Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:32]=[C:31]([C:33](=[N+]=[N-])[C:34]([O:36][CH3:37])=[O:35])[C:30]2[C:26](=[CH:27][N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:29]=2)[CH:25]=1>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:23][C:24]1[CH:32]=[C:31]([CH:33]([O:22][CH2:21][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)[C:34]([O:36][CH3:37])=[O:35])[C:30]2[C:26](=[CH:27][N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:45])[CH3:47])[N:29]=2)[CH:25]=1
Reactant: COC(=O)C(=[N+]=[N-])c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12

Procedure:
To a suspension of tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.26 g, 7.30 mmol) and rhodium(II) acetate dimer (4.84 mg, 11 μmol) in benzene (4 mL) at reflux was added a solution of methyl 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-diazoacetate (1.39 g, 3.65 mmol) in benzene (3 mL) via syringe pump over 60 h. After addition was complete, the reaction was cooled. It became a very viscous solution. The reaction mixture was diluted with 20% ethyl acetate/n-hexane and loaded onto a column. Column chromatography (20% ethyl acetate/n-hexane→25% ethyl acetate/n-hexane) gave 1.88 g (78%) as a yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.29 (dd, J=8.5, 5.2 Hz, 2H), 7.06 (s, 1H), 6.97 (dd, J=8.9, 8.5 Hz, 2H), 5.68 (d, J=10.7 Hz, 1H), 5.65 (d, J=10.7 Hz, 1H), 5.42 (s, 1H), 3.71 (bs, 2H), 3.61 (s, 3H), 3.60 (t, J=8.6 Hz, 2H), 3.39 (d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.16 (m, 1H), 2.08 (m, 1H), 1.93 (m, 2H), 1.42 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 170.5, 161.5 (d, J=246 Hz), 155.0, 145.6, 138.3, 128.9 (d, J=7.7 Hz), 127.9, 125.5, 122.8, 122.5, 119.5, 115.2 (d, J=21 Hz), 82.1, 79.4, 78.6, 76.4, 67.7, 52.3, 41.4, 40.0 (br), 32.1, 31.9, 28.6, 17.9, −1.4. Mass spec.: 662.53 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.37 g., 0.004 mole), potassium iodide (0.67 g., 0.004 mole), pyrrolidine (0.853 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and then concentrated in vacuo. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized to give 8-chloro-1-(pyrrolidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a stirred suspension of 5 (27.02 g, 150 mmole) in methanol (150 mL) at 4° C. was added sodium borohydride (5.67 g, 150 mmole) over a period of 0.25 h. After the addition was complete, the solution was warmed to room temperature and stirred for 0.25 h. The methanol was evaporated under vacuum. Water (150 mL) was added to the residue and the precipitate was filtered, washed with cold water, and air dried to afford 1-(2-amino-5-nitro-phenyl)-ethanol 6 (27.0 g, 99% yield). 1HNMR (400 MHz, DMSO-d6) δ1.27 (d, 3H, J=6.3), 4.77-4.82 (m, 1H), 5.36 (d, 1H, J=4.3 Hz), 6.50 (s, 2H), 6.63 (d, 1H, J=9.0 Hz), 7.85 (dd, 1H, J=2.8, 9.0 Hz), 8.07 (d, 1H, J=2.6); MS m/z 182 (M+).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[S:4]
Reactant: CC(=O)NCCCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)NCCCC(=NNC(N)=S)c1ccccc1
Yield: 60.7 %

Procedure:
Thiosemicarbazide (2.85 g, 31.3 mmol) was added to a solution of N-(4-oxo-4-phenyl-butyl)-acetamide (4.28 g, 20.9 mmol), prepared in the previous step, in 75 ml of methanol plus 5.6 ml of 1 N HCl, plus 5.6 ml of water and the reaction stirred at room temperature for 42 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 4.77 g of a yellow solid Recrystallization of this solid from ethyl acetate gave the title compound (3.53 g, 61%) as an off-white solid, mp 74-83° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH:11]1[CH2:16][C:15](=O)[O:14][C:12]1=[O:13].C(Cl)(=O)C>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH:11]1[CH2:16][C:15](=[O:14])[N:6]([C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]1=[O:13]
Reactant: O=C1CC(CCl)C(=O)O1
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Temperature: 100 °C
Yield: 93 %

