Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36]>C1(C)C=CC=CC=1.[Pd]>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:19]1[C:18](=[O:36])[CH:17]([NH:16][CH:10]2[CH2:9][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:13][C:11]2=[O:12])[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]1=2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC2CC(c3ccccc3)OC2=O)CCc2ccccc21
Reaction time: 18 h

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction, the catalyst is filtered off, 50 ml of acetic acid are added and volatiles are distilled off at 110–120° C. inner temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([OH:14])[CH:5]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:11])([CH3:12])[CH3:13])=[C:6]([O:14][CH2:20][CH2:19][CH2:18][O:17][CH3:16])[CH:5]=1
Reactant: COC(=O)c1ccc(C(C)(C)C)c(O)c1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1C(C)(C)C

Procedure:
A mixture of 4-tert-butyl-3-hydroxy-benzoic acid methyl ester (1.56 g, 7.49 mmol), 3-bromopropyl methyl ether (1.72 g, 11.2 mmol) and anhydrous K2CO3 (1.55 g, 11.2 mmol) in MeCN (30 mL) is refluxed overnight. After cooling, the mixture is filtered, the filtrate is diluted with CH2Cl2 and the organics are washed with aqueous 0.5M NaOH, aqueous 0.5M HCl and water, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 97:3) gives the title compound as colorless oil. MS: 281.1 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.22 min. 1H-NMR (CDCl3): δ 1.43 (s, 9H), 2.17 (m, 2H), 3.41 (s, 3H), 3.65 (m, 2H), 3.93 (s, 3H), 4.18 (m, 2H), 7.36 (dd, 1H), 7.96 (d, 1H), 7.60 (dd, 1H) ppm.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[Se:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.BrBr.O.[Br-].[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[C:30]([SeH+]C=2C=1)=[CH:29][C:28](Br)=CC=3>C(O)(=O)C>[Br-:19].[CH2:12]([N:13]([C:3]1[CH:2]=[CH:1][C:14]2[NH:13][C:12]3[C:7]([SeH+:6][C:5]=2[CH:4]=1)=[CH:8][C:9]([N:24]([CH2:23][CH2:22][CH2:21][CH3:20])[CH2:25][CH2:30][CH2:29][CH3:28])=[CH:10][CH:11]=3)[CH2:14][CH2:5][CH2:4][CH3:3])[CH2:11][CH2:10][CH3:9]
Reactant: Brc1ccc2c(c1)[SeH+]c1cc(Br)ccc1N2
Reactant: c1ccc2c(c1)Nc1ccccc1[Se]2
Agent: BrBr
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCN(CCCC)c1ccc2c(c1)[SeH+]c1cc(N(CCCC)CCCC)ccc1N2
Reaction time: 18 h
Yield: 17 %

Procedure:
To a stirred solution of phenoselenazine (1.00 g) in glacial acetic acid (170 cm3), under nitrogen and cooled in an ice-bath was added a solution of bromine (10 cm3) in glacial acetic acid (10 cm3). After 10 minutes the reaction mixture was poured into rapidly stirred water (400 cm3). The resultant 3,7-dibromo-phenoselenazin-5-ylium bromide was deposited as a dark solid and was collected by filtration, washed with diethyl ether and dried. A portion of the product (1.24 g) was added to a vigorously stirred solution of dibutylamine (5.00 g) in dichloromethane (200 cm3) under an atmosphere of nitrogen. The reaction mixture was stirred for 18 hours and then washed successively with water, dilute aqueous hydrobromic acid (5% w/w) and finally water. The organic phase was dried (MgSO4) and the solvent removed by rotary evaporation. Flash column chromatography over silica gel 60 A was performed on the crude material using a mobile phase of chloroform with increasing methanol content to a maximum of 2%. 3,7-Bis-(N,N-dibutylamino)-phenoselenazin-5-ylium bromide was isolated as a dark blue solid in 17% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](Cl)=[S:16])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:16])=[CH:11][CH:10]=1
Reactant: S=C(Cl)N(Cc1ccc(Br)cc1)C1CCCC1
Reactant: Nc1ccccc1
Product: S=C(Nc1ccccc1)N(Cc1ccc(Br)cc1)C1CCCC1
Yield: 0.8 %

