Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45]([OH:47])=[O:46].C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45]([OH:47])=[O:46])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combined filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625 M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625 M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12 N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder.
Reaction SMILES: O[C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[O:13])[CH:5]=[CH:4][C:3]1=2.C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[O:13])[CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: O=Cc1ccc2c(c1)CCC[C@@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCCc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S)-5-Hydroxy-5,6,7,8-tetrahydronapthalene-2-carbaldehyde (19.73 mmol) was dissolved in 50 mL of toluene and cooled to 0° C. Diphenylphosphoryl azide (29.6 mmol, 1.5 eq) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (23.07 mmol, 1.2 eq). After stirring at room temperature overnight, the solvent was evaporated. The residue was purified by SiO2 chromatography (5→30% ethyl acetate in dichloromethane) to afford the title compound. MS (m/z): 204.2 (M+H).
Reaction SMILES: CS(O[C@H:6]([CH3:28])[CH2:7][O:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=O)=O.Cl.[CH:30]12[NH:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][CH2:31]2>>[CH:33]12[N:36]([C@@H:6]([CH3:28])[CH2:7][OH:8])[CH:30]([CH2:35][CH2:34]1)[CH2:31][CH2:32]2
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Reactant: C1CC2CCC1N2
Agent: Cl
Product: C[C@@H](CO)N1C2CCC1CC2

Procedure:
The title compound was synthesized as described in Intermediate 39 (steps 2-3) using (R)-1-(trityloxy)propan-2-yl methanesulfonate and 7-azabicyclo[2.2.1]heptane hydrochloride as starting materials. 1H NMR (DMSO-d6): δ 4.36 (t, 1H), 3.42 (m, 3H), 3.07 (m, 1H), 2.26 (m, 1H), 1.54 (m, 4H), 1.18 (m, 4H), 0.96 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc3ccccc3n2)nc1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
A solution of 2-bromoquinoline (1.00 g, 4.81 mmol) [Aldrich, cat. #716278] in N,N-dimethylformamide (10.0 mL) (degassed with nitrogen) was treated with 2-(tributylstannyl)pyridine (1.83 mL, 4.81 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.337 g, 0.481 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 110° C. for 17 h. The reaction mixture was then diluted with water (50 mL) and ether (50 mL) and filtered over Celite. The solids were washed with additional ether (150 mL). The filtrate was washed with water (150 mL) and brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.771 g, 78%). LCMS calculated for C14H11N2 (M+H)+: m/z=207.1. found: 207.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.Cl[C:10]1C(CCl)=CC=C(Cl)[N:11]=1>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:11][CH3:10])=[CH:5][N:6]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: ClCc1ccc(Cl)nc1Cl
Solvent: ClCCl
Product: CNCc1cnc(Cl)s1

Procedure:
The reaction procedure of Reference Example 11 was repeated except that crude 2-chloro-5-chloromethyl-thiazole was used in lieu of 2,6-dichloro-3-pyridylmethyl chloride and that CH2Cl2 was used as the extractant. The procedure gave the title compound as a crude oil.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O=S(Cl)Cl.[C:20]1([CH3:32])[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH2:30]O)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:30][CH2:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:32])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:11])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Yield: 80.9 %

Procedure:
A mixture of 5-chlorosulfonyl-2-methoxybenzoic acid (Intermediate 6, 3.0 g, 12.0 mmol) and SOCl2 (6 mL) was heated to reflux temperature for 2 h. Then excess SOCl2 was removed by distillation. The resulting residual oil was dissolved in 20 mL of CH2Cl2 and 2-(p-toluenesulfonyl)ethanol (available from Aldrich 2.0 g, 10 mmol) in 10 mL of CH2Cl2 was added at room temperature. The resulting mixture was heated to reflux temperature for 3 h. Thereafter volatile materials were removed under reduced pressure and the residual oil was purified by column chromatography (silica gel, hexane:CH2C2=1:1 to CH2Cl2) to give 3.5 g (81%) of 2-(p-toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate (Intermediate 7) as clear thick oil.
Reaction SMILES: CO[C:3](=[O:20])[C@H:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[NH2:5].[CH3:21][N:22]=[C:23]=[S:24]>>[CH2:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:23](=[S:24])[N:22]([CH3:21])[C:3]1=[O:20])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Reactant: CN=C=S
Product: CN1C(=O)C(CCCNC(=O)OCc2ccccc2)NC1=S