Procedure:
In a variant of (b), into a toluene solution of 33.3 g (0.3 moles) 4-fluoroaniline, a toluene solution of 44.6 g (0.3 moles) 2-chloromethylsuccinic acid anhydride were added dropwise at room temperature while stirring. The temperature of the mixture rose to 40° C. during the operation. To the suspension of the semi-anilide obtained, 0.35 moles of acetylchloride was added dropwise at 60° C. while stirring, the addition being carried out so slowly that the ensuing gas development could be easily controlled. After 3 hours the reaction mixture was heated to 100° C. and held at that temperature until the gas development was terminated. The semi-anilide thereby dissolved. When the reaction mixture was cooled down, the desired product crystallized. The actual yield was 93% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]([CH3:21])[CH2:15][O:16][CH2:17][C:18](O)=[O:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6].S(Cl)(Cl)=O.CN(C=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:14]([CH3:21])[CH2:15][O:16][CH2:17][C:18]1=[O:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(NC(C)COCC(=O)O)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2C(=O)COCC2C)c(Cl)c1

Procedure:
Prepared analogously to Example 41c from ethyl 3-chloro-4-[2-(hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoate and thionyl chloride with DMF in dichloromethane.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Cl.[Cl:18][C:19]1[CH:25]=[C:24]([F:26])[C:22]([NH2:23])=[C:21]([F:27])[CH:20]=1.CCCCCC>C(O)(C)C>[ClH:2].[Cl:18][C:19]1[CH:25]=[C:24]([F:26])[C:22]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:21]([F:27])[CH:20]=1
Reactant: Nc1c(F)cc(Cl)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1cc2ncnc(Nc3c(F)cc(Cl)cc3F)c2cc1OC
Yield: 14.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (210 mg, 0.8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2,6-difluoroaniline hydrochloride (177 mg, 0.89 mmol) in isopropanol (8 ml) were heated at reflux for 2 hours. The reaction mixture was then allowed to cool, hexane added and the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2,6-difluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (45 mg, 16%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26]([N:3]3[CH2:4][CH:5]([CH3:8])[NH:6][CH2:7][CH:2]3[CH3:1])(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1
Reactant: CC1CNC(C)CN1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1CN(S(=O)(=O)c2cccc3cnccc23)C(C)CN1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
In 30 ml of methylene chloride were dissolved 1.75 g of 2,5-dimethylpiperazine and 1.53 g of triethylamine, and to the solution was added dropwise 20 ml of a methylene chloride solution containing 1.73 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution obtained was stirred at a temperature of 5° C. to 10° C. for three hours, and then the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. After the methylene chloride was distilled therefrom, the residue obtained was subjected to an alumina column chromatography (alumina: 50 g; solvent: chloroform) to give 1.38 g of 1-(5-isoquinolinesulfonyl)-2,5-dimethylpiperazine, Compound (40) in a yield of 59%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]1(=O)[C:28]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]1=O>>[F:12][C:11]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[C:26]1[C:27](=[N:8]2)[C:28]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]1=2
Reactant: Nc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Product: FC(F)(F)c1cccc2nc3c4ccccc4c4ccccc4c3nc12
Yield: 76 %

Procedure:
When 0.034 mole each of 2-amino-3-nitrobenzotrifluoride and phenanthrenequinone were reacted by the method of Example 1, 9 g. (76 percent yield) of 10-(trifluoromethyl)dibenzo[a,c]phenazine, mp = 195°-196° C., were obtained.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCOc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCCOc2ccccc2)cc1

Procedure:
A mixture of 7.0 g of ethyl p-[(11-phenoxyundecyl)amino]benzoate, 7.0 g of potassium hydroxide and 150 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is made acidic while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give white crystals, mp 117°-119° C. Recrystallization from ethanol gives white crystals, mp 118°-119.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1)#[CH:2].[CH:18]1([NH:21][C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](I)[CH:24]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH:18]1([NH:21][C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]#[C:1][C:3]3[CH:8]=[N:7][C:6]([NH:9][CH2:10][CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[CH:5][CH:4]=3)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: C#Cc1ccc(NCCN2CCOCC2)nc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1I
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1C#Cc1ccc(NCCN2CCOCC2)nc1
Temperature: 90 °C

