][CH3:55])=[C:49]([O:56][CH3:57])[C:48]=4[O:58][CH3:59])=[O:44])[CH2:25]1)[NH:32][C:31]([C:39]([O:41][CH3:42])=[O:40])=[CH:30]3
Reactant: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CO
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CCl
Temperature: 20 °C
Yield: 63.6 %

Procedure:
Dichlorotriphenylphosphorane (1.65 g, 5.1 mmol) was added to a solution of 56 (1.34 g, 2.55 mmol) in pyridine (75 mL) and the solution stirred at 20° C. After 10 min more dichlorotriphenylphosphorane (2.06 g, 6.4 mmol) was added, and after a further 10 min the solution was poured into H2O and the mixture stirred for 5 min. The precipitated solid was filtered off, washed with H2O, and redissolved in CH2Cl2 (400 mL). This solution was filtered through Celite, eluting with CH2Cl2, and the filtrate was dried (Na2SO4) and evaporated. The resulting orange solid was recrystallized from CH2Cl2 giving methyl 1-(chloromethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (31) as an orange powder (0.88 g, 64%), mp 246-247.5° C. The mother liquor was evaporated onto silica and purified by chromatography (50% EtOAc-petroleum ether) to give further 31 (0.50 g, 36%). 1H NMR (CDCl3) δ 10.39 (s, 1 H, NH), 9.42 (s, 1 H, NH), 9.39 (s, 1 H, H-4), 7.31 (d, J=2.2 Hz, 1 H, H-8), 6.97 (d, J=2.4 Hz, 1 H, H-3'), 6.86 (s, 1 H, H-4'), 4.80 (t, J=10.0 Hz, 1 H, H-2), 4.69 (dd, J=10.8, 4.4 Hz, 1 H, H-2), 4.32-42.3 (m, 1 H, H-1). 4.09 (s, 3 H, OMe), 4.05 (dd, J=11.4, 3.9 Hz, 1 H, CH2Cl), 4.02 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.77 (dd, J=11.4, 8.8 Hz, 1 H, CH2Cl); 13C NMR [(CD3)2SO] δ 160.5, 160.0, 149.2, 140.0, 139.0, 137.5, 133.6, 132.1, 131.3, 130.2, 127.7, 126.1, 125.5, 123.2, 111.3, 107.5, 106.4, 97.9, 61.1, 60.9, 55.9, 54.1, 52.3, 47.0, 42.0. Anal. Calculated for C25H23ClN4O8 : C, 55.3; H, 4.3; N, 10.3. Found: C, 55.4; H, 4.1; N, 10.3%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:32])[C@@H:12]2[C:15]([CH3:31])([O:17]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:16])[C:9]=1[C:33]([O:35]CC1C=CC([N+]([O-])=O)=CC=1)=[O:34])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+:50]>O.O1CCOCC1.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:32])[C@@H:12]2[C:15]([OH:17])([CH3:16])[CH3:31])[C:9]=1[C:33]([O-:35])=[O:34])(=[O:3])[CH3:2].[Na+:50]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCSC1=C(C(=O)[O-])N2C(=O)[C@H](C(C)(C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5% palladium-charcoal (40.0 mg), water (0.96 ml) and dioxane (2.24 ml) was shaken for 30 minutes under hydrogen atmosphere (40 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (40.0 mg) in a mixture of water (0.24 ml) and dioxane (0.56 ml), and shaken for 2 hours under hydrogen atmosphere (40 psi) at ambient temperature. The resulting mixture was added with 1% aqueous sodium hydrogen carbonate (0.522 ml) at 0° C. and filtered by using diatomaceous earth. The filtered cake was washed with water (3×5 ml) and the combined filtrates were concentrated, washed with ethyl acetate (3×20 ml) and evaporated in vacuo. The residue was dissolved in water (25 ml) containing sodium chloride (0.7 g) and chromatographed on a non ionic adsorption resin HP-20 (trademark, made by Mitsubishi Chemical Industries) (1.0×20 cm) eluting with a mixture of water and acetone (100:0 to 7:3, 200 ml). The fractions containing the product were combined and lyophilized to give sodium (5R,6S)-3-(2-acetamido-ethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6.9 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][C:12]2=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(OC(N(C)C)N(C)C)(C)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:1][N:8]([CH3:14])[CH3:9])[C:12]2=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CC1CN(Cc1ccccc1)C2
Agent: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
To 3-benzyl-3-aza-bicyclo[3.2.1]octan-6-one (3.2 mmol) was taken up in Brederick's reagent (tris-(N,N-dimethylamino)methane, 10 mL) and heated for 8 h at 100° C. Excess Brederick's was removed in vacuo and the crude product was used as is in subsequent steps. 1H NMR (CDCl3, 400 MHz) δ 7.50 (m, 5H), 3.56 (s, 3H), 2.99 (s, 6H), 2.40–2.20 (m, 4H), 1.95 (m, 2H), 2.56 (m, 2H); APCl MS m/z 271.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:7]=1[NH2:8].CO[C:19](=O)[CH2:20][C:21](=[O:28])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:6]2[C:2]3[N:3]([CH2:4][CH2:5][N:1]=3)[C:19](/[CH:20]=[C:21](/[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)\[OH:28])=[N:8][C:7]=2[CH:9]=1
Reactant: COc1cc(N)c(C2=NCCN2)cc1OC
Reactant: COC(=O)CC(=O)c1cccnc1
Product: COc1cc2c(cc1OC)C1=NCCN1C(/C=C(\O)c1cccnc1)=N2
Reaction time: 1 h
Yield: 28.1 %