Procedure:
Using an analogous procedure to Example 1 Nδ-benzyloxycarbonyl-L-ornithine methyl ester may be reacted with methyl isothiocyanate to give the title compound
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(-c3cnn(C)c3)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2-c2cnn(C)c2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](O)=O>Cl>[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[NH:1][CH:13]=1
Reactant: COC(=O)c1cccc(N)c1N
Reactant: O=CO
Agent: Cl
Product: COC(=O)c1cccc2nc[nH]c12
Temperature: 25 °C

Procedure:
2.000 g of methyl 2,3-diaminobenzoate are suspended in 35 ml of 4M aqueous HCl. The suspension is admixed at room temperature with 1.350 ml of formic acid and heated to reflux over one hour. The reaction solution is cooled to room temperature and the precipitated solid is filtered off. The filtercake is taken up in 50 ml of methanol and the mixture is heated to reflux until all solids have dissolved. The hot solution is treated with 0.500 g of activated carbon and subsequently clarified by filtration. The filtrate is admixed with 0.62 ml of conc. H2SO4 and heated to reflux over 24 hours. The reaction solution is cooled to room temperature and made neutral with saturated aqueous sodium carbonate solution (6 ml). The mixture is subsequently admixed with 50 ml of water and 100 ml of ethyl acetate, and the phases are separated. The aqueous phase is extracted with ethyl acetate (2×100 ml) and the combined organic phases are subsequently washed with 100 ml of saturated sodium carbonate solution and 100 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a beige solid. Rt=2.02.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH:25][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Powdered 1-chloro-isoquinoline-5-sulfonyl chloride (10.0 g, 38.2 mmol) is added in portions to a stirred solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (7.33 g, 45.8 mmol) and NEt3 (10.7 mL, 76.4 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 4 hours. The mixture is concentrated and chromatographed on silica gel (gradient 0-5% CH3OH in CH2Cl2) to give 13.8 g (35.8 mmol, 94% yield) of the title compound as foam. ESIMS: m/z 386 [(M+H)+, 35Cl], 388 [(M+H)+, 37Cl]. Analysis for C16H20ClN3O4S: calcd: C, 49.80; H, 5.22; N, 10.89; found: C, 49.70; H, 5.22; N, 10.72.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][C:6](=O)[C:2]12[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>C(O)(=O)C>[C:14]([O:16][CH:4]1[C:3](=[O:1])[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH2:5]1)(=[O:15])[CH3:13]
Reactant: O=C(O)CCCCCCC12OC1CCC2=O
Solvent: CC(=O)O
Product: CC(=O)OC1CC=C(CCCCCCC(=O)O)C1=O
Yield: 78.7 %