Procedure:
5-Ethynyl-N-(2-morpholinoethyl)pyridin-2-amine (0.54 g, 2.36 mmol), N-cyclopropyl-3-iodo-4-methylbenzamide (0.71 g, 2.36 mmol), and triethylamine (0.49 mL, 3.54 mmol) were dissolved in dioxane (10 mL) before these were sparged with nitrogen for 15 min.; palladium dichloro-bis-triphenylphosphine (83 mg, 0.12 mmol) and copper (I) iodide (45 mg, 0.24 mmol) were added before the reaction mixture was heated to 90° C. for 6 h. The reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow oil. MS (ES+): 406 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[Br:8][C:9]1[C:13]2=[N:14][C:15]([CH2:18][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:17]=[C:12]2[S:11][CH:10]=1.[CH:38]([C:40]1[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]2([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:63][CH2:62]2)[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[Br:8][C:9]1[C:13]2=[N:14][C:15]([CH:18]=[CH:38][C:40]3[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]4([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:62][CH2:63]4)[CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=3)=[CH:16][CH:17]=[C:12]2[S:11][CH:10]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=O)c2)CC1
Reactant: Brc1csc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=Cc3ccc4scc(Br)c4n3)c2)CC1
Reaction time: 0.33 h

Procedure:
A 1 molar solution of potassium t-butoxide (0.57 mL, 0.57 mmol) was added to a -78° C. suspension of the phosphonium salt (0.290 g, 0.55 mmol) of Step 4, in 3 mL of THF. The temperature was brought to 0° C. for 20 min then lowered back to -78° C. followed by the addition of a 0.5 molar solution of methyl 1-(((1(R)-(3-formylphenyl)3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetate (1.47 mL, 0.44 mmol) of Step 17 of Example 1. The bath was brought to 0° C. for 1 hr and the reaction mixture was quenched with a 25% aqueous NH4OAc. The organic solvents were evaporated and the title product was purified by flash chromatography on silica with EtOAc:hexane 30:70 to yield 0.270 g (94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.FC(F)(F)[C:14](O)=[O:15].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>O>[CH:14]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[C:3]([O:2][CH3:1])=[O:11])=[O:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Methyl-4-hydroxybenzoate (4.56 g, 30 mmol) was mixed with trifluoroacetic acid (24 ml) and hexamethylenetetramine (8.41 g, 60 mmol) (Duff reaction). The reaction medium was heated to 80° C. for three hours and cooled to 0° C., followed by successive addition of 15 ml of 50% sulfuric acid and 90 ml of demineralized water. After stirring for one hour at room temperature, the medium was extracted with ethyl ether, washed with water, dried over magnesium sulfate and filtered, and the solvents were evaporated off. The product was purified by passage through a column of silica and was eluted with dichloromethane. After evaporation of the solvents, 1.92 g of a crystallized white solid are obtained, equivalent to a yield of 36%. Its properties were as follows:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:21]=[C:20]([CH2:22][OH:23])[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:21]=[C:20]([CH:22]=[O:23])[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: OCc1cc(Br)c2cccnc2c1-c1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cc(Br)c2cccnc2c1-c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
Dimethyl sulfoxide (0.038 mL, 0.54 mmol) was added to oxalyl chloride (0.0286 mL, 0.339 mmol) in methylene chloride (1.26 mL) at −78° C. After 10 minutes, [5-bromo-8-(3-fluorophenyl)quinolin-7-yl]methanol (0.075 g, 0.22 mmol) in methylene chloride (2.53 mL) was added and the resulting mixture was stirred at −78° C. for 30 minutes. Triethylamine (0.157 mL, 1.13 mmol) was then added and the mixture was stirred for 5 hours to room temperature. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting mixture was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (49 mg, 66%). LCMS calculated for C16H10BrFNO (M+H)+: m/z=330.0; Found: 330.0.