Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[C:29]([CH2:30][F:31])=[C:28]4[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26][N:27]4[CH:32]4[CH2:34][CH2:33]4)=[CH:22][C:21]=3[F:39])[CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.Cl>Br.C(O)(=O)C.[OH-].[Na+]>[CH:32]1([N:27]2[C:28]3[C:23](=[CH:22][C:21]([F:39])=[C:20]([C:16]4[CH:17]=[C:18]5[C:13](=[CH:14][CH:15]=4)[CH2:12][NH:11][CH2:19]5)[C:29]=3[CH2:30][F:31])[C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26]2)[CH2:33][CH2:34]1
Reactant: O=C(O)c1cn(C2CC2)c2c(CF)c(-c3ccc4c(c3)CN(C(=O)OCc3ccccc3)C4)c(F)cc2c1=O
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(CF)c(-c3ccc4c(c3)CNC4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In 3.2 ml of 30% hydrogen bromide-acetic acid solution was suspended 0.16 g of 7-[2-(benzyloxycarbonyl)isoindolin-5-yl]-1-cyclopropyl-6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the suspension was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure and to the residue was added ethanol, and the crystals formed were collected by filtration. The crystals obtained were dissolved in dilute aqueous sodium hydroxide solution, and the pH was adjusted to 7 with dilute hydrochloric acid. The crystals precipitated were collected by filtration, to obtain 68 mg of colorless, crystalline 1-cyclopropyl-6-fluoro-8-fluoromethyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH3:22])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1.[H][H]>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: [H][H]
Reactant: COc1cc2c(NC(C)c3cnn(C)c3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CCOC(C)=O
Product: COc1cc2c(NC(C)c3cnn(C)c3)c(N)cnc2cc1-c1c(C)noc1C
Yield: 91.5 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-3-nitroquinolin-4-amine (0.20 g, 0.473 mmol, for preparation see Intermediate 23) was dissolved in EtOAc (80 ml) and hydrogenated using a flow hydrogenator (H-Cube™ settings: full Hydrogen mode, atmospheric pressure, 20° C., 1 ml/min flow rate) to give an orange solution. The eluant was evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)quinoline-3,4-diamine (0.17 g, 0.433 mmol, 91% yield) as an orange gum which was used without further purification. LCMS (formate) Rt 0.66 min, MH+ 393.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:12]2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:4]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:12]2)=[CH:7][CH:6]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 3',4'dihydro-7'[2-(trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2'(1'H)-naphthalene] (1.45 g, 5.02 mmol) and suspended K2CO3 (0.50 g) in methanol (20 ml) was stirred at room temperature for 30 minutes. The solution was then filtered and concentrated in vacuo. The residue was absorbed onto silica gel (2 g) and purified by chromatography on silica gel (11 g) eluting with diethyl ether:hexane (1:9) to give 7'-ethynyl-3',4'-dihydrospiro[1,3-dioxolane-2,2'(1'H)-naphthalene] as a solid (0.85 g). 1H NMR (CDCl3, 200 MHz) δ: 1.94 (t, J=7 Hz, 2H, CH2), 2.95 (s, 2H, CH2), 2.98 (t, J=7 Hz, 2H, CH2), 3.01 (s, 1H, ethynyl H), 4.02 (s, 4H, OCH2CH2O), 7.07 (d, J8 Hz, 1H, Ar), 7.19 (s, 1H, Ar), 7.24 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].CC(C)([O-])C.[K+].[CH2:24]([O:26][CH:27](Cl)[CH3:28])[CH3:25]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]([CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[C:6]=1[Cl:7]
Reactant: CCOC(C)Cl
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(C)n1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To 4,5-dichloro-2-(3,4-dichlorophenyl)-pyrrole-3-carbonitrile (5.0 g, 0.016 mol) dissolved in 300 mL of tetrahydrofuran is added, portionwise, potassium t-butoxide (2.75 g, 0.025 mol) with ice cooling and stirring. The cooled mixture is treated with a solution of 1-chloroethyl ethyl ether (2.31 g, 0.021 mol) in 15 mL of tetrahydrofuran at 10° C. over a 5 minute period. The mixture is stirred for 1/2 hour at ambient temperatures, evaporated to a volume of 50 mL and poured into a mixture of 200 mL of ethyl acetate and 100 mL of water. The organic layer is separated, washed with water (2×100 mL), saturated NaCl solution (1×100 mL), dried over anhydrous magnesium sulfate and evaporated to give the title product 5.9 g, mp 124°-126° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:12][C:7]=2[CH:6]=[C:5]([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:4][CH2:3]1.C(CC(O)=O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:12][C:7]=2[CH:6]=[C:5]([C:20]([OH:22])=[O:21])[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCC(=O)O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