Procedure:
A solution of (±)-7-(1,2-epoxy-5-oxocyclopentyl)-heptanoic acid (3.0 g) in glacial acetic acid (75 ml) was heated at reflux for 8 hours. The excess acetic acid was then removed in vacuo to give an oil which crystallised on standing. Recrystallisation from a mixture of water and ethanol gave (±)-7-(4-acetoxy-5-oxocyclopent-1-enyl)heptanoic acid (1.4 g), m.p. 62°-65° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[CH3:13].[CH2:15](Br)[CH:16]=[CH:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH2:15][CH:16]=[CH:17][CH3:18])[CH:8]=[CH:7][C:6]=2[CH3:13]
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3,8-Dimethyl-5-hydroxycarbostyril (3 g, 15.86 mmol) was dissolved in dimethylformamide (30 ml). To the solution, crotyl bromide (2.06 ml, 20.45 mmol) and potassium carbonate (4.4g, 31.84 mmol) were added. The mixture was stirred at 70° C. for 2 hours. After spontaneous cooling, water (90 ml) was added to the mixture. Precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform, washed with water and saturated aqueous NaCl solution in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-n-hexane. As a result, 2.43 g of the title compound was obtained as colorless crystals (63%).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g-see Preparation 8), 6-(2-bromoethyl)-1,4-benzodioxan (0.26 g-see Preparation 21), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. On cooling to room temperature, water (40 ml) was added and the mixture was extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give title compound as a colourless foam, yield, 0.21 g.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[C:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CN(C(=O)CCl)C(C)(C)C
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN(C)C(C)(C)C)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 24.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and N-tert-butyl-2-chloro-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.4 mg) was obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:30].FC1C(C#[N:41])=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(CC1C=CC=CC=1C(F)(F)F)C3=O>>[F:29][C:26]([F:28])([F:27])[C:25]1[C:20]([CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:5]4[CH:6]=[C:7]5[C:2](=[CH:3][C:4]=4[O:32][CH2:31]3)[NH:41][N:9]=[CH:8]5)[C:11]2=[O:30])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ncccc2C(F)(F)F)c2ccccc21
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1cc3[nH]ncc3cc12

Procedure:
Following the procedure as described in EXAMPLE 46 and making non-critical variations using 6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile, 1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-one was obtained (47%): mp 152-154° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 12.79 (br s, 1H), 8.80 (d, J=6.0 Hz, 1H), 8.24-8.21 (m, 1H), 7.87 (s, 1H), 7.57-7.53 (m, 1H), 7.26-7.17 (m, 3H), 7.02-6.89 (m, 3H), 5.25 (ABq, 2H), 4.87 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.5, 160.1, 153.2, 152.9, 143.5, 141.6, 135.5, 135.4, 134.1, 132.7, 129.1, 126.7, 124.0, 123.6, 123.2, 122.5, 119.1, 116.0, 109.5, 89.4, 80.0, 56.9, 42.4; MS (ES+) m/z 436.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:13]1[S:14][C:10]([Br:9])=[CH:11][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(Br)s2)c1Br
Yield: 30 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-bromothiophene-2-sulfonyl chloride in 30% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 240° C. (dec).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4(-methyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([Br:38])=[CH:40][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccc(Br)cc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(Br)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 84.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-bromobenzyl chloride (0.75 g) as starting materials, 5-benzyloxy-N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O)C.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5csc(C)n5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), ethanol (0.85 mL), DMF (0.15 mL) and 4-methoxybenzaldehyde (0.022 g, 0.165 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 17 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on preparative silica TLC plates, which were eluted with dichloromethane/methanol (v/v; 9:1). The isolated compound was further purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.010 g, 13%); 1H-NMR (500 Mz, DMSO-d6): δ 2.62-2.73 (m, 4H, piperazine N(CH2)2), 3.18 (s, 3H, Me), 3.60-3.74 (m, 4H, piperazine N(CH2)2), 3.85 (s, 3H, OMe), 4.00-4.20 (br s, 2H, NCH2), 7.11 (d, J=8.5 Hz, 2H, ArH), 7.33 (s, 1H, thiazole 5-H), 8.15 (d, J=9.0 Hz, 2H, ArH), 8.21 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 3.14 min—499/501 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 499.0916, calculated for C22H23BrN6OS (M+H)+: 499.0915.
Reaction SMILES: C([Li])CCC.[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.Br[CH2:23][C:24]([CH3:26])=[CH2:25]>C1COCC1>[CH3:25][C:24](=[CH2:23])[CH2:26][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: C=C(C)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamino (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and coolling to −78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.