Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][O:32][C:33]2[C:34]([O:41][CH3:42])=[CH:35][C:36]([CH:39]=[O:40])=[N:37][CH:38]=2)=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][O:32][C:33]2[C:34]([O:41][CH3:42])=[CH:35][C:36]([CH:39]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)[OH:40])=[N:37][CH:38]=2)=[CH:29][CH:28]=1
Reactant: COc1cc(C=O)ncc1OCc1ccc(Cl)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)ncc1OCc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 180 mg, 0.450 mmol) was dissolved in tetrahydrofuran (2.5 mL) and the reaction was cooled to −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.00 M, 0.243 mL) was added. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 5-(4-chloro-benzyloxy)-4-methoxy-pyridine-2-carbaldehyde (641, 80.0 mg, 0.288 mmol) in tetrahydrofuran (0.75 mL) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, methanol: dichloromethane, to provide the desired product, (642, 94 mg, 59%). 1H-NMR was consistent with the desired compound. MS (ESI) [M+H+]+=552.4, 554.4, 555.4.
Reaction SMILES: C([C:3]1[C:4](CC)=[C:5]([CH:12]([C:16](C(O)=O)=O)[C:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH3:11])C.C(=O)([O-])[O-].[K+].[K+].[CH3:29][CH2:30]OCC>C=O>[CH2:29]([O:15][C:13](=[O:14])[C:12]([C:5]1[CH:4]=[CH:3][C:8]([O:9][CH2:10][CH3:11])=[CH:7][CH:6]=1)=[CH2:16])[CH3:30]
Reactant: CCOCC
Reactant: CCOc1ccc(C(C(=O)[O-])C(=O)C(=O)O)c(CC)c1CC
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C(=O)OCC)c1ccc(OCC)cc1

Procedure:
The keto-ester III (143.8 g) was stirred in dilute formaldehyde solution (62 ml 37% formaldehyde+water 220 ml) and to the suspension potassium carbonate solution (54.5 g, in water 280 ml) was added dropwise. At the end of the addition, ether was added to the stirred suspension to dissolve the gummy precipitate which formed and after an additional 15 minutes, gas evolution commenced. When this gas evolution ceased (after about 2 hours) the reaction mixture was extracted with additional ether and the combined ether extracts were washed with water and evaporated after drying with Na2SO4. The yield of the ethyl-2-(p-ethoxyphenyl)acrylate (II) (isolated as a yellow oil) was 97.8 g (79.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(Cl)cn1
Yield: 51.1 %

Procedure:
A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10% Pd—C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4×25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51% yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) δ ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(O)c1
Product: COC(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A catalytic quantity of concentrated sulphuric add (1.0 ml) was added to a solution of (3-hydroxy)phenylacetic acid (17.38 g, 0.114tool) in methanol (100 ml). The reaction mixture was stirred for 3 hours at room temperature and then concentrated in vacuo. The residue was partitioned between diethyl ether (200 ml) and a saturated aqueous solution of sodium hydrogen carbonate (200 ml). The ether phase was separated and washed with non-saturated sodium hydrogen carbonate solution (200 ml) and saturated brine solution (100 ml). The ether extract was dried over magnesium sulphate. The solvent was evaporated and the residue dried to afford methyl 3-hydroxyphenylacetate as an amber oil (18.61 g, 98%); δH (360 MHz, CDCl3) 3.58 (2H, s, CH2), 3.70 (3H, s, COOCH3), 5.54 (1H, br s, OH), 6.74 (2H, m, ArH), 6.81 (1H, d, J 8 Hz, ArH), 7.17 (1H, t, J 8 Hz, ArH).
Reaction SMILES: Cl.[CH3:2][CH:3]([C:9](=O)[CH3:10])[C:4](OCC)=[O:5].[SH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>ClCCl>[CH3:2][C:3]1[C:4]([OH:5])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[S:12][C:9]=1[CH3:10]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C)c(C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dry hydrogen chloride gas was bubbled through a mixture of ethyl 2-methyl-3-oxobutanoate (7.6 g, 50 mmol) and methyl 2-mercaptoacetate (11.2 g, 100 mmol) at -10° C. until saturated. The oil was allowed to stand for 3 hours at room temperature, diluted with dichloromethane and washed with brine. After drying with sodium sulphate and evaporation of solvent the oil was dissolved in methanol (10 ml) and added dropwise to methanolic potassium hydroxide (2N; 75 ml), stirring at room temperature for 1 hour. The solution was diluted with iced water (125 ml) and acidified with 3N hydrochloric acid at -3° to 0° C. to pH1. The precipitate was filtered and washed with water (5.5 g, m.p. 50°-51° C., methanol).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(=O)[nH]c2)n1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(=O)[nH]c4)c3)c2cc1OC
Yield: 61.7 %