Procedure:
Analogously to Example 3, 19 grams (0.2 mole) of aniline were reacted with 34 grams (0.1 mole) of N-4-bromobenzyl-N-cyclopentylthiocarbamoyl-chloride, 0.31 grams of N-4-bromobenzyl-N-cyclopentyl-N'-phenylthiourea were obtained. Yield: 80%. Melting point: 129°-131° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[C:25]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=2)[CH2:10][CH2:11][C:2]1([CH3:18])[CH3:1])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
3.0 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 11) were added to 30 ml of pyridine, and 2.6 g of benzoyl chloride was further added to the solution. The mixture was stirred at room temperature for 15 hours, followed by addition of ice-water and extraction with ether. The ethereal solution was washed with 10% hydrochloric acid, water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Ether was distilled off to give 3.9 g of methyl 2-(1-benzoyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 17).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[NH:11]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:11]2[CH:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:17])[CH2:13][CH2:14][CH2:15][NH:10]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCCCCc1ccccc1)C1CCCNN1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCCc1ccccc1)C1CCCNN1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Cyclohexylisocyanate (0.38 g, 3.0 mmol) was added to a CH2Cl2 solution containing 4-phenylbutyl perhydropyridazinecarboxylate (0.72 g, 2.75 mmol) and triethylamine (0.42 ml, 3 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere, and then diluted to 50 ml CH2Cl2. The organic layer was washed with water, dried, and concentrated. The crude material was purified by silica gel column to yield 0.95 g (89%) final product as clear oil. Rf=0.28 (2:1 hexane:EtOAc). 1H NMR (CDCl3, 400 MHz): δ 1.10 (m, 3H); 1.33 (m, 3H); 1.69 (m, 10H); 1.88 (m, 2H); 2.62 (m, 2H); 2.72 (m, 1H); 2.87 (m, 1H); 3.60 (m, 1H); 4.13 (m, 3H); 4.38 (m, 1H); 5.11 (d, 1H, J=8.3); 7.23 (m, 5H). Anal. Calcd. for C22H28N3O3-0.14H2O: C, 67.75; H, 8.60; N, 10.77. Found: C, 67.75; H, 8.45; N, 10.90.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>CO>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1

Procedure:
15 g (49.12 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] are dissolved in 150 ml of methanol, and this solution is treated with 0.75 g of Nishimura catalyst and hydrogenated (RT, standard pressure) until there is no further uptake of hydrogen. The catalyst is filtered off, the solvent is removed, and the residue is chromatographed on silica gel (toluene/ethyl acetate, 5:1). The title compound is obtained as a thick, viscous oil. IR (CH2Cl2) inter alia: 3431, 1774, 1711, 1501 und 1170 cm-1. FAB-MS (M+1)+ =312. 1H-NMR (DMSO-d6) inter alia: 6.80 (d, 1H); 4.40 (m, 1H); 3.66 (m, 1H); 2.58-2.43 (m, 2H); 2.37 (dxq, 1H); 2.14 (m, 1H) and 1.39 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[CH:17]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc(F)c(N)c(Cl)c2)cc1OC
Yield: 31.3 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.442 mmol) and 3,4-dimethoxyphenylboronic acid (80 mg, 0.62 mmol) as a pale-yellow solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:7]=1)(=[O:4])=[O:3].C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[CH3:1][S:2]([O:5][C:6]1[N:7]=[C:8]2[N:13]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:25]([OH:26])=[N:12][C:9]2=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)Oc1ccc(N)c(NC2CCCCC2)n1
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc2nc(O)n(C3CCCCC3)c2n1
Temperature: 70 °C
Yield: 61.1 %

Procedure:
5-Amino-6-(cyclohexylamino)pyridin-2-yl methanesulfonate (1.44 g, 5.05 mmol) was dissolved in THF (30 mL) and CDI (2.455 g, 15.14 mmol) was added. The mixture was heated at 70° C. for 3 h. THF was removed and the residue was dissolved in EtOAc. The resulting solution was washed with water followed by 1 M HCl, dried over MgSO4 and concentrated under reduced pressure to give the title compound (0.96 g) without further purification. LCMS m/z=312.50 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[O:12])[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cccc3cc[nH]c23)CC1
Reaction time: 1 h
Yield: 48 %

Procedure:
Indole-7-carboxylic acid (3.20 g, 0.020 mole) was dissolved in 30 ml of dimethylformamide (DMF) and chilled with an ice-water bath. N,N'-Carbonyldiimidazole was added (3.3 g, 0.020 mole) and the reaction mixture was stirred for 1 hour in the cold. At the end of this time N-methylpiperazine was added (2.5 g, 0.025 mole) and the reaction was allowed to come to room temperature overnight (about 16 hours). The DMF was removed under reduced pressure and the residue was passed over a column of basic alumina (50% methanol-ether) to remove residual imidazole.Recrystallization of the product from CH2Cl2 -pentane gave 2.35 g (48%) of 1-(1H-indole-7-ylcarbonyl)-4-methylpiperazine, m.p. 176°-178° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17]>C(N(CC)CC)C.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.[Cu]I>[Cl:12][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH2:15][N:14]([CH3:18])[CH3:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCN(C)C)cc1Cl
Temperature: 60 °C

