Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]([CH2:18][CH2:19][CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][C:29]([S:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][C:25]=2[O:24][CH2:23][C:22]1=[O:45])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[O:45]=[C:22]1[N:21]([CH2:20][CH2:19][CH2:18][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:26]2[CH:27]=[CH:28][C:29]([S:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1ccccn1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCNc1ccccn1)c1ccccc1

Procedure:
To a solution of titanium (IV) chloride in tetrahydrofuran under nitrogen atmosphere, is added and equimolar amount of stannous chloride dihydrate, and the mixture is stirred 1 hour at room temperature. Then, a solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is added and the mixture heated 3 hours at 40° C. After evaporation of the solvent, ice and aqueous sodium bicarbonate are added, the mixture extracted with ethyl acetate, and the organic layers are combined and dried over sodium sulfate. The solvent is evaporated and ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is isolated by column chromatography. A solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate in acetic acid is treated with a solution of 30% hydrobromic acid in acetic acid at room temperature overnight. The solvent is evaporated under reduced pressure, and the residue is treated with a saturated sodium bicarbonate solution. The aqueous mixture is extracted with dichloromethane. The organic extracts are dried over sodium sulfate, evaporated to small volume and the product is purified by flash chromatography
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:7]2[CH:8]=[C:9]([CH2:12][O:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([CH2:24][CH3:25])[CH:15]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[N:33]=[N:34][N:35](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:36]=1>CO.C(O)C>[ClH:1].[Br:2][C:3]1[C:7]2[CH:8]=[C:9]([CH2:12][O:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([CH2:24][CH3:25])[CH:15]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[NH:36][N:35]=[N:34][N:33]=1
Reactant: CCc1cc(OCc2ccc3oc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c(Br)c3c2)c2c(n1)CCCC2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCc1cc(OCc2ccc3oc(-c4ccccc4-c4nnn[nH]4)c(Br)c3c2)c2c(n1)CCCC2
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (1 ml) was added to a suspension of 4-[(3-bromo-2-(2-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline (A) (650 mg) in methanol (2 ml) and ethanol (4 ml). The mixture was warmed gently until the solid dissolved and then left to stand for 2 hours. The precipitated solid was filtered off, slurried with ether (10 ml) and recrystallised from methanol to give 4-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline hydrochloride, m.p. 210°-212° C.; NMR (d6 -DMSO): 1.3(t, 3H), 1.65-1.9(m, 4H), 2.5-2.7(m, 2H), 2.9-3.1(m, 4H), 5.6(s, 2H), 7.55(s, 1H), 7.6(s, 2H), 7.7(s, 1H), 7.75-7.85(m, 2H), 7.9-8.0(m, H); mass spectrum (+ve fast atom bombardment (+FAB), DMSO/Methanol/nitrobenzyl alcohol(NBA)): 532 (M+H)+ ; microanalysis, found: C, 57.0; H, 4.6; N, 12.4%; C27H24BrN5O2.HCl requires: C, 57.2; H, 4.45; N, 12.4%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:37])=[O:17])[CH2:15][C@@:7]3([OH:45])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36]([NH:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:37])=[O:17])[CH2:15][C@@:7]3([OH:45])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)Nc1ccccc1)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)[C@@H]1OC(=O)Nc1ccccc1
Yield: 18.9 %

Procedure:
To (1S,2R,4aR,8R,8aR)-8a-hydroxy-2-[(1H-imidazol-1-ylcarbonyl)oxy]-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 142, 510 mg, 0.83 mmol) in anhydrous pyridine (10 ml) was added aniline hydrochloride (500 mg, 3.8 mmol) and 4-dimethylaminopyridine (240 mg, 2.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 days before pouring into dichloromethane (100 ml) and washing with saturated aqueous citric acid solution (2×50 ml). The organic fraction was dried (Na2SO4) and concentrated in vacuo to give a yellowish solid (490 mg, 93%). The crude product was purified by flash column chromatography on silica gel eluting with a hexane:ethyl acetate gradient (1:1 to 1:5). The pure fractions were collected and concentrated in vacuo to give (1S,2R,4aS,5S,8R,8aR)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-2-{[(phenylamino)carbonyl]oxy}-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (440 mg, 83%). To a solution of the (1S,2R,4aS,5S,8R,8aR)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-2-{[(phenylamino)carbonyl]oxy}-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (100 mg, 0.157 mmol) in ethyl acetate (30 ml) was added platinum(IV) oxide (10 mg, 0.044 mmol) and the resulting mixture was hydrogenated at room temperature under 60 psi hydrogen for 10 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product, was purified by flash column chromatography on silica gel eluting with hexane ethyl acetate (1:1). The product was further purified to give the title product (19 mg, 19%).
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])[O:14][N:13]=1)C.Cl>O.O1CCOCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([OH:24])=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:25])=[O:6])[CH:16]=2)[CH:22]=1
Reactant: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Add a solution of LiOH.H2O (2.14 g, 51.0 mmol) in water (30 mL) to a rapidly stirred solution of 5-[5-(5-chloro-2-hydroxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (3.30 g, 10.2 mmol) in dioxane (60 mL), stir at room temperature overnight. After 1 hour, acidify to pH 1 with 5N HCl solution and place in refrigerator. Filter out solids and rinse with water to afford the title compound (2.73 g, 91%). MS (IS) 296 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[K+].[Br-].[CH2:19](O)[CH3:20]>>[CH2:19]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([OH:1])[CH:10]=[C:9]([OH:11])[CH:8]=1)[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc(O)cc(O)c1

Procedure:
To a solution of 3,5-dihydroxy benzoic acid, 1 (19 g, 123 mmol) in dry ethanol (250 mL) was added 2-3 mL of concentrated sulphuric acid drop wise and refluxed for 8 h. Ethanol was evaporated on rotavapor, diluted with water and extracted with ether. Combined ethereal layers were again washed with saturated sodium bicarbonate solution, water and dried over sodium sulphate, filtered and evaporated to dryness to afford 3. Yield 16.8 g (75%); mp 128-130° C.; MS (FAB) 183 (M++1); IR (KBr) 3496, 1819, 1687; 1H NMR (200 MHz, DMSO-d6) δ 9.89 (s, 2H), 7.06 (d, J=2.2 Hz, 2H), 6.69 (t, J=2.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.52 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])=[CH:4][C:3]=1[N+:18]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: [H][H]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1ccc(F)c(N)c1
Yield: 60.8 %

Procedure:
A mixture of N-[(4-fluoro-3-nitrophenyl)carbamoyl]glycine, ethyl ester (8 g, 0.029 mol) and 5% platinum on activated carbon (0.5 g) in ethyl acetate is hydrogenated at 50 psi until hydrogen uptake is complete. The reaction mixture is then filtered and cooled in an ice-bath until a solid forms. The solid is collected by filtration and air-dried to give the title product as a white solid (4.5 g, mp 152°-153° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:5]>C1COCC1.[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g) was dissolved in THF (70 ml) and ACOH (5 ml) and Zn (10 g) were added. The mixture was stirred for 1 h and filtered through Celite®. The filtrate was rinsed with EtOAc and the organics were evaporated to a residue which was purified on silica gel chromatography (40% EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[Cl:18])=[C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(CC)C1C=CC=CC=1)C.C1(C)C=CC=CC=1>CCCCCC.CCOC(C)=O>[Cl:22][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[Cl:18])=[C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2cnn3c(O)cc(C)nc23)c(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cnn3c(Cl)cc(C)nc23)c(Cl)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 mmol), N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) was stirred at reflux temperature for 3 hours, then it was cooled to ambient temperature. The volatiles were removed in vacuo. Flash chromatography (EtOAc:hexane::1:2) on the residue gave 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (900 mg, 84% yield) as a yellow oil: NMR (CDCl3, 300 Hz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 71.6 (d, 1H, J=7), 6.80 (s, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS: 306 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([N+:21]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CCOC(C)=O>[NH2:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:24])[N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:20][CH2:19]2
Reactant: CC(C)(C)c1ccc(N2CCc3cccc([N+](=O)[O-])c3C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2CCc3cccc(N)c3C2=O)cc1
Reaction time: 3 h

Procedure:
A solution of the nitro compound (Step D, 100 mg, 0.31 mmol) and EtOAc (5 mL) was hydrogenated over 10% Pd/C (20 mg) at atmospheric pressure and RT. After 3 h, the mixture was filtered through Celite® and concentrated in vacuo. Purification by silica flash chromatography (0-15% EtOAc:hexane) gave the desired compound as a white solid. MS m/e 295 (M+H)+. Calc'd for C19H22N2O-294.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:23]#[C:22][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3cccnc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (420 mg, 1.0 mmol) and commercially available 3-Ethynylpyridine (102 mg, 0.9 mmol) according to general procedure II. Obtained as an orange solid (230 mg, 58%). MS (ISP) 398.9 [(M+H)+]; mp 214–215° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:16][C:17]1[S:18][C:19]([C:23](O)=[O:24])=[C:20]([CH3:22])[N:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:23]([C:19]2[S:18][C:17]([Br:16])=[N:21][C:20]=2[CH3:22])=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
To a stirred mixture of 1-methyl-4-aminopiperidine (125 μL, 114 mg, 1 mmol) and triethylamine (570 μL, 414 mg, 4.1 mmol) in anhydrous tetrahydrofuran (1.0 mL), 2-bromo-4-methyl-thiazole-5-carboxylic acid (266 mg, 1.2 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide hydrochloride (232 mg, 1.2 mmol) and 1-hydroxy-benzotriazole (164 mg, 1.2 mmol) were sequentially and the mixture was stirred at room temperature for 22 h. After dilution with dichloromethane (20 mL), the mixture was washed with water (3×10 mL), dried over MgSO4 and concentrated. In this manner the title compound (277 mg, 0.87 mmol, 87%) was obtained as a yellow solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20](O)[C:21]#[CH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C1COCC1>[Br:50][C@H:20]([C:21]#[CH:22])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: C#C[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#C[C@@H](Br)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.75 h
Yield: 96.8 %