Procedure:
Following the procedure in Example 115C, phenyl 3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (8 mg, 0.0227 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (8 mg, 0.025 mmol) (prepared as described in Example 113A) to afford 1-(3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (7.8 mg, 0.014 mmol, 62%). 1H NMR (300 MHz, DMSO-d6) δ 12.1 (br s, 1H), 9.03 (br s, 1H), 8.56 (br s, 2H), 7.53-7.26 (m, 7H), 6.91 (d, 1H), 6.43-6.35 (m, 2H), 4.05 (s, 6H), 1.22 (s, 9H); LC-MS (ESI) m/z 556 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:29])([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:29])([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([OH:15])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Yield: 52.8 %

Procedure:
The nonpolar isomer tert-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.087 g, 0.21 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 4 hours. Then the mixture was evaporated in vacuo and vacuum dried to yield the nonpolar isomer of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-proline (0.04 g, HPLC RT=2.51 min, Method A; LCMS m/z=361).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][C:9]([Br:34])=[CH:8][N:7]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Product: CCc1ccc(-n2nnnc2-c2cc(Br)cnc2NC(C)(C)C)c(F)c1F

Procedure:
Compound 1082 can be further reacted with NBS according to procedures analogous to those provided herein to provide N-tert-butyl-5-bromo-3-(1-(4-ethyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1083).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: CC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1

Procedure:
1-(5-(4-(Trifluoromethoxy)phenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 1-bromo-4-(trifluoromethoxy)benzene according to general procedure A.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH2:13]>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 2,6-dichloro-3-nitro-pyridine and methylamine (40% in water) in ethanol.
Reaction SMILES: C([Mg]Cl)(C)C.O1CCCC1.I[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Reaction time: 2.5 h

Procedure:
Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 1.5 mL, 3.00 mmol) was added dropwise to a solution of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (740 mg, 2.00 mmol) in Tetrahydrofuran (12 mL, 150 mmol) at room temperature. The mixture was stirred for 2.5 hours. Tributyltin chloride (0.8138 mL, 3.000 mmol) was added and the mixture was stirred for 18 hours. The mixture was mixed with sat aq. NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and purified on 25 g silica column eluting with 15-20% ethyl acetate in heptane. Yield 160 mg (15%). MS (ESI+): 535.2
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]([OH:16])[CH2:13][CH:14]=[CH2:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>O1CCCC1>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C@H:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:22]
Reactant: CCOC(CBr)OCC
Reactant: C=CC[C@@H](O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 98.8 g, 2.47 mol) in tetrahydrofuran (1 L) at room temperature was added drop-wise over 30 minutes a solution of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) (190 g, 0.988 mol) in tetrahydrofuran (500 mL), while the reaction temperature was maintained below 30° C. After 30 minutes, a solution of 2-bromo-1,1-diethoxyethane (390 g, 1.98 mol) in tetrahydrofuran (500 mL) was added drop-wise. The reaction mixture was stirred at room temperature for 1 hour, then the temperature was gradually increased to 70° C. and the reaction mixture was left to stir at 70° C. for 18 hours. It was then cooled to room temperature, subsequently cooled in an ice bath, and quenched by slow addition of ice/water (200 mL), while keeping the internal reaction temperature at approximately 18° C. The mixture was partitioned between saturated aqueous sodium chloride solution (1 L) and ethyl acetate (1 L), and the organic layer was washed with saturated aqueous sodium chloride solution (1 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was effected by filtration through a pad of silica (Gradient: 0% to 20% ethyl acetate in heptane) to afford the product as an orange oil. Yield: 257 g of 60% purity, approximately 500 mmol, 51% yield and 57.76 g of 90% purity, approximately 170 mmol, 17% yield. 1H NMR (400 MHz, CDCl3), product peaks only: δ 7.26-7.38 (m, 5H), 5.78-5.90 (m, 1H), 5.02-5.13 (m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H), 2.31-2.37 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.F[C:38]1[N:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=[O:41].Cl>CN1C(=O)CCC1>[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:46]=[CH:45][CH:44]=[CH:43][C:39]=4[C:40]([OH:42])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(O)c1cccnc1F
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.10 g, 0.42 mmol, Compound C of Example 1) and 2-fluoronicotinic acid (Aldrich, 0.084 g, 0.59 mmol), in anhydrous NMP (0.50 mL), was added HCl (4N in 1,4-dioxane, 0.42 mL, 1.7 mmol). The mixture was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 120° C. for two hours followed by 140° C. for six hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to afford the desired compound (0.13 g, 82%) as an off-white solid. 1H NMR (DMSO-d6) δ 13.75 (br s, 1H), 12.11 (s, 1H), 10.60 (s, 1H), 8.40 (dd, 1H, J=4.7, 1.9 Hz), 8.24 (dd, 1H, J=7.7, 1.9 Hz), 8.10-8.20 (m, 2H), 7.30-7.49 (m, 3H), 6.90 (dd, 1H, J=7.7, 4.8 Hz), 6.48 (d, 1H, J=5.8 Hz), 6.31-6.40 (m, 1H); HRMS(ESI+), 365.1050 (M+H)+ calc, 365.1038 (M+H)+ found.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>>[N:13]1([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCCn1ccnc1
Product: N#Cc1cc([N+](=O)[O-])ccc1NCCCn1ccnc1
Yield: 52 %