Procedure:
To a stirred solution of 4-bromo-2-chlorobenzoic acid, methyl ester (18.69 g) in triethylamine (110 ml), was added 1-dimethylamino-2-propyne (12.1 ml), bis(triphenylphosphine)palladium(II) chloride (1.26 g), and copper(I) iodide (0.136 g). The mixture was heated slowly to 60° C., and the temperature maintained for one hour. The reaction was cooled to room temperature, filtered through diatomaceous earth, and the collected solid washed with ethyl acetate. The solvent was removed in vacuo, the resulting residue redissolved in ethyl acetate, and washed with water (3×). The combined organic extract was dried over anhydrous sodium sulfate, and the solvent removed in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel (225 g), eluting with 40% ethyl acetate/hexane. After removing the solvent in vacuo, the title compound was obtained as a viscous oil (17.7 g), MS (+FAB), m/z: 252 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: Oc1ccc(F)cc1F
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCOc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorophenol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenoxy)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=397.1). 1H NMR (DM50-d6, 400 MHz) δ 4.41 (m, 2H), 4.53 (m, 2H), 6.63 (m, 1H), 6.72 (m, 1H), 6.99 (m, 1H), 7.23 (m, 4H), 7.55 (br s, 2H, NH2), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6O2+0.5H2O): C, 56.30; H, 3.73; F, 9.37; N, 20.73; 0, 9.87. Found C, 56.36; H, 3.59; N, 18.51.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][C:12]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([NH:22][C:10]1[C:9]([NH2:8])=[CH:14][CH:13]=[C:12]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(NC(=O)c2ccccc2C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(N)c(NC(=O)c2ccccc2C(C)(C)C)c1
Reaction time: 12 h
Yield: 98 %

Procedure:
To a mixture of N1-(t-butoxycarbonyl)-N2-(t-butylbenzoyl)-4-(ethoxycarbonylmethoxy)-1,2-benzenediamine (878 mg, 1.87 mmol) and CH2C12 (20 mL) was added TFA (1.5 mL, 19.5 mmol). After 12 h, the reaction was diluted with CH2Cl2 (300 ml) and washed with sat. aq. NaHCO3 (3×50 mL). The organic layer was MgSO4 dried, and concentrated. The crude material was chromatographed (65 g silica, 20% EtOAc/hexanes to 50% EtOAc/hexanes) to give the title compound (98%); IR(CHCl3): 1176, 1512, 1668, 1755, 2968 cm−1; NMR(300 MHz, DMSO-d6): 1.22 (t, 3H, J=7.2 Hz); 1.33 (s, 9H); 4.17 (q, 2H, J=7.2 Hz); 4.62 (s, 2H); 6.64 (d, 1H, J=8.7 Hz); 6.74 (d, 1H, J=8.7 Hz); 6.95 (d, 1H, J=3.0 Hz); 7.54 (d, 2H, J=8.7 Hz); 7.91 (d, 2H, J=8.1 Hz); 9.59 (s, 1H); MS(FD): 370.
Reaction SMILES: Br[C:2]1[N:21]=[C:20]([N:22]2[CH2:26][C@@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[CH2:23]2)[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:19]2[C:20]([N:22]3[CH2:26][C@@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[CH2:23]3)=[N:21][CH:2]=[C:3]([C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)=[O:5])[CH:18]=2)[CH:34]=[N:35][CH:36]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](CO)[C@H](O)C2)nc1Br
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using bromo-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 92.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.93 min, m/z=493.2 [M+H], m/z=491.4 [M−H]+, m/z=537.4 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.18 (m, 1H) 2.83-2.96 (m, 1H) 3.07-3.18 (m, 1H) 3.18-3.32 (m, 2H) 3.41-3.50 (m, 2H) 3.93-4.03 (m, 1H) 4.62-4.71 (m, 1H) 4.99 (d, J=4.27 Hz, 1H) 7.36 (d, J=9.03 Hz, 2H) 7.82-7.93 (m, 3H) 8.08 (d, J=2.38 Hz, 1H) 8.52 (d, J=1.63 Hz, 1H) 8.61 (d, J=2.63 Hz, 1H) 8.78 (d, J=2.38 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[CH:9]=[C:8]([F:15])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][C:13](=[S:14])[NH:12][C:10]1[CH:9]=[C:8]([F:15])[CH:7]=[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=S)Nc1cc(F)cc(OC(C)(C)C)c1
Temperature: 0 °C