Procedure:
A mixture of 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (0.15 g, 0.68 mmol) and methyl-3-oxo-3(3-pyridinyl)propanoate (0.20 g, 1.12 mmol) was stirred at 155. for 1 hour. The reaction mixture was purified by column chromatography on silica-gel (dichloromethane/methanol, 25/1) to give (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol (66.9 mg, 28%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1.O1[CH2:33][CH2:32]OCC1.O.[NH4+]>CS(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]>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:33]4[CH:32]=[CH:9][CH:10]=[CH:2][CH:3]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH:16]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C1COCCO1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Reaction time: 0.08 h

Procedure:
5-Bromo-3-(1,1-dioxido-2-phenyltetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (100 mg, 0.224 mmol) was placed in a microwave vial and combined with 1,4-Dioxane (3 mL) and Water (1.5 mL). Argon was bubbled through the mixture for 10 mins, stirring and then PdCl2(dppf) (8.18 mg, 0.011 mmol) was added, and argon was bubbled another 10 mins. The vial was sealed and put under microwave 5 mins at 100° C. with high absorption parameter. The crude was evaporated to remove the most of the dioxane. Then it was partitioned between EtOAc and water. Organic layer was dried over magnesium sulfate and solvent removed under vacuum to afford 155 mg of crude material as a gummy brown oil which was dissolved in 1-2 mL of DMSO, and run through the ammonium Gilson to afford 17 mg of (racemic)-3-(1,1-dioxido-2-phenyltetrahydro-2H-thiopyran-4-yl)-5-phenyl-1H-indole-7-carboxamide.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][C@H:17]([C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:27])[NH:23][N+:24]([O-:26])=[O:25])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>CCOC(C)=O>[NH2:1][C@H:2]([C:14]([NH:16][C@H:17]([C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:27])[NH:23][N+:24]([O-:26])=[O:25])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H](N)CC(=O)OCc1ccccc1)C(=O)NCC(=O)OC

Procedure:
A sample of the tetrapeptide (10) suspended in EtOAc is cooled to -40° under slow nitrogen flow, and is saturated with HCl gas, keeping the temperature from rising above -10°. Five min after saturation, the solution is purged with nitrogen for 60 min; addition of 80 mL of ether precipitates the title compound (11) as a white solid, which is collected by filtration, washed with ether, and dried in vacuo.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.O[C:28]1([C:49]2[C:57]([OH:58])=[CH:56][C:52]3[O:53][CH2:54][O:55][C:51]=3[CH:50]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=2)[C:29]1=[O:48]>>[OH:58][C:57]1[C:49]([CH:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=3)[C:29]2=[O:48])=[CH:50][C:51]2[O:55][CH2:54][O:53][C:52]=2[CH:56]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCO4)c3ccccc32)cc1
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: COC(=O)c1ccc(CN2C(=O)C(c3cc4c(cc3O)OCO4)c3ccccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 2C, and making the variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with methyl 4-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate, the title compound was obtained (98%) as a solid: MS (ES+) m/z 418.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH2:18][OH:19]>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9]
Reactant: BrCCCCCCBr
Reactant: OCCCc1ccccc1F
Product: Fc1ccccc1CCCOCCCCCCBr

Procedure:
(4.71 g), T.l.c. (ER- CX 1:79) Rf 0.22, from 1,6-dibromohexane (14.28 g) and 3-(2-fluorophenyl)-1-propanol (3.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:29])[N:7]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:6]=12.C([Sn](=O)CCCC)CCC.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:48][N:47]=[N:46][N:28]=4)=[CH:19][CH:20]=3)[C:8](=[O:29])[N:7]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:6]=12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 41.6 %

Procedure:
A mixture of 4′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.33 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (3.5 g) and toluene (30 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 41%).
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:13]=[CH:14]/[N:15](C)C)=[C:4]([N+]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(OCC)(=O)C.[H][H]>[Ni].O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:15][CH:14]=[CH:13][C:3]=12
Reactant: COc1ncc(Br)c(/C=C/N(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc(Br)c2cc[nH]c12
Yield: 56 %

Procedure:
(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to Ra-Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred for 30 minutes at 30 psi of hydrogen and room temperature. The reaction mixture was filtered, and concentrated. The residue was triturated with dichloromethane, and the solid collected by filtration to provide 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (5.82 g). The mother liquor was evaporated and the residue triturated again with dichloromethane and filtered to provide an additional 1.63 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine. Total yield=7.45 g, 72% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[NH:13][C:12]1=O.[BH4-].[Na+].C1COCC1.FC(F)(F)C(O)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[NH:13][CH2:12]1
Reactant: O=C1NS(=O)(=O)CCC1c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2CCS(=O)(=O)NC2)c(F)c1
Temperature: 0 °C