Procedure:
Starting with 36.5 g (0.2 mol) of 2-chloro-5-nitrobenzonitrile and 31.3 g (0.25 mol) of 3-imidazol-1-ylpropylamine, and after purification by recrystallization from refluxing at 96 ° ethanol, 28.2 g of yellow crystals melting at 177° C. (Kofler) were obtained, the elemental analysis of which, calculated for C13H13N5O2, was:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[CH3:32][S:33]([CH:36]=[CH2:37])(=[O:35])=[O:34]>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: C=CS(C)(=O)=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(CCS(C)(=O)=O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and methylvinylsulfone were reacted to give 543. LCMS m/z: 525.3 (MH+)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:11]2)=[CH:6][CH:5]=1.[Na:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:11]2)=[CH:6][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na:18]
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=S(=O)(O)c1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 2 h

Procedure:
A 60% dispersion of sodium hydride (0.37 g, 9.22 mmol) in mineral oil is washed with hexanes twice and suspended in 40 mL of DMF. To this mixture is added slowly via an addition funnel 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (1.25 g, 5.08 mmol) in 25 mL of DMF at room temperature. The reaction mixture is stirred for 2 hours during which time mild bubbling is observed (H2 evolution). The mixture is treated with benzyl bromide (1.5 mL, 12.6 mmol) and stirred for 18 hours at room temperature. Ice is added to decompose the excess NaH and the resultant mixture is concentrated in vacuo. The residue is suspended in acetone and concentrated in vacuo two times and then is dried under high vacuum. The solid is suspended in acetone, filtered and dried to yield the crude 7-benzyloxynaphthalene-2-sulfonic acid, sodium salt as a beige solid. A mixture of the sulfonic acid, sodium salt (2.47 g) in 8 mL of thionyl chloride is heated at 80° C. for 4 hours. A drop of DMF is added with vigorous bubbling resulting and the mixture is heated for an additional 30 minutes. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted in EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to yield the title compound as a beige solid (1.26 g, 3.78 mmol). The crude product is of sufficient purity to be used in subsequent reactions.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([CH3:54])=[C:36]([N:40]2[CH2:49][CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([N:50]([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:51][N:50]([CH3:52])[C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:53])[N:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH3:54])[CH2:49][CH2:48]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: Cc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 100 °C
Yield: 31.1 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (77 mg, 0.18 mmol), 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (63 mg, 0.18 mmol), potassium phosphate (74 mg, 0.35 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (5.0 mg, 0.010 mmol), and bis(dibenzylidineacetone)palladium(0) (3.0 mg, 0.0052 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (33 mg, 0.056 mmol). MS (ESI) 593.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:25][C:26]([CH:29]2[CH2:31][CH2:30]2)=[N:27][N:28]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[N:27][N:28]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: ClCc1nnc(C2CC2)o1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1nnc(C2CC2)o1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x9 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 75 mg, 0.331 mmol) in DMSO (2 mL) followed by sodium tert-butoxide (35.0 mg, 0.364 mmol) and 2-(chloromethyl)-5-cyclopropyl-1,3,4-oxadiazole (68.2 mg, 0.430 mmol). 1H NMR (400 MHz, DMSO-d6) δ 0.92-1.00 (m, 2 H), 1.07-1.16 (m, 2 H), 2.14-2.25 (m, 1 H), 2.92-3.03 (m, 1 H), 3.03-3.11 (m, 1 H), 3.11-3.20 (m, 1 H), 3.34-3.51 (m, 1 H), 3.53-3.58 (m, 1 H), 3.59-3.72 (m, 1 H), 3.85-4.00 (m, 2 H), 4.20-4.29 (m, 1 H), 4.53-4.63 (m, 1 H), 4.79-4.88 (m, 1 H), 7.56 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C15H17ClN6O2, 348.11; found 348.2.