Procedure:
A flask was charged with (S)-1-[(tert-Butyldiphenylsilyl)oxy]-3-butyn-2-ol (1) (1.30 g, 4 mmol), triphenylphosphine (2.52 g, 9.60 mmol), THF (30 mL), pyridine (360 mg, 4.56 mmol). To this mixture was added carbon tetrabromide (1.53 g, 4.60 mmol) in THF (10 ml) over a 5 minute period. The resulting reaction mixture was stirred for 45 minutes. Hexanes (50 mL) was added, and the mixture was filtered and concentrated in vacuo. The residue was taken up into hexanes (50 mL), washed with 1 M HCl (40 mL), saturated NaCl (40 mL). The organic extracts were dried (MgSO4) and concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (98:02 hexane/EtOAc) afforded (R)-2-bromo-1-[tert-butyldiphenylsilyloxy]-3-butyne (4) (1.50 g, 97%) as a colorless oil (Note: this material is unstable and should be used immediately): Rf 0.74 (90:10 hexane/EtOAc); IR (neat) 3308, 1437, 1112, 701 cm-1 ; 1H NMR (CDCl3) δ 7.70 (m, 4 H), 7.42 (m, 6 H), 4.46 (dt, J1 =6.66 Hz, J2 =2.36 Hz, 1 H), 3.91 (ddd, J1 =10.7 Hz, J2 =6.32, Hz, J3 =3.78 Hz, 2H), 2.59 (d, J=2.4 Hz, 2 H), 1.08 (m, 9H); 13C NMR (CDCl3); δ 135.8, 132.8, 129.6, 127.6, 80.3, 75.6, 67.5, 36.2, 26.8, 19.3. ##STR19##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[O:19])[CH:5]=[C:6]2[C:14]=1[C:13](=[CH2:15])[C:12]1([OH:17])[O:16][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2>CO.[Pd].[H][H]>[OH:19][CH2:18][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([OH:1])[CH:3]=1)[CH:13]([CH3:15])[C:12]1([OH:17])[O:16][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2
Reactant: [H][H]
Reactant: C=C1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Solvent: CO
Product: CC1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Reaction time: 2 h

Procedure:
6,9-Dihydroxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (5 mg) was dissolved in methanol (2 ml), and the solution was subjected to catalytic reduction for 120 minutes using 10% palladium on carbon in hydrogen gas under atmospheric pressure at room temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness to give an oily residue of 4-hydroxymethyl-8-methyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-6,9-diol. This oil was dissolved in pyridine (1 ml) and to this solution was added acetic anhydride (20 μl), followed by allowing to stand at room temperature overnight. The resultant mixture was evaporated to dryness to give an oil, which was subjected to preparative thin layer chromatography. Development was carried out with a mixture of methanol and chloroform (5:95, v/v) to afford 4-acetoxymethyl-11-acetyl-9-hydroxy-8-methyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl acetate (3 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:25][N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH:28]=3)=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCN(C)CC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1 g, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (70 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (0.03 g, 0.03 mmol) in 10 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (0.6 mL, 1.2 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to room temperature, diluted with 100 mL DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide (0.10 g) as a pale yellow solid. Found MS (ES+): 399(M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])(=O)=O>ClCCl.C(OCC)(=O)C>[Si:54]([O:37][CH2:36][C:35]([CH3:39])([CH3:38])[O:34][C:31]1[CH:30]=[CH:29][C:28]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:33][CH:32]=1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.49 g) and 2,6-lutidine (0.33 mL) in dichloromethane (10 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.32 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.50 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][CH3:12])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH3:12])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)cc2cc(OC)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-5-methoxylindole (5.10 g, 31.6 mmol) in DMF (200 mL) is added sodium hydride (60%, 1.9 g, 47.4 mmol) at 0˜5° C., stirred for 30 min, ethyl 2-bromoacetate (8.35 g, 50 mmol) is added. After 2 hr at room temperature, the reaction is quenched by water, extracted with ether. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration yields the crude title product, which is used for next step without further purification.