Procedure:
4-(2-Fluoro-4-nitrophenyl)dihydro-2H-1,2-thiazin-3(4H)-one 1,1-dioxide (2.43 g, 8.44 mmol) and sodium borohydride (3.83 g, 101.3 mmol) are placed under nitrogen and dry THF (70 ml) added. To the ice cooled suspension is added trifluoroacetic acid (7.8 ml, 101.3 mmol) over 5 min. After stirring for 16 hr additional trifluoroacetic acid (20.0 ml, 260 mmol) is added followed by methanol (20 ml). The solution is evaporated and the residue dissolved in ethyl acetate (150 ml) and washed with sodium bicarbonate solution (3×100 ml) and brine (50 ml). Evaporation gives a yellow gum which is chromatographed over silica gel (90 g) eluting with 1-3% methanol-chloroform. The title compound is obtained as a gum (1.99 g, 86%): Calcd for C10H11FN2O4S: C, 43.79; H, 4.04; N, 10.21. Found: C, 43.72; H, 4.07; N, 10.11.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:37]=[CH:36][C:8]([CH2:9][O:10][C@@H:11]2[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23](=[O:35])[NH:24][C@H:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[ClH:38]>C(Cl)Cl>[C@H:25]1([NH:24][C:23]([C@H:13]2[NH:14][CH2:15][C@@H:11]([O:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:37][CH:36]=3)[CH2:12]2)=[O:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.[ClH:38]
Reactant: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)N[C@@H]3CCCc4ccccc43)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CO[C@@H]2CN[C@H](C(=O)N[C@@H]3CCCc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4S)-tert-butyl 4-((4-(methoxycarbonyl)benzyl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (1.31 g, 2.58 mmol) in DCM (10 mL) was added HCl (4.0 M solution in dioxane, 12.9 mL, 51.5 mmol). The reaction mixture was stirred at rt for 1.5 h and concentrated in vacuo to give the title compound as a HCl salt (1.15 g, 100%, white solid). 1H NMR (DMSO-d6) δ 8.83 (d, J=8.4 Hz, 1H), 8.74 (d, J=8.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.26-7.00 (m, 3H), 5.05-4.88 (m, 1H), 4.56 (q, J=12.8 Hz, 2H), 4.31 (br. s., 2H), 3.86 (s, 3H), 3.55-3.46 (m, 1.5H), 2.81-2.61 (m, 2.5H), 2.48-2.21 (m, 2H), 1.84-1.53 (m, 4H); MS(ESI+) m/z 409.4 (M+H)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH2:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:10]1[N:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: BrC1=Cc2ccccc2C1
Reactant: c1cc[nH]c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: C1=C(n2cccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.1 %

Procedure:
In three-necked round-bottom flask (1 L), equipped with an Allihn condenser and magnetic stirrer bar and under an argon atmosphere, to a mixture of 49.0 g (231 mmol) of anhydrous K3PO4, 30.0 g (154 mmol) of 2-bromo-1H-indene, and 11.5 ml (11.1 g, 165 mmol) of pyrrole in 500 ml of toluene and 50 ml of DME, 4.59 g (15.4 mmol) of 2-[di(tert-butyl)-phosphino]biphenyl and 1.73 g (7.70 mmol) of Pd(OAc)2 were added at ambient temperature. This mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered through the layer (d 100 mm, l 40 mm) of SilicaGel 60 (40-63 um) on a glass frit funnel. The SilicaGel layer was additionally washed by 200 ml of methyl-tert-butyl ether (MTBE). The combined extract was evaporated to dryness. The crude product was purified using flash chromatography (SilicaGel 60, 40-63 um, d 40 mm, l 500 mm; eluent hexanes/MTBE=10/1). This procedure gave 5.62 g (20%) of white crystalline product.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[C:23](OC([O-])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in dimethylformamide (100 ml) was added triethylamine (1 ml), followed by tert-butyl dicarbonate (2.05 ml), and this was followed by stirring at room temperature for 1 hour. The solvent was evaporated off under reduced pressure. To the residual oil dichloromethane (50 ml) was added, after which it was washed with a 10% aqueous solution of citric acid, then with water. After drying the organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residual solid was recrystallized with ethyl ether to obtain 1.4 g of a colorless crystal having a melting point of 117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:19]([C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[S:29])[CH:24]=[CH:25][CH:26]=1)#[N:20]>C(OCC)(=O)C.ClCCl>[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: N#Cc1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C#N)c1
Yield: 84.4 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol) and 3-cyanophenyl isothiocyanate (0.649 g, 4.0 mmol). Trituration in boiling ethyl acetate/dichloromethane (1:1) gave the product (1.358 g); m.p. 183-185° C.