Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([N:22]=[C:23]([NH2:25])[NH2:24])#[N:21].[OH-].[K+]>COCCO.O>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]3[N:24]=[C:23]([NH2:25])[N:22]=[C:20]([NH2:21])[N:13]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: Nc1nc(N)nc(C2CN(C(c3ccccc3)c3ccccc3)C2)n1
Temperature: 25 °C

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinecarbonitrile (500 mg, 2.01 mmol), dicyandiamide (220 mg, 2.62 mmol) and KOH (34 mg, 0.604 mmol) in 2-methoxyethanol (10 mL) was heated at reflux for 4 hours, diluted with water, and cooled to room temperature. The precipitate was rinsed with water and dried under vacuum to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37]C)=[O:36])O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=3)[C:35]([OH:37])=[O:36])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 0.15 h
Yield: 25.7 %

Procedure:
A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.10 g, 0.30 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.096 g, 0.36 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.057 g, 0.122 mmol) and Na2CO3 (0.095 g, 0.912 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 30% acetonitrile/70% water (0.1% TFA V/V) initially, proceeding to 60% acetonitrile/40% water (0.1% TFA V/V) in a linear fashion over 9 min) to afford (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (32 mg, 25%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.97 (s, 1H), 9.26 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 8.13-8.11 (m, 1H), 7.71 (t, 1H, J=7.8 Hz), 7.51 (t, 1H, J=7.8 Hz), 6.69 (d, 1H, J=7.5 Hz), 6.16 (d, 1H, J=8.1 Hz), 4.22-4.17 (m, 1H), 3.63-3.54 (m, 1H), 3.44-3.39 (m, 1H), 2.06-1.95 (m, 3H), 1.67-1.61 (m, 1H), 1.07 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 415, tR=1.669 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.01 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][O:1][CH2:2][CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COCCOCCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)NCCO)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine-N-(2-hydroxylethyl)amide (7.0 g, 20.4 mmol) in dry dichloromethane (150 ml) under an argon atmosphere was added 2-methoxyethoxymethyl chloride (5.6 ml, 49.0 mmol) and diisopropylethylamine (10.7 ml, 61.4 mmol). The reaction mixture was stirred overnight at room temperature, after which time starting material was still detectable by TLC. The solvent volume was concentrated to one third, an equal volume of DMF was added and the reaction mixture was stirred for a further 60 hours at room temperature. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetateand washed successively with 1M hydrochloric acid, sat. aq. sodium hydrogencarbonate and brine. The organic phase was dried over sodium sulphate, filtered and concentrated to afford the desired product as a pale yellow oil which crystallised when left under high vacuum for ca. 1 hour. Yield: 8.0 g (90%). 1H--NMR; δ(CDCI3), 7.33-7.14 (10H, m), 6.84 (1H, br s), 5.89 (1H, br s), 5.01 (2H, m), 4.54 (2H, s), 4.46 (1H, m), 3.56-3.26 (11H, m), 3.02 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[C:12]3[C:13]4[N:14]([CH:30]=2)[CH2:15][C:16](=O)[NH:17][C:18]=4[CH:19]=[C:20]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:21]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([NH:41][C:16]1[CH2:15][N:14]2[CH:30]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[O:9])[C:11](=[O:31])[C:12]3[C:13]2=[C:18]([CH:19]=[C:20]([CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:21]=3)[N:17]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(CN4CCOCC4)cc(c32)N1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)N=C(NCc1ccccc1)C2

