Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:46][N:47]([CH3:59])[C:48]1[C:53]([C:54]#[N:55])=[C:52]([F:56])[C:51]([CH:57]=O)=[CH:50][CH:49]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:37]([CH2:36][C:12]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:57][C:51]3[C:52]([F:56])=[C:53]([C:48]([N:47]([CH3:59])[CH3:46])=[CH:49][CH:50]=3)[C:54]#[N:55])[CH2:5][CH2:6]2)[CH2:13]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CN(C)c1ccc(C=O)c(F)c1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1ccc(CN2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)c(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (200 mg, 0.4 mmol) in THF (10 mL) and triethylamine (0.1643 mL, 1.179 mmol) was added 6-(dimethylamino)-2-fluoro-3-formylbenzonitrile (75.52 mg, 0.3929 mmol). The solution was stirred at room temperature for 30 minutes before the addition of sodium triacetoxyborohydride (249.8 mg, 1.179 mmol). The mixture was stirred at room temperature overnight. After addition of aqueous NaHCO3, and EtOAc, the organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. Purification by HPLC afforded 150 mg of the product 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile as a white solid. LC/MS: 669.2 (M+H)+.
Reaction SMILES: C([N:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5]1=[O:26])C=C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1COCC1.O>C([O-])(O)=O.[Na+].C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C@@H:8]3[NH:4][C:5](=[O:26])[CH2:6][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: C=CCN1C(=O)CC[C@@H]1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC[C@H](c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)N1
Temperature: 25 °C

Procedure:
Under argon, (5R)-1-allyl-5-[4′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]-2-pyrrolidinone (XVII-1) (0.41 g, 1.14 mmol) is initially charged in a Schlenk tube together with Pd[PPh3]4 (131.7 mg, 0.114 mmol) and p-toluenesulphonic acid hydrate (0.52 g, 2.74 mmol), and THF (2 ml, degassed) and 1 ml of H2O are added. The yellow suspension is heated under reflux for 3 h. For work-up, the mixture, which was cooled to room temperature, is diluted with NaHCO3 solution and admixed with ethyl acetate and filtered through kieselguhr. The combined organic phases are dried (Na2SO4) and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[NH2:31]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:12][CH:13]([C:25]3[O:26][N:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)[N:29]=3)[CH2:14][N:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:16]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Product: CS(=O)(=O)c1ccc(C2CC(c3nc(-c4cccc(C(F)(F)F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.15 mmol) of the compound from Example 198A and 46 mg (0.23 mmol) of N′-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 2. Yield: 61 mg (69% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18]O)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([Cl:14])[C:5]=2[N:15]=1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:14][C:6]1[C:5]2[N:15]=[C:2]([NH2:1])[N:3]([CH2:16][CH2:17][CH2:18][Cl:22])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1CCCO
Solvent: ClCCCl
Product: Nc1nc2c(Cl)nc3ccccc3c2n1CCCCl
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 103.6 %