In ethyl acetate (7.0 ml) was dissolved tert-butyl 1-methyl-7-(4-methylphenyl)-2,3-dihydro-1-benzoazepine-4-carboxylate (490 mg), and to the mixture was added 4N hydrochloric acid (ethyl acetate) (7.0 ml). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure, and the residue was washed with hexane (10 ml×3) to give 1-methyl-7-(4-methylphenyl)-2,3-dihydro-1-benzoazepine-4-carboxylic acid hydrochloride (443 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[NH:35][C@H:36]([C:40]([OH:42])=[O:41])[CH:37]([CH3:39])[CH3:38]>CCOCC>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[NH:35][C@H:36]([C:40]([OH:42])=[O:41])[CH:37]([CH3:39])[CH3:38].[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:40]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)=[O:41]
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of N-(2-chloro-4-trifluoromethylphenyl) valine (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20% ether/hexane, gives the 4-fluoro-3-phenoxybenzyl ester of N-(2-chloro-4-trifluoromethylphenyl) valine, [4-fluoro-3-phenoxybenzyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate].
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([N:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4Br)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4Br)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[Si:41](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([N:20]4[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Si:41]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]4=5)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1N(c1cccc(-n2c3ccccc3c3ccccc32)c1)c1ccccc1Br
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc([Si]2(c3ccccc3)c3ccccc3N(c3cccc(-n4c5ccccc5c5ccccc54)c3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
N-(3-(9H-carbazol-9-yl)phenyl)-2-bromo-N-(2-bromophenyl)aniline (4.05 g, 7.13 mmol) was added into a 250-mL round bottom flask and solubilized in dry THF (100 ml). The mixture was cooled down to −78° C. Butyllithium (5.70 ml, 14.25 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours. Dichlorodiphenylsilane (1.467 ml, 7.13 mmol) was then added dropwise. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water, extracted three times with diethyl ether and washed three times with water. The crude material was purified by column chromatography using hexane and dichloromethane (85/15) as the eluent. After most of the impurities came out, the eluent was gradually changed to 25% dichloromethane in hexane. The white powder was then triturated in acetone and then recrystallized three times from dichloromethane and hexane. 1.5 g of 5-(3-(9H-carbazol-9-yl)phenyl)-10,10-diphenyl-5,10-dihydrodibenzo[b,e][1,4]azasiline was sublimed to afford 1.4 g yield of 33%.
Reaction SMILES: Cl.N1C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[C:23]3[C:18](=[CH:19][C:20]([O:39]C)=[CH:21][CH:22]=3)[O:17][CH2:16]2)=[CH:11][CH:10]=1>CO.O.C(=O)([O-])O.[Na+]>[OH:39][C:20]1[CH:19]=[C:18]2[C:23]([C@@H:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:27][CH:26]=3)[C@H:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[CH2:16][O:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 135 °C

Procedure:
A mixture of anhydrous pyridine hydrochloride (0.289 g, 2.50 mmol) and (±)-trans-3-(4-fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane (0.11 g, 0.25 mmol) was heated to 135° C. for 18 h. The resulting dark brown solid was dissolved in a mixture of methanol (10 ml), water (50 ml) and sodium hydrogen carbonate solution (5 ml), and the product extracted into 9:1 dichloromethane /methanol (3×50 ml). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to an orange gum. The product was purified by column chromatography on silica gel 60, with 5% methanol in dichloromethane eluent, giving the purified product as a colourless wax.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[CH2:11][CH2:10][C@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C(OCC)C.CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][C@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1C(=O)O
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To an ice cold solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-2-carboxylic acid (1.17 g, 4.07 mmol) in 70 mL diethyl ether and 0.330 mL methanol was added lithium borohydride (2M in THF, 4.0 mL, 8.14 mmol). After 10 minutes, the ice bath was removed and the reaction was heated at reflux overnight. As the reaction had not proceeded, a solvent swap to THF was performed, and the resulting mixture was heated at 70° C. overnight. The reaction mixture was cooled to 0° C. and quenched with 1N HCl and then extracted into ethyl acetate, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product as a white semi-solid (886 mg)