Procedure:
N-(4-Chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide (Example 3, 30 mg) is heated under reflux with benzylamine (0.5 mL) for 18 h. The benzylamine is evaporated and the product is triturated with ether to give the title compound (18 mg), which is crystallized from ethyl acetate. Physical characteristics: M.p. 235-240° C.; 1H NMR (CDCl3) δ2.36, 3.51, 3.57, 4.55, 4.63, 7.2-7.5, 7.64, 8.20, 8.62, 10.5; HRMS m/z 555.2128 (C31H30ClN5O3).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])=[CH:31][CH:32]=1
Reactant: CC(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CC(C)NC(=O)OC(C)(C)C)cc1
Yield: 55.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (260 mg, 0.80 mmol) was reacted with tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate (430 g, 1.2 mmol) to afford the desired product (212 mg, 55%) as a yellow oil: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:16].[H-].[Na+].Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:28][CH3:29])[N:21]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:28][CH3:29])[N:21]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Reactant: COc1nc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(C)c2)ccc1C#N
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To a solution of tert-butyl 4-bromo-3-methylphenylcarbamate (4.36 g, 15.24 mmol) in N,N-dimethylformamide (60 mL) on an ice bath under a nitrogen balloon was added sodium hydride (0.610 g, 15.24 mmol). The reaction was stirred on an ice-water bath for 10 min. The ice bath was removed and to the solution was added a solution of 6-chloro-2-methoxynicotinonitrile (3.85 g, 22.86 mmol) in N,N-dimethylformamide (40 mL) dropwise. After addition completed, the mixture was stirred overnight at 50° C. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the crude product. The crude was then purified by silica gel column (100% hexanes to 8:2 hexanes/ethyl acetate) to give tert-butyl 4-bromo-3-methylphenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (3.15 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9H), 2.30 (s, 3H), 3.55 (s, 3H), 7.00 (dd, J=2.6, 8.4 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]1[C:24]([SH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=O)(O)[O-].[Na+]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[S:25][C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:18])[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Cc1ccccc1S
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1Sc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), o-thiocresol (12.4 g), and 1N sodium bicarbonate (300 ml) was refluxed for 3 hours. After cooling, the precipitated sodium salt of 3-nitro-5-sulphamyl-4-o-tolylthio-benzoic acid was filtered off and washed with 1N sodium bicarbonate solution. The sodium salt was dissolved in hot water (250 ml), and the acid was precipitated by the addition of 4N hydrochloric acid (17 ml). After isolation, recrystallization from aqueous ethanol, and drying at 115°C and 10 mm Hg for 3 hours, the acid was obtained with a melting point of 165°-166°C.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C[O:7][C:8]([CH2:10][C:11]1[CH:20]=[C:19]([C:21]#[N:22])[C:18]([Cl:23])=[CH:17][C:12]=1[C:13](OC)=[O:14])=O.COC(CC1C(Cl)=C(C#N)C=CC=1C(OC)=O)=O>O.O1CCCC1.C(O)C>[Cl:23][C:18]1[CH:17]=[C:12]([CH2:13][OH:14])[C:11]([CH2:10][CH2:8][OH:7])=[CH:20][C:19]=1[C:21]#[N:22]
Reactant: COC(=O)Cc1cc(C#N)c(Cl)cc1C(=O)OC
Agent: COC(=O)Cc1c(C(=O)OC)ccc(C#N)c1Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(CCO)c(CO)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Calcium chloride (0.33 g, 3 mmol) and sodium borohydride (0.23 g, 6 mmol) were added to a mixture (0.80 g, 3 mmol) of methyl 2-methoxycarbonylmethyl-4-cyano-5-chlorobenzoate and methyl 2-methoxycarbonylmethyl-4-cyano-3-chlorobenzoate in a mixed solution (1:1, 10 mL) of ethanol and tetrahydrofuran. The resulting mixture was stirred at room temperature overnight. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a 0.6:1 mixture (0.57 g, 89%) of the title compound and 2-chloro-3-(2-hydroxyethyl)-4-hydroxymethylbenzonitrile.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:48])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[O:47])=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:48])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[O:47])([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)O)C3=O)cc1)O2

Procedure:
A mixture of 570 mg of t-butyl α-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin3-yl}acetate (prepared as described in Example 51) and 6 ml of a 4N dioxane solution of hydrogen chloride was treated in the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 80°-85° C.
Reaction SMILES: [OH:1][C:2]1[C:26]([CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH2:33][O:34][CH3:35])[CH:24]=[C:23]([O:36][CH2:37][O:38][CH3:39])[C:3]=1[C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH2:33][O:34][CH3:35])[CH:24]=[C:23]([O:36][CH2:37][O:38][CH3:39])[C:3]=1[C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:8]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2O)cc1CC=C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2O)cc1CCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Then, 80 ml of an ethyl acetate solution of 7.22 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3,3'-bis(3-methyl-2-butenyl)chalcone was added to a suspension of 1.67 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed in advance, and the mixture was stirred at room temperature under atmospheric pressure in a hydrogen gas atmosphere for 4 hours. After the reaction, the suspension was filtered and the solvent was removed from the filtrate by distillation to obtain 6.23 g (yield=85.3%) of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3-isopentyl-4-methoxymethoxyphenyl)-1-propanone in the form of a syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)OC1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)OC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 97.6 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (18.0 mg, 0.094 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 0.094 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (250.0 mg, 98%) was isolated by chromatography (0-3% EtOAc-hexanes) as an orange oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]([NH:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:13]([NH:21][C:22]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:26][CH2:25]1)=[O:30])(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Reactant: ClCc1cccc2ccccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2cccc3ccccc23)CC1