Procedure:
1-tert-Butoxy-3-fluoro-5-isothiocyanatobenzene (24.0 g) and triethylamine (10.9 g) are dissolved in iso-propanol (150 ml). The reaction mixture is refluxed for 18 hours and the solvent is removed by vacuo. The crude product is dissolved in hexane: diethyl ether (19:1). The diethyl ether is removed in vacuo and the solution is cooled to 0° C. for 3 hours. The solution is filtered to give the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:27]3[N:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]4=[N:30][C:26]=3[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:35])=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C>[Br:1][C:22]1[CH:21]=[C:20]2[C:25]([C:26]3[N:30]=[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][N:28]4[C:27]=3[N:18]([C:15]3[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=3)[C:19]2=[O:35])=[CH:24][CH:23]=1
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
N-Bromosuccinimide (1.2 equiv., 0.358 mmol, 0.061 g) was added to a solution of 1 (1.0 equiv., 0.295 mmol, 0.105 g) in DMF (3 ml). The reaction mixture was stirred at room temperature for 4 h. Water was added, the resulting precipitate was isolated by filtration and washed with water, isopropanol and isopropyl ether successively to give 3-bromo-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (101) (0.050 g, yield=36%, purity (LC)=93%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[CH2:21]Br)[C:10]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]>CN(C=O)C.COC(C)(C)C>[C:1]([O:4][CH2:21][C:20]1[CH:19]=[CH:18][C:9]([C:10](=[O:11])[NH:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])=[CH:8][C:7]=1[Br:6])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(CBr)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(C(=O)NC[Si](C)(C)C)cc1Br
Yield: 39.1 %

Procedure:
A mixed solution of sodium acetate (2.8 g), 3-bromo-4-(bromomethyl)-N-[(trimethysilyl)methyl]benzamide (6.5 g) in DMF (30 ml) was stirred for 3 hours at 70° C. The reaction liquor was returned to room temperature and diluted with t-butyl methyl ether. The mixture was washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After separating the drying agent by filtration, the reaction liquor was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-bromo-4-{[(trimethysilyl)methyl]carbamoyl}benzyl acetate (2.4 g).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:23]
Reactant: O=C1c2ccccc2C2CNCCN12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1NCCN2C(=O)c3ccccc3C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindol-6-one (described in Example 8, 7.5 g, 0.04 mol) in 150 ml of benzene is added to sodium hydride (1.7 g of a 50% dispersion in mineral oil, 0.036 mol) in 200 ml of benzene and stirred at room temperature for 30 min. A solution of ethyl bromoacetate (8.8 g, 0.044 mol) in 150 ml of benzene is added and the reaction is refluxed with stirring for 3 hr and cooled. Water is cautiously added and the benzene layer is separated, washed with water, dried, and evaporated. The residue is chromatographed on silica gel using 50% acetone in benzene and the eluates are evaporated to give 6-oxo-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-1-acetic acid ethyl ester (5.5 g), nmr (CDCl3) δ1.3(t), 2.4-2.6(m), 2.8-3.5(m), 4.2(q), 4.6(m) and 7.3-7.7(m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([O:16][CH3:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.[NH2:21][C:22]1[C:30]([C:31](O)=[O:32])=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][C:23]=1[CH3:34].S(Cl)(C)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:15][C:31](=[O:32])[C:30]4[C:29]5[NH:28][N:27]=[CH:26][C:25]=5[CH:24]=[C:23]([CH3:34])[C:22]=4[N:21]=3)=[CH:11][C:10]([O:16][CH3:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid (40 g, 157 mmol) and acetonitrile (1000 mL) was added 6-amino-5-methyl-1H-indazole-7-carboxylic acid (30 g, 157 mmol). To the resulting brown suspension were added sequentially pyridine (57 mL, 706 mml) and dropwise mesylchloride (43 mL, 549 mmol). The reaction mixture was stirred for 6 h at 50° C. and 15 hours at ambient temperature. The reaction mixture was concentrated in vacuo. The residue was suspended in water and stirred for 15 min. The resulting yellow suspension was filtrated. The filtercake was washed sequentially with water and heptane/AcOEt 2:1 and dried to afford the title compound as beige powder, which was submitted to the next step without further purification. LC/MS: 409 (M+H)+.