Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1>CC#N>[CH3:21][CH:22]1[N:27]([CH2:2][C:3]2[C:11]3[O:10][CH:9]=[CH:8][C:7]=3[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=2)[CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1cc(CBr)c2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc([N+](=O)[O-])cc2ccoc12
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
A mixture of 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol %, 0.39 mmol; Intermediate 64), K2CO3 (162 mg, 1.17 mmol) and tert-butyl 3-methylpiperazine-1-carboxylate (94 mg, 0.47 mmol) in dry MeCN (5 mL) was heated at 80° C. while stirring for 1 h 45 min using a StemBlock. The solvent was evaporated under reduced pressure and the residue was partitioned between water and DCM (×2). The organic layers were combined, dried (Na2SO4) and purified using flashtube (10% MeOH in DCM). This afforded the title product (115 mg, 78%) as a light yellow sticky oil. HPLC 99%, RT=2.47 min (System A; 5-60% MeCN over 3 min), 99%, RT=2.27 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H25N3O5 m/z 376 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of N-tert-butyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 201 mol) in dichloromethane (3 mL) was added trifluoroacetic acid (458 mg, 309 μL, 4.01 mmol) and the reaction mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL) and the mixture stirred at room temperature for 1 h. After concentration in vacuo, the mixture was triturated with water and filtered to collect the solid. The solid was washed with ether and dried to give N-tert-butyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (58 mg, 185 mol, 92%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.18 (s, 1H), 9.11 (s, 1H), 7.90 (d, J=3.2, 1 H), 7.86 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 3.80 (s, 3H), 1.43 (s, 9H); MS (EI/CI) m/z: 314.1 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Cl[C:26]1[C:27]([C:44]#[N:45])=[N:28][CH:29]=[C:30]([C:32]#[C:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][C:35]=2[CH3:43])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:41][N:40]([CH3:42])[C:37]1[CH:38]=[CH:39][C:34]([C:33]#[C:32][C:30]2[CH:29]=[N:28][C:27]3[C:26]([CH:31]=2)=[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]2=[N:8][C:44]=3[NH2:45])=[C:35]([CH3:43])[CH:36]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: Cc1cc(N(C)C)ccc1C#Cc1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)nc(N)c1ncc(C#Cc3ccc(N(C)C)cc3C)cc12
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.3 eq.) and 3-chloro-5-((4-(dimethylamino)-2-methylphenyl)ethynyl)picolinonitrile (from the previous step) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (10 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.17 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-((4-(dimethylamino)-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1cnccn1
Reactant: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnccn3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 22 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.08 0 mL, 0.60 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 30) (202 mg, 0.49 mmol) in DCM (5 mL) and stirred at ambient temperature for 50 minutes. 2-Amino-pyrazine (CAS no. 5049-61-6) (94 mg, 0.98 mmol) and pyridine (0.80 mL, 0.98 mmol) were added and the reaction stirred for 16 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (40 mL), washed with saturated sodium bicarbonate (20 mL), water (10 mL), and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product. The residue was purified by chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to give product (53 mg, 22%). 1H NMR δ300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.59 (m, 2H), 4.24 (t, 2H), 4.70 (t, 2H), 4.94 (t, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.39 (d, 1H), 7.48 (s, 1H), 8.12 (d, 1H), 8.27 (q, 1H), 8.33 (d, 1H), 8.39 (d, 1H), 8.66 (s, 1H), 9.66 (s, 1H); m/z 489 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:19]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:21])[CH3:20]>>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH:19]([CH3:20])[CH3:21])[CH:24]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)Oc1cccc(C(=O)Cl)c1
Reactant: OCCC1(c2ccc(C(F)(F)F)cc2)CCNC1
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCO)(c3ccc(C(F)(F)F)cc3)C2)c1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3-isopropoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C1(=O)[N:5]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH:7]=[CH:8][CH2:9][N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11]1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/Cn1cnc2ncccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC=CCn1cnc2ncccc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
A solution of 1-[(E)-4-phthalimido-2-butenyl]-1H-imidazo[4,5-b]pyridine (2.19 g, 6.87 mmol) in ethanol (100 mL) at room temperature was treated with hydrazine monohydrate (3.33 mL, 68.7 mmol). After 10 min., the reaction mixture was warmed to 60° C. for 2 h, allowed to cool to 25° C., and recooled to 0° C. in an ice bath. The resulting slurry was filtered, and the filtrate was concentrated in vacuo. Purification by flash chromatography (6% NH4OH/ethanol) afforded 0.92 g of the title compound; mass (CI) m/z=211 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:33]