Procedure:
1-Chloromethylnaphthalene (0.88 g, 0.005 m), 4-benzoylureidopiperidine (1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acidified with ethanolic HCl. The title compound was filtered off and dried as the hydrochloride salt, hemihydrate (1.2 g), m.p. 185°-186° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=3[C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:5]3[C:4]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:3][C:2]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[N:7][C:6]=3[C:8]=2[CH:14]=1
Reactant: CN1CCN(c2nc(Cl)nc3c2oc2ccc(Cl)cc23)CC1
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(N3CCN(C)CC3)c3oc4ccc(Cl)cc4c3n2)cc1
Temperature: 200 °C

Procedure:
To a solution of 2,8-dichloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidine (1.3 g, 3.0 mmol) in pyridine (4 mL) was added 4-methoxybenzylamine (4 mL, 30 mmol). After heating at 200° C. for 1 h in the microwave, the resulting mixture was concentrated and the residue was purified by FCC (CH2Cl2/MeOH) to give [8-chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-(4-methoxy-benzyl)-amine. The intermediate was then dissolved in TFA (7 mL) and heated at 65° C. for 3 h. The mixture was diluted with CH2Cl2 (20 mL) and H2O (20 mL). The product was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with 1 N NaOH (20 mL), dried, and concentrated. The residue was purified by reverse-phase chromatography to afford the desired product (523 mg, 55%). MS: 318.1. 1H NMR (CDCl3): 7.99 (d, J=1.99 Hz, 1H), 7.48-7.47 (m, 2H), 4.76 (s, 2H), 4.08-4.06 (m, 4H), 2.57-2.55 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[S:17][C:10]=2[C:9]=1[OH:31])=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1C(O)=C2C=C(C3C=CC(OC4C=CC=CC=4)=CC=3)SC2=C(Br)N=1)=O)CCC>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)[S:17][C:10]=2[C:9]=1[OH:31])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(-c3ccc(Oc4ccccc4)cc3)sc2c1O
Agent: CCCCOC(=O)c1nc(Br)c2sc(-c3ccc(Oc4ccccc4)cc3)cc2c1O
Product: CCCCOC(=O)c1ncc2cc(-c3ccc(Oc4ccccc4)cc3)sc2c1O

Procedure:
The title compound was prepared from a mixture of 4-bromo-7-hydroxy-2-(4-phenoxy-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 7-bromo-4-hydroxy-2-(4-phenoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 7-c, under conditions analogous to experimental example 13-a with isolation of the higher Rf isomer. MS: (+) m/z 420.03 (M+1).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24](C)[CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:27][C:28]1[N:36]=[CH:35][C:34]([I:1])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH2:24][CH3:25]
Reactant: NC(=O)CCC(=O)NI
Reactant: CC(C)COc1ncccc1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (25 mL) were added to 2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was refluxed for 2.5 h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].Br[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=2)[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: Cc1ccc(Br)nc1
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation, see Intermediate 52) (153 mg, 0.434 mmol) and 2-bromo-5-methylpyridine (224 mg, 1.302 mmol) in toluene (10 mL) were successively added sodium tert-butoxide (417 mg, 4.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (398 mg, 0.434 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (342 mg, 0.868 mmol). The resulting mixture was stirred at 100° C. for 3 h then cooled to room temperature. The insoluble material was washed with 5% MeOH in DCM. The combined filtrate and washings were concentrated in vacuo and the residue was dissolved in a 1:1 MeOH/DMSO mixture and purified via MDAP (modifier: formic acid). The appropriate fractions were combined and the solvents evaporated using a blow down apparatus to give 4-{(2S,4R)-1-acetyl-2-methyl-4-[(5-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (27.5 mg, 0.066 mmol, 15%) as an off white solid.
Reaction SMILES: O[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N+:5]([O-:12])=[N:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>>[Cl:15][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N+:5]([O-:12])=[N:4][N:3]=1
Reactant: [O-][n+]1nnc(O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: [O-][n+]1nnc(Cl)c2ccccc21

Procedure:
The amino-benzotriazine N-oxide (16) is diazotized with NaNO2/HCl and the intermediate diazonium salt (not shown) is hydrolysed to form the hydroxybenzotriazine N-oxide compound (17). Reaction of the hydroxybenzotriazine N-oxide compound (17) with phosphorus oxychloride in the presence of a non-interfering base such as N,N-dimethylaniline gives the chlorobenzotriazine N-oxide compound (18). The chlorination reaction is typically carried out with heating, for example at reflux temperatures.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([P:22](Cl)(Cl)=[O:23])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1cccc(F)c1
Product: O=P1(c2cccc(F)c2)c2ccccc2CN1c1ccccc1
Yield: 13 %

Procedure:
The procedure of Example 38 was employed utilizing N-benzylaniline and 3-fluorophenyl phosphonic dichloride to yield 1-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.3 g, 13% yield) as a white solid having a melting point of 209°-210° C. and the following analysis: