Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18].Br[CH2:23][C:24]1[C:36]([F:37])=[CH:35][C:27]([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])=[C:26]([F:38])[CH:25]=1>CS(C)=O.Cl>[Cl:7][C:8]1[CH:9]=[C:10]([O:21][CH2:23][C:24]2[C:36]([F:37])=[CH:35][C:27]([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])=[C:26]([F:38])[CH:25]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: Oc1cnc(OCCC(F)(F)F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(COc2cnc(OCCC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Potassium carbonate (61 mg, 0.229 mmol) was added to a solution of 5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-ol (Preparation 67, 45 mg, 0.19 mmol) in DMSO (2 mL) and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 5 minutes. 4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 10, 63 mg, 0.19 mmol) was then added and the resulting mixture stirred under nitrogen at room temperature for 120 hours. The reaction mixture was diluted with aqueous hydrochloric acid solution (2 M, 15 mL), extracted with EtOAc (20 mL). The organic layer was washed with aqueous hydrochloric acid solution (2 M, 2×10 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude solid was triturated with TBME/heptane (2:1), washed with heptane and dried in vacuo to yield the title compound as an off-white solid (73 mg, 74%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2([C:21](OCC)=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:16]1)(=[O:9])=[O:10]
Reactant: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Cl)N1CCN(C2(CO)CCC2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 8 %

Procedure:
Ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclobutanecarboxylate was dissolved in THF (1 ml). Lithium aluminum hydride (0.5 ml, 1.0 M in THF) was added at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes. It was quenched by careful addition of H2O at 0° C. The mixture was stirred for another 30 minutes before 1N NaOH and equal volume of brine were added. The mixture was extracted with EtOAc three times. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 7% MeOH/CH2Cl2) to give the title compound (20 mg, 8% 3 steps) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 1.38-1.48 (m, 1 H), 1.67-1.78 (m, 1 H), 1.80-1.89 (m, 1 H), 1.91-2.00 (m, 1 H), 2.34-2.51 (m, 4 H), 2.56-2.68 (m, 2 H), 2.64 (bs, 1 H), 3.28-3.31 (m, 4 H), 3.57 (ddd, J=16.8, 10.9, 5.9 Hz, 2 H), 7.36-7.41 (m, 1 H), 7.45-7.53 (m, 2 H), 8.01 (dd, J=7.8, 1.5 Hz, 1 H); ESI-MS: m/z 345.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=N)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([N:23]=[C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Dissolve 2-(R)-(2-(R)-amino-1-(S)-hydroxy-3-phenylpropyl)-piperazine-1-carboxylic acid tert-butyl ester (98 mg, 0.29 mmol) in dry dichloromethane and add benzophenoneimine (0.083 ml, 0.49 mmol) by syringe, stir overnight, and purify (silica gel chromatography, eluting with ethyl acetate and 98:2 ethyl acetate:triethylamine) to obtain (144 mg, 95% yield) of the title compound (144 mg, 95%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(O)(C)C>[O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
2.4 Grams of 6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril and 1.6 g of sodium iodide were mixed with 60 ml of isopropanol and the mixture was stirred at 40°-50° C. for 2 hours. Then to this reaction mixture were added 2.0 g of 4-phenylpiperazine and 3.0 g of DBU (1,5-diazabicyclo[5,4,0] undecane-5) and refluxed by heating for 6 hours. Then the reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate solution and stirred at a room temperature for 1 hour. The insoluble matters were collected by filtration, washed with water and dried, then recrystallized from ethanol-chloroform to obtain 1.9 g of 6-[1-oxo-3-(4-phenylpiperazinyl)-propyl]-3,4-dihydrocarbostyril in colorless flake-like crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:47][CH2:48][CH2:49][NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:50][CH2:49][CH2:48][OH:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCO)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 2-hydroxylethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3074.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([NH2:15])=O)[CH2:5][CH2:6][Cl:7]>O=S(Cl)Cl.N#N>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]#[N:15])[CH2:5][CH2:6][Cl:7]
Reactant: NC(=O)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N#N
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
A solution of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (1) (VII) (0.20 g, 0.57 mol) in SOCl2 (5 mL) was heated under reflux in N2 for 84 h. Excess SOCl2 was removed under reduced pressure, and the residue was chromatographed on silica gel. Elution with EtOAc/petroleum ether (3:7) gave 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzonitrile (7) (Ic: X=Cl, R=CN) (0.16 g, 87%), mp (CHCl3) 127° C. 1H NMR (CD3COCD3) δ 8.79 (s, 1 H, H-3), 8.19 (s, 1 H, H-6), 3.93 (s, 8 H, NCH2CH2Cl). 13C NMR δ 148.55 (C-5), 140.98, 139.07 (C-2,4), 129.50, 126.10 (C-3,6), 115.05 (C-1), 112.84 (CN), 54.18 (CH2N), 42.20 (CH2Cl). Anal. (C11H10Cl2N4O4) C,H,N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Br-].O1CCOC1[C:15]1[S:19][C:18]([Zn+])=[CH:17][CH:16]=1>O1CCCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:19]1[CH:15]=[CH:16][CH:17]=[C:18]1[C:6]1[CH:5]=[CH:4][N:3]=[CH:2][N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: [Zn+]c1ccc(C2OCCO2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1csc(-c2ccncn2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a degassed 0.50 M solution of 2,4-dichloropyrimidine (1.0 eq.) and 5-(1,3-dioxolan-2-yl)-2-thienylzinc bromide 31 (1.0 eq.) in tetrahydrofuran was added tetrakis(triphenylphosphine)palladium(0) (0.050 eq.). The mixture was stirred for 16 h at 70° C. and then returned to ambient temperature and diluted with ether. The solution was washed sequentially with a 0.5 M aqueous pH 9 solution of EDTA and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (1:1:1 hexanes:ethyl acetate:dichloromethane) to give compound 32. ES/MS m/z 269 (MH+), C11H9ClN2O2S=269 g/mol.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[N:5]=[C:4]([CH2:14][CH3:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)CCC>[CH2:14]([C:4]1[N:3]=[C:2]([NH:17][NH2:18])[C:7]2[S:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[N:5]=1)[CH3:15]
Reactant: CCc1nc(Cl)c2c(n1)N(C)C(=O)CS2
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CCc1nc(NN)c2c(n1)N(C)C(=O)CS2
Yield: 81.2 %