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:16])[O:4][N:3]=1.[CH2:17]([Li])CCC.CCCCCC.CI>O1CCCC1>[CH2:16]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:17]
Reactant: [Li]CCCC
Reactant: Cc1noc(C)c1-c1cc2ccccc2[nH]1
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1onc(C)c1-c1cc2ccccc2[nH]1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 g (0.024 mole) of 2-(3,5-dimethyl-4-isoxazolyl)-indole in 100 ml of dry tetrahydrofuran is cooled to -60° and treated by dropwise addition with 32.4 ml of 1.6 M n-butyllithium in hexane (0.052 mole) maintaining temperature at -60° C. The resulting mixture is then stirred at -60° C. for 30 min. and then treated by dropwise addition of 4.01 g (0.028 mole) of methyl iodide in 10 ml dry tetrahydrofuran. The resulting mixture is stirred at -60° for 4 hours and quenched by the addition of 6 ml saturated ammonium chloride solution. The mixture is then warmed to room temperature and treated with 50 ml of water and extracted with methylene chloride. The organic layers are dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is then purified by filtration through silica gel to give 2-(5-ethyl-3-methyl-4-isoxazolyl)-indole as a viscous oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:9]=3[C:8]([CH2:26][CH3:27])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:29]([OH:32])(=O)=[O:30].[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].S(Cl)(Cl)(=O)=O>ClCCl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C:16]4[CH:21]=[C:20]([S:29]([N:38]5[CH2:39][CH2:40][N:35]([CH2:33][CH3:34])[CH2:36][CH2:37]5)(=[O:32])=[O:30])[CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:9]=3[C:8]([CH2:26][CH3:27])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCOc1ccccc1-c1nc2c(c(CC)nn2C2CCCC2)c(=O)[nH]1
Reactant: CCN1CCNCC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(c(CC)nn2C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.7 %

Procedure:
1-Cyclopentyl-3-ethyl-6-(2-n-propoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (WO 96/28448) (500 mg, 1.36 mmol) was added portionwise to chlorosulphonic acid (1.6 g, 13.6 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was poured into a mixture of ice water (30 ml) and dichloromethane (30 ml) with stirring, the layers separated and the aqueous extracted with dichloromethane (2×30 ml). The combined organic solutions were washed with brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure, to give a foam. N-Ethylpiperazine (108 mg, 0.95 mmol) was added dropwise to an ice-cold solution of this intermediate sulphonyl chloride in dichloromethane (3 ml) and the reaction stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (10 ml), washed consecutively with water (5 ml), saturated sodium bicarbonate solution (5 ml) and brine (5 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 96:4) to afford the title compound, (81 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]1[N:23]([CH:24]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)[N:22]=[CH:21][CH:20]=1.N.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>ClCCl.O>[NH:26]1[CH2:25][CH:24]([N:23]2[C:19]([C:10]3[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=3[OH:8])=[CH:20][CH:21]=[N:22]2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(C(F)(F)F)cc1-c1ccnn1C1CNC1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a stirred solution of tert-butyl 3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate, (Preparation 857, 375 mg, 0.001 mol) in dichloromethane (10 mL) under nitrogen and the solution was stirred for 3 hours. The pink solution was evaporated and the residue dissolved in methanol and then the solvents were removed in vacuo. This was repeated a further two times. The residue was then suspended in diethyl ether and the solvents removed in vacuo to give an off-white foam. The foam was dissolved in water and treated with aqueous ammonia solution (7.5 molar) until pH10 to give a white precipitate. The mixture was extracted with ethyl acetate (6×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×20 mL), dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give a solid. The solid was triturated with diethyl ether to give the title compound as a white solid (200 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:3][CH2:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)[N:22]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2cccc(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cccc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
433 mg (0.264 ml, 3.64 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 400 mg (1.82 mmol) [6-(3-Chloro-phenyl)-pyridin-2-yl]-methanol in 25 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (409 mg, 94%) used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[O:20]1[CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:21]12>C1COCC1>[CH3:1][N:2]1[C:6]([C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:21]2[OH:20])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: C1CCC2OC2CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1O
Yield: 13 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-methylpyrazole (3.66 g, 44.6 mmol), N,N,N′,N′-tetramethylethylenediamine (6.68 mL, 44.6 mmol), n-butyl lithium (1.63 M solution in hexane; 32 mL, 52.2 mmol), 1,2-epoxycycloheptane (5.0 g, 44.6 mmol) and THF (60 mL), to yield the title compound (1.13 g, 13%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[S:37][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[O:20])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[S:37][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][OH:20])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CCn3ccnc3C=O)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc2c(=O)n(CCn3ccnc3CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution (40 mL) of 4′-{[6-ethyl-3-[2-(2-formyl-1H-imidazol-1-yl)ethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (2.2 g) in methanol was added sodium borohydride (0.27 g), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.0 g, 91%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1)#[N:20].[N:36]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[OH:44][CH2:43][CH2:42][N:36]1[CH2:41][CH2:40][N:39]([C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[C:6]([C:30]2[CH:29]=[CH:28][C:27]([C:22]3[C:21]([C:19]#[N:20])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:32][CH:31]=2)=[O:7])=[O:18])[CH2:38][CH2:37]1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: OCCN1CCNCC1
Product: CON=C1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)c2ccc(-c3ccccc3C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and 2-(1-piperazinyl)ethanol, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=476.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH3:50][C:51]([CH3:68])([CH2:65][CH:66]=[CH2:67])[CH2:52][O:53][C:54]([NH:56][C@@H:57]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:58](O)=[O:59])=[O:55].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][C:51]([CH3:68])([CH2:65][CH:66]=[CH2:67])[CH2:52][O:53][C:54]([NH:56][C@@H:57]([C:61]([CH3:63])([CH3:62])[CH3:64])[C:58]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:59])=[O:55]
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 67.1 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of, (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-2-((2,2-dimethylpent-4-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (201 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((2,2-dimethylpent-4-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (235 mg, 0.398 mmol, 67% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83-0.94 (m, 6H) 0.97-1.02 (m, 1H) 1.06-1.10 (m, 1H) 1.12-1.19 (m, 7H) 1.95-2.07 (m, 2H) 2.46-2.59 (m, 1H) 2.88 (d, J=12.80 Hz, 1H) 2.92-3.03 (m, 3H) 3.65-3.74 (m, 1H) 3.74-3.79 (m, 3H) 3.79-3.86 (m, 1H) 4.00-4.09 (m, 1H) 4.14-4.21 (m, 1H) 4.31-4.42 (m, 1H) 4.85-4.92 (m, 1H) 4.95-5.09 (m, 2H) 5.17-5.26 (m, 1H) 5.38-5.49 (m, 1H) 5.67-5.84 (m, 2H) 6.60-6.75 (m, 1H) 7.25-7.30 (m, 1H) 7.30-7.42 (m, 6H) 7.61-7.68 (m, 1H). LCMS: r.t.=2.25 min., [M+H]+=591 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water 5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=2)[CH:17]([CH2:28][CH3:29])[CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[ClH:1].[Cl:27][C:26]1[C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]2[CH2:28][CH3:29])=[N:22][CH:23]=[CH:24][N:25]=1
Reactant: CCC1CN(Cc2ccccc2)CCN1c1nccnc1Cl
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCC1CNCCN1c1nccnc1Cl
Product: Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
1-Chloroethyl chloroformate (2.11 g, 15.2 mmol) was added with a syringe during 1 h to an ice cold (˜0° C.) solution of 4-benzyl-l,-(3-chloro-2-pyrazinyl)-2-ethylpiperazine (3.22 g, 10.1 mmol, from Step 2) in dry CH2Cl2 (30 mL). The reaction was allowed to slowly reach room temperature and stirred for 48 h. The solvent was evaporated from the reaction mixture and MeOH was added to the resulting oil. The mixture was heated to reflux for 2 h, the solvent was evaporated and the resulting oil was partitioned between CHC13/H2O. The aqueous phase was made alkaline and extracted with CHCl3 (×3). The combined organic phases were dried (MgSO4), and the solvent was evaporated. The resulting oil was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5:0.2) as eluent to give a quantitative yield (2.35 g) of the free base of the title compound as a slightly yellow oil. An analytical sample was prepared as its hydrochloric acid salt (from HCl/ether): mp 195-197° C. Anal. (C10H15ClN4.HCl) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:10]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[NH2:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(N)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(N)c(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a degassed solution of 2-bromo-4-methylbenzenamine (0.301 g, 1.618 mmol), phenyl boronic acid (0.296 g, 2.427 mmol), and tetrakistriphenylphosphine palladium(0) (0.187 g, 0.162 mmol) in DME (8 mL) was added 2M sodium carbonate solution (3 ml, 6 mmol) and the mixture was stirred for 16 h at 80° C. Water (30 ml) was added and the product was extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated and purified by silica gel chromatography to provide 2-phenyl-4-methylbenzenamine as a thick syrup (0.22 g, 75% yield). 1H NMR (400 MHz, CDCl3): δ 7.47-7.41 (m, 4H), 7.36-7.32 (m, 1H), 6.99-6.96 (m, 2H), 6.71 (d, J=8.0 Hz, 1H), 2.28 (s, 3H); MS (ESI) m/z: 184.2 (M+H+).