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25]1>ClCCl>[CH:24]1([NH:27][C:28]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[N:16]4)=[CH:18][CH:19]=2)=[O:29])[CH2:26][CH2:25]1
Reactant: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Reactant: O=C=NC1CC1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1)NC1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
A mixture of 4-(3-morpholin-4-yl-quinoxalin-6-yl)-phenylamine [Intermediate Example 4.1] (100 mg) in dichloromethane (3.3 mL) was cooled (ice bath) and treated with cyclopropyl isocyanate (30 mg, 0.36 mmol) and stirred at room temperature for 3 days. The resulting precipitate was filtered, washed with dichloromethane and dried to give the title compound (96 mg). UPLC-MS: RT=1.01 min; m/z (ES+) 390.24 [MH+]; required MW=389.46.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].[I-].[K+].Cl>CO.O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCCCCCCO)cc1

Procedure:
229.2 g (1.66 mol) of p-hydroxy-benzoic acid were dissolved in 600 ml of methanol and treated at 0° C. within 10 minutes with a solution of 151 g (3.77 mol) of NaOH in 480 ml of H2O. 271.2 g (1.99 mol) of 6-chloro-hexanol were slowly added dropwise to this solution. Finally, 0.75 g of potassium iodide was added and the batch was boiled under reflux for 60 hours. For the working up, the yellow solution was poured into 3 1 of H2O and treated with 10% HCl (about 600 ml) until a pH value of 1 had been achieved. The milky suspension was filtered over a large suction filter. The residue was sucked dry and recrystallized twice from about 1.5 l of ethanol. This gave 229.6 g of 4-(6-hydroxy-hexyloxy)-benzoic acid as a fine white powder; m.p. 136-141° C.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].CS([C:13]1[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]2[CH:26]=[CH:27][C:28]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][CH:33]=3)=[CH:29][C:15]=2[N:14]=1)(=O)=O>C1COCC1.C(#N)C>[OH:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]#[C:30][C:28]2[CH:27]=[CH:26][C:16]3[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:13]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:14][C:15]=3[CH:29]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)CO
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(C#Cc3ccc(CO)cc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(C#Cc3ccc(CO)cc3)ccc21
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (12.0 mg, 60% suspension in mineral oil, 0.30 mmol). A solution of hydroxyacetic acid methyl ester (54.0 mg, 0.60 mmol) in THF (1.0 mL) was added dropwise to the vial. Immediately after the addition was complete, a solution of {4-[2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-ylethynyl]-phenyl}-methanol (compound 47-1, 49.1 mg, 0.100 mmol) in THF (1 mL) was added. The resulting yellowish suspension was stirred at it for 5 min, then diluted with ACN (2 mL) and quenched by addition of water (2 mL). The resulting solution was stirred at it for 5 min, then an additional 15 min at 65° C. The solution was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water and evaporated to dryness in vacuo to give the crude product as yellowish solid. LR-MS (APT-ES): mixture of two N-SEM isomers, calculated for C24H27ClN2O5Si 486.2, observed m/e 487.0 (M+H)+ (Rt 3.09, 3.20 min). The crude product was used in the next step without further purification.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[OH-].[Na+].CN([CH:21]=[O:22])C>>[CH3:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH:21]=[O:22])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CN(C)C=O
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c2ccccc2c1C=O
Reaction time: 2 h
Yield: 89 %

Procedure:
To a dried 300 mL two-neck round bottom flask under argon at 0° C., N,N-dimethylformamide (3 mL) was added, followed by POCl3 (1.05 mL, 11.3 mmol). After stirring for ten minutes, 2-methylindole (1.23 g, 9.37 mmol) dissolved in DMF (6 mL) was added dropwise via an addition funnel under argon. After two hours, 1 N NaOH (70 mL) was added slowly, upon which a white precipitate formed. The solid was filtered and dried under vacuum, yielding 1.32 g (89%) of white solid. 1H NMR (600 MHz, d6-DMSO): δ 11.998 (s, 1H, N—H), 10.050 (s, 1H, CHO), 8.044-8.032 (d, J=7.2, 1H, indole-4H), 7.388-7.375 (d, J=7.8, 1H, indole-7H), 7.183-7.135 (m, 2H, indole-5,6H), 2.679 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 184.3, 148.6, 135.4, 125.6, 122.7, 121.9, 120.0, 113.7, 111.4, 11.5. Melting Point: 195-200° C. TLC (ethyl acetate:hexanes 4:1) Rf=0.39. Elemental analysis calculated for C10H9NO: C, 75.45; H, 5.70; N, 8.80. found: C, 75.23; H, 5.70; N, 8.93.