Procedure:
To a round-bottomed flask containing 3-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (7.17 g, 25.9 mmol) was added 1,2-dichloroethane (210 mL) and the suspension was stirred for 5 minutes. To the stirred suspension was added thionyl chloride (5.6 mL, 77.7 mmol) and the reaction was heated to 50° C. overnight. The reaction was cooled to ambient temperature, filtered, and the residue was washed with 1,2-dichloroethane (100 mL) and diethyl ether (3×100 mL) to afford the product. The product was dried under reduced pressure to afford 4-chloro-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-2-amine (7.92 g) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][CH2:28][C@@:29]1([OH:58])[C:34](=[O:35])[O:33][CH2:32][C:31]2[C:36]([N:38]3[C:50](=[CH:51][C:30]1=2)[C:49]1N=C2C(C(CC[Si](C)(C)C)=CC=C2)=C[C:40]=1[CH2:39]3)=[O:37]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:27][CH2:28][C@@:29]1([OH:58])[C:34](=[O:35])[O:33][CH2:32][C:31]2[C:36]([N:38]3[C:50](=[CH:51][C:30]1=2)[C:49]1[C:40](=[C:8]([CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:39]3)=[O:37]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CC[Si](C)(C)C)cccc3nc2-1
Reactant: C[Si](C)(C)CCC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To a solution of 1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one (3) (34 mg) and CDE ring moiety (4) (24 mg) in acetic acid (0.5 mL) and toluene (1 mL) was added p-toluenesulfonic acid (1 mg). The reaction solution was stirred for 20 hours at 100° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and the residue was washed with hexane (10 mL), water (10 mL), and a mixture of acetone (5 mL) and hexane (5 mL). The yellow solid was evaporated to dryness in vacuo to yield 39 mg (98% Yield) of BNP1350 (Karenitecin; Cositecan; 7-(2′-trimethylsilyl)ethyl camptothecin; IUPAC Nomenclature: (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′:4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]2[C:7]3[C:12]([CH2:13][CH2:14][C:3]=12)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3.[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN1CCCC1=O.C(Cl)(Cl)Cl.CCOC(C)=O.CCCCCCC>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([N:5]4[C:4]5[C:7]6[C:12]([CH2:13][CH2:14][C:3]=5[CH2:2][O:6]4)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=6)[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccc2c(c1)-c1noc(Cl)c1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)C1=C(CC2)CON1N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole (2.0 g, 8.51 mmol), 4-(6-fluorobenzisoxazol-3-yl)-piperidine (2.8 g, 12.76 mmol) and K2CO3 (2.35 g, 17.02 mmol) in 10 ml of N-methylpyrrolidinone under N2 was lowered into an oil bath preheated to 150° C. The mixture was heated while stirring under N2 for 90 minutes. At that time TLC (CH2Cl2) showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature. Upon dilution of the reaction mixture with H2O, a solid precipitated which was collected, dried, dissolved in CH2Cl2 and filtered through neutral alumina. The fractions containing desired product were combined and concentrated, and the resultant solid obtained was triturated with Et2O to provide a solid, mp of 181°-183° C., homogeneous by TLC [silica, 2:1 Heptane:EtOAc, Rf=0.15]. The IR (CHCl3), NMR (CDCl3) and Mass Spectrum (M+ =419, EI, 70 eV) were consistent with the structure. The yield was 1.1318 g (2.70 mmol, 31.70%).
Reaction SMILES: C([O:8][C@H:9]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][Cl:16])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]=O>[Cl:16][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH2:10][C@@H:9]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[OH:8])=[O:17]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OCc1ccccc1
Agent: O=[Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(=O)CCCCl

Procedure:
A solution of 0.4 g of (R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 20 ml of glacial acetic acid is treated with 0.120 g of palladium oxide and hydrogen. The catalyst is removed by filtration under suction and the filtrate is dried under reduced pressure. There is obtained (R)-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine of melting point 48° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:20]=[N:21][N:22](COCC[Si](C)(C)C)[CH:23]=3)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:32][N:33](COCC[Si](C)(C)C)[C:34]([NH:35][CH:36]3[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]3)=[C:11]2[N:10]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)[CH:15]=[CH:14][C:13]=2[C:12]2[NH:32][N:33]=[C:34]([NH:35][CH:36]3[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc3c(c2)c(-c2c(F)cccc2F)nc2c(NC4CCN(S(C)(=O)=O)CC4)n(COCC[Si](C)(C)C)nc23)cn1
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(-c4cn[nH]c4)ccc23)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 10.3 %