Procedure:
4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido-[5,4-b][1,4]thiazin-7-one from Example 119 (2.4 g, 9.93 mmole) was suspended in approximately 100 ml of n-butanol. Hydrazine monohydrate (0.99 g, 19.9 mmole) was added and the resultant mixture was refluxed for about 20 hours. The reaction mixture was allowed to cool and the precipitate was separated by filtration, washed with water and dried, providing 1.93 g (81%) of 6,7-dihydro-2-ethyl-4-hydrazino-8-methylpyrimido [5,4-b][1,4]thiazin-7-one. Infrared and nuclear magnetic resonance spectral analyses confirmed the structural assignment.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[F:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([NH:23][C:24]2[CH:25]=[C:26]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]5[CH2:42][CH:41]5[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH:44]=[CH:45][C:46]=2[F:47])=[O:10])[N:5]([CH3:11])[N:4]=1)[CH3:2]
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (158 mg, 1.03 mmol) in tetrahydrofuran (3.8 mL) were added N,N-dimethylformamide (20 μL, 0.26 mmol) and oxalyl chloride (90 μL, 1.03 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (250 mg, 0.73 mmol) in N,N-dimethylacetamide (5.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate alone) and recrystallized from hexane/ethyl acetate to give the title compound (201 mg, 57%) as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1ccc2ccccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccc2ccccc2c1
Yield: 78.5 %

Procedure:
105 g (0.48 mol) of 25 and 90 g (0.5 mol) of N-bromosuccinimide were dissolved in 2000 cm3 of tetrachloromethane at room temperature, 3 g of azobisisobutyronitrile were added, and the mixture was refluxed for 4 hours. The succinimide which precipitated was filtered off, the solvent was removed in vacuo, and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1), giving 112 g (79%) of 26 as a colorless lachrymatory oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][O:15][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OCCF)cc1O
Product: COC(=O)c1ccc(OCCF)cc1OCC(C)(C)CNC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 4-(2-fluoroethoxy)-2-hydroxybenzoate (3.6 g, 17.8 mmol) is alkylated with 3-tert-butoxycarbonylamino-2,2-dimethylpropanol (3.62 g, 17.8 mmol) to afford methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)benzoate (5.12 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[N:4][C:5]([N:30]([CH2:36][CH2:37][O:38][CH3:39])[CH2:31][C@@H:32]2[CH2:34][C@H:33]2[CH3:35])=[CH:6][C:7]=1[C:8]1[O:12][C:11]([C@@:13]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][N:9]=1.O[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:40]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[N:4][C:5]([N:30]([CH2:36][CH2:37][O:38][CH3:39])[CH2:31][C@@H:32]2[CH2:34][C@H:33]2[CH3:35])=[CH:6][C:7]=1[C:8]1[O:12][C:11]([C@@:13]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][N:9]=1
Reactant: OCc1ccccn1
Reactant: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c(Cl)c(NS(C)(=O)=O)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c(Cl)c(N(Cc2ccccn2)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of tert-butyl (1R)-1-(5-{3-chloro-6-((2-methoxyethyl){[trans-2-methylcyclopropyl]methyl}amino)-2-[(methylsulfonyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethylcarbamate (intermediate 8.4.2, 0.028 g, 0.043 mmol) in toluene (1 ml) at 0 oC was added 2-(hydroxymethyl)pyridine (0.004 ml, 0.043 mmol) and triphenylphosphine (0.011 g, 0.043 mmol) followed by diisopropyl azodicarboxylate (0.008 ml, 0.043 mmol). The ice bath was removed and the solution stirred at room temperature overnight. The next day the solution was concentrated in vacuo, taken up in DMF and filtered. The product was purified by reverse phase HPLC affording 0.015 g of tert-butyl (1R)-1-(5-{3-chloro-6-((2-methoxyethyl){[trans-2-methylcyclopropyl]methyl}amino)-2[(methylsulfonyl)(pyridin-2-ylmethyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethylcarbamate LCMS [M+H]740.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc(CC(=O)Nc2nc(-c3c[nH]c4ncccc34)cs2)c1
Yield: 55 %