Reaction SMILES: [Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH2:24]Br)[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:26][C:27]([F:38])([F:37])[C:28]([NH:30][CH2:31][CH2:32][O:33][CH2:34][C:35]#[CH:36])=[O:29]>>[Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH2:24][C:36]#[C:35][CH2:34][O:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[C:27]([F:26])([F:37])[F:38])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CBr)c(=O)[nH]c2=O)O1
Reactant: C#CCOCCNC(=O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CC#CCOCCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O1

Procedure:
Next, 5′-O-tert-butyldimethylsilyloxy-5-bromomethyl-2′,3′-dideoxyuridine (3) can be coupled with an alkyne, in this case 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, to form the 5′-O-tert-butyldimethylsilyloxy-(5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl))-2′,3′-dideoxyuridine (4). It will be readily appreciated by one of skill in the art that the coupling of an alkyl halide with an alkyne can be carried out by a number of methods known in the art. Without being limiting in any way, one example of such a method known in the art is the so-called Castro-Stephens coupling, see for example, White, J. D., et. al. J. Am. Chem. Soc., 123(23), 5407-5413 (2001) and Stephens, R. D., et. al. J. Org. Chem., 28, 3313 (1963). For example, as shown in Scheme 1,5′-O-tert-butyldimethylsilyloxy-5-bromomethyl-2′,3′ dideoxyuridine (3) can be contacted with a mixture comprising a copper reagent, for example copper iodide (CuI), an alkyne, for example 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, and a base, for example 1,8-diazobicyloclo[5.4.0]undec-7-ene (DBU), to form 5′-O-tert-butyldimethylsilyloxy-(5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl))-2′,3′-dideoxyuridine (4), where an acetylide anion is formed in the mixture comprising CuI, 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, and DBU.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:13][C:12]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[CH2:28]([N:25]([CH2:26][CH3:27])[C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=1)[CH3:29]
Reactant: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCNC2
Temperature: 85 °C

Procedure:
To a solution of [7-benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-2-yl]-diethyl-amine (0.052 g, 0.13 mmol) in EtOH (1.5 mL) was added 10 wt % Pd/C and 1,4-cyclohexadiene (0.062 mL, 0.66 mmol). The mixture was heated at 85° C. for 2 h and cooled to rt. The mixture was concentrated and the residue was purified by FCC (2 M NH3/MeOH in CH2Cl2) to afford the title compound. HPLC: Rt=9.7 min. MS (ESI): mass calcd. for C17H21FN4, 300.4; m/z found, 301.4 [M+H]+. 1H NMR (CDCl3): 7.60 (dd, J=8.8, 5.5, 2H), 7.11 (t, J=8.8, 2H), 3.93 (s, 2H), 3.63 (q, J=7.0, 4H), 3.02 (t, J=5.7, 2H), 2.64 (t, J=5.7, 2H), 1.18 (t, J=7.0, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=[C:4]([NH:15][CH3:16])[N:3]=1.[C:17]([C:19]1[C:24]([F:25])=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:29])#[N:18].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:25][C:24]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@H:9]3[CH3:14])[N:5]=[C:4]([NH:15][CH3:16])[N:3]=2)[CH:21]=[C:20]([F:29])[C:19]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2CCOC[C@H]2C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Temperature: 140 °C
Yield: 43.9 %

Procedure:
To a 20-mL microwave vial was added 4-chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (500 mg, 2.060 mmol), (4-cyano-3,5-difluorophenyl)boronic acid (754 mg, 4.12 mmol), PdCl2(dppf).CH2Cl2 adduct (84 mg, 0.103 mmol), K2CO3 (2 M, 3.09 mL, 6.18 mmol), and 1,4-dioxane (9 mL). The reaction mixture was heated at 140° C. for 10 mins in a microwave reactor. The 1,4-dioxane was removed, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organics were dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in hexanes, 12 g column) to afford the title compound (312 mg) as a yellow solid. LC-MS (ES) m/z=346 [M+H]+.