Procedure:
73 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2H-pyrazolo[4,3-c]isoquinolin-3-amine are introduced into 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.58 ml of TFA is added and the mixture is stirred at RT for 5 h. The reaction mixture is concentrated under RP and the solid obtained is taken up in 23 ml of water, neutralized with 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and then with a DCM/methanol mixture (90/10 by vol.), to give 5 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow solid). 1H NMR: 1.61-1.74 (m, 2 H) 2.06-2.16 (m, 2 H) 2.87 (s, 3 H) 2.89-2.95 (m, 2 H) 3.52-3.60 (m, 2 H) 3.75-3.84 (m, 1 H) 5.98 (d, J=8.2 Hz, 1 H) 7.31 (t, J=8.0 Hz, 2 H) 7.65-7.71 (m, 2 H) 7.82-7.88 (broad m, 1 H) 8.15-8.24 (broad m, 1 H) 8.18 (broad d, J=8.3 Hz, 1 H) 8.40 (d, J=8.3 Hz, 1 H) 12.66 (s, 1 H) 13.05 (broad s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:3]=1.C([O-])(=O)C.[Na+]>[C].[Pd].C(O)(=O)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[CH:2]=[N:3][C:4]([C:22]([O:24][CH3:25])=[O:23])=[C:5]2[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1nc(Cl)c2cc(OC)c(OC)cc2c1-c1ccncc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ncc2cc(OC)c(OC)cc2c1-c1ccncc1
Reaction time: 19 h
Yield: 87.6 %

Procedure:
To acetic acid (80 ml) are added 4-(1-chloro-6,7-dimethoxy-3-methoxycarbonylisoquinolin-4-yl)pyridine (6.11 g), sodium acetate (1.4 g) and 10% palladium-carbon (2.5 g), and the mixture is subjected to hydrogenation at 50° C. for 19 hours under pressure (2.7 atm). The palladium-carbon is removed by filtration, and the filtrate is concentrated to give 4-(6,7-dimethoxy-3-methoxycarbonylisoquinolin-4-yl)pyridine (4.84 g).
Reaction SMILES: [Cl:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:27]1[O:29][CH2:28]1>>[Cl:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:27][CH2:28][OH:29])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCC1CNC1C(=O)NC(C(C)Cl)C1OC(SC)C(O)C(O)C1O
Reactant: C1CO1
Product: CCCCC1CN(CCO)C1C(=O)NC(C(C)Cl)C1OC(SC)C(O)C(O)C1O

Procedure:
A sample of 3-Butyl-azetidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared in example 91 was alkylated with ethyleneoxide as depicted in scheme 19 (R6=2-hydroxyethyl) to provide the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[N+]([CH:12]=CC1SC=CC=1)([O-])=O.C=O.Cl>>[S:1]1[C:2]2[CH2:6][CH2:7][NH:8][CH2:12][C:3]=2[CH:4]=[CH:5]1
Reactant: O=[N+]([O-])C=Cc1cccs1
Reactant: NCCc1cccs1
Agent: C=O
Agent: Cl
Product: c1cc2c(s1)CCNC2

Procedure:
U.S. Pat. No. 4,906,756 to Lodewijk et al. proposes the reaction of 2-(2-thienyl)ethylamine, prepared from 2-(2-nitrovinyl)thiophene, with formaldehyde to produce the formimine, cyclizing the formimine with hydrochloric acid to produce 4,5,6,7-tetrahydrothieno[3,2,c]pyridine, and converting this compound to ticlopidine free base by reaction with o-chlorobenzylchloride. The free base is then converted to ticlopidine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](F)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:21](#[N:25])[CH:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:22]([CH3:24])([CH3:23])[C:21]#[N:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(C)C#N
Reactant: CCOc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(C)(C)C#N)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
2-(3-Ethoxy-phenyl)-2-methyl-propionitrile was prepared using a procedure adapted from literature (Organic Syntheses, Vol. 79, pp. 209-215). To a solution of 1-ethoxy-3-fluoro benzene (3.0 g, 19.4 mmol) in 25 mL of toluene was added solid potassium bis(trimethylsilyl)amide (5.84 g, 29.2 mmol, 1.5 eq) followed by isobutyronitrile (7.08 mL, 77.8 mmol, 4 eq). The reaction mixture was stirred at 100° C. for 12 hr. It was diluted with 75 mL of ethyl acetate and 75 mL of 1N aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (1×50 mL), brine (1×50 mL), and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of methylene chloride and applied to a 40 g silica gel cartridge. The product was eluted using a gradient of ethyl acetate in hexanes to yield 2.96 g (15.6 mmol, 80%) of pure 2-(3-ethoxy-phenyl)-2-methyl-propionitrile. LR-MS: 190.12 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:23][N:22]([CH3:24])[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:21][N:22]([CH3:24])[CH2:23]4)[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:28]=1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ccn3)CC2)C1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.4 %

Procedure:
To a solution of 4-(1-methyl-azetidin-3-yl)piperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (121 mg) in tetrahydrofuran (50 ml) was added 20% palladium hydroxide carbon (91.3 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with tetrahydrofuran:methanol=1:1. The filtrate was concentrated to provide the titled compound (113 mg, 100%) as a yellow amorphous substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:3]=1[CH3:23].[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[NH:27][CH2:26]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[N:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:3]=2[CH3:23])[CH2:26]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: COc1cccc(Cc2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cccc(Cc2nc3cc(F)cc(F)c3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-2-(3-methoxybenzyl)-3-methylquinoline (50 mg, 0.150 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (35.0 mg, 0.150 mmol), Pd2dba3 (13.7 mg, 0.015 mmol), XPhos (14.3 mg, 0.030 mmol), sodium tert-butoxide (43 mg, 0.449 mmol), and toluene (1.5 mL) at 100° C. for 30 min. Purification by reverse-phase HPLC (0-90% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-2-(3-methoxybenzyl)-3-methylquinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.59-7.66 (1H, m), 7.47-7.54 (1H, m), 7.15-7.23 (1H, m), 6.91-7.00 (1H, m), 6.72-6.83 (3H, m), 5.50-5.56 (1H, m), 4.34-4.44 (2H, m), 3.78-3.83 (1H, m), 3.67-3.74 (7H, m), 3.51-3.59 (1H, m), 2.92 (4H, q, J=5.1 Hz), 2.16-2.23 (3H, m), 1.47-1.54 (3H, m), 1.40-1.47 (3H, m). Mass Spectrum (ESI) m/e=531.2 (M+1).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=S)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]>O1CCOCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)=[N:21][CH:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Hg+2]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-1-carboxylate (5.61 g, 10.3 mmol) in 1,4-dioxane (96 mL) was added mercury (II) trifluoroacetate (4.38 g, 10.3 mmol) and the reaction mixture was stirred at ambient temperature for about 2 h then filtered through a pad of Celite®. The Celite® pad was rinsed with EtOAc (50 mL) and the filtrate was concd under reduced pressure. The crude residue was dissolved in EtOAc (40 mL) and the organic phase was washed with saturated aqueous NaHCO3 (2×40 mL), brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-tert-butyl 3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (4.4 g, 87%): LC/MS (Table 1, Method b) Rt=2.49 min; MS m/z: 496 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][N:34]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:27])[CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[C:4]([O:28][CH3:29])[CH:3]=2)[CH2:33]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 295 mg, 0.75 mmol), ((3S)—N,N-dimethylpyrrolidin-3-amine (103 mg, 0.90 mmol) and DIPEA (0.196 mL, 1.13 mmol) were dissolved in DMA (3 mL) and sealed into a microwave tube. The mixture was heated to 100° C. for 45 minutes in a microwave reactor, then cooled to r.t., diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and then eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 2-7% methanolic ammonia in CH2Cl2 gave the title compound (235 mg, 64%) as a red solid; 1H NMR: 1.83 (1H, m), 2.17 (1H, m), 2.22 (6H, s), 2.72-2.86 (1H, m), 3.17 (2H, m), 3.26 (1H, m), 3.47 (1H, m), 3.88 (3H, s), 3.97 (3H, s), 6.58 (1H, s), 7.12 (1H, t), 7.19 (1H, d), 7.21-7.31 (1H, m), 7.52 (1H, d), 8.01 (1H, s), 8.23-8.33 (2H, m), 8.36 (1H, d), 8.58 (1H, s); m/z: ES− MH+ 488.35.