Procedure:
2-(3-Nitro-phenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1 g, 2.6 mmol) was dissolved in MeOH (100 ml) and added 10% Pd/C (100 mg) followed by ammonium formate (3eq, 500 mg). The reaction mixture was refluxed overnight. Then the reaction mixture was filtered and concentrated to give a white solid. The solid was taken up in EtOAc, filtered again, concentrated to give white solid. (500 mg, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:45]([N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:48]([O:47][C:45]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:54][CH2:53]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCCc1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a solution of 1 g 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 15 ml CH2Cl2 1.5 ml N-NEM and subsequently 962 mg TOTU were added. After stirring for 1 h at RT 881 mg Boc-(4-amino)piperidine in 5 ml CH2Cl2 were added and the mixture was stirred for additional 2 h followed by addition of 20 ml saturated NaHCO3 solution. The organic layer was separated and dried over Na2SO4 and the solvent evaporated. The residue was recrystallized from ethyl acetate/heptane to afford a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[C:32]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:33]=[C:34]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:35]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[C:32]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:33]=[C:34]([N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)[CH:35]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(N5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc(N6CCOCC6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 86 %

Procedure:
(S)—N-(3-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-morpholinophenyl)methanesulfonamide (27 mg, 0.02 mmol) was treated with trifluoroacetic acid (0.45 ml, 5.84 mmol) and a solution of ammonia (7N in methanol, 0.45 ml, 3.15 mmol) according to the method described in Example 27 to give 11 mg (71% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1

Procedure:
Starting from compound D1 and 4-bromo-benzenesulfonyl chloride the title compound can be obtained analogously as described for compound D2.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se-:9][Se-:10].[Mg+2].Cl>O>[CH2:1]([Se:9][Se:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: [Se-][Se-]
Agent: Cl
Agent: [Mg+2]
Solvent: O
Product: c1ccc(C[Se][Se]Cc2ccccc2)cc1

Procedure:
About 12.6 grams (0.1 moles) benzylchloride is now added by dropwise addition over a period of 15 minutes to the magnesium diselenide reagent. In about 5 to 10 minutes after the mixture of these materials, the reddish brown color of the solution appears discharged. This solution is diluted further by the addition of 200 milliliters water and the addition of 10 milliliters concentrated hydrochloric acid. Upon cooling of this solution, the solids contained within the flask are collected by filtration and recrystallized from ethanol. Yield: 14 grams of yellow crystals (m. p. 94° C). Infrared spectral analysis of this material confirms that it is dibenzyl diselenide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:14][C@H:15]3[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]3)=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[CH:31]=[CH2:32].[ClH:33]>>[ClH:33].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:14][C@H:15]3[CH2:19][NH:18][C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]3)=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[CH:31]=[CH2:32]
Reactant: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(=O)[nH]c2cc1OC
Agent: Cl
Product: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(=O)[nH]c2cc1OC
Reaction time: 1.5 h

Procedure:
To the product from Step 3, 1-tert-butyl 2-methyl (2S,4R)-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate (2.02 g, 4.54 mmol) was added HCl (4M in dioxane) (22.72 ml, 91 mmol) at r.t. After 1.5 h, the solvent was removed in vacuo. The residue was taken up in Et2O and the solvent was removed in vacuo to yield 1.73 (99%) g of the title compound as a tan solid. LRMS ESI+ (M+H)+ 345.4.