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:16][C:12]1[C:13]([C:1](=[O:3])[CH3:2])=[CH:14][C:15]2[C:6]([CH3:19])([CH3:5])[CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]=2[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a 250 ml three-necked round bottomed flask fitted with a magnetic stirring bar and a reflux condenser containing acetyl chloride (2.3 g, 29.7 mmol) and 50 ml of DCM was added 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 1b (5 g, 24.8 mmol) followed by slow addition (ca. 0.5 g portions) of AlCl3 (7.5 g, 56.2 mmol). The brown mixture was stirred for 30 min and then heated at reflux for 15 min. Additional AlCl3 (1-2 g) was necessary to effect the completion of the reaction. The cooled reaction mixture was poured into 200 ml of vigorously stirred ice water followed by acidification with 20% aqueous hydrochloric acid 50 ml and addition of 100 ml of ethyl acetate. Stirring was continued until the organic layer was yellow 15 min. The organic layer was extracted with ethyl acetate (2×100 ml), dried over MgSO4, filtered and concentrated in vacuo. Kugelrohr distillation (80-120° C., 3×10−4 torr) gave an analytically pure sample of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)ethanone 5.31 g (88%) as a white solid; m.p. 54-56° C.
Reaction SMILES: [S:1]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:14])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>C(O)C>[S:1]([CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=1)[OH:4])[CH2:12][CH:13]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)[OH:14]
Reactant: O=C(CSCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CSCC(O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of Example 159A (5.0 g, 11.68 mmol) in ethanol (78 mL) was added sodium borohydride (0.972 g, 25.7 mmol) portionwise and the mixture was stirred at room temperature for 20 minutes. Afterwards the solution was concentrated, then a solution of 1N aqueous hydrochloric acid (100 mL) was added and extracted with EtOAc. The organic extract was dried, filtered and concentrated to 5.05 g (100%) of a colorless solid as the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([C:14]#[C:15][CH2:16][OH:17])=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH2:16][OH:17])[N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: OCC#Cc1cnc(Cl)nc1NC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc2cnc(Cl)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A dry nitrogen-flushed 5 L 4-neck round bottom flask is charged with 100 g (Purity: 98%, 0.389 mol 1.0 eq.) of 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-1-ol, (A1d), 880 g (1000 mL) of peroxide free tetrahydrofuran and 753 g, (856 mL) of tetrabutylammonium fluoride, 1.0M solution in THF. The content is stirred at 25° C. for 10 min, and then the solution is warmed to 60° C. This temperature is maintained for 1.5 h until the starting material, A1d, is ≦2.5±0.5% as determined by HPLC analysis. The resulting solution is cooled to below 30±3° C.2, and distilled under reduced pressure to remove THF. 79 g (100 mL) of 2-propanol is added. The sample is stirred for 15 min and 1000 g (1000 mL) of water then add slowly over 30 min The sample is stirred at 20±3° C. for 30 min and then filtered. The cake is washed twice with 200 g (2×100 mL) of water. The solids are dried at 50° C. for 16 h to afford Compound A1c as a tan, crystalline solid, mp=174-176° C.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]1[CH2:10][C:9]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.Cl>C(O)(=O)C.C(OCC)C>[Br:22][C:14]1[C:8]2[O:7][CH2:6][C@H:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH2:10][C:9]=2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=1
Reactant: BrBr
Reactant: COc1cccc2c1C[C@@H](NC(C)C)CO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(Br)c2c1C[C@@H](NC(C)C)CO2
Yield: 62 %

Procedure:
(R)-3-(N-Isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (4.02 g, 18.2 mmol) and anhydrous sodium acetate were dissolved in acetic acid (80 mL). To the stirred mixture was bromine (0.93 mL, 18.2 mmol) dissolved in acetic acid (40 mL) added dropwise under 1.5 h. The solvent was removed in vacuo, taken into a 2M NaOH solution and extracted twice with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent was removed in vacuo to give the crude residue. The hydrochloride salt was made by dissolving the pure base in diethyl ether and adding an excess of an ethereal HCl solution to give a white solid. The salt was recrystallized twice from ethanol/diethyl ether to give 3.8 g (62% yield) Mp: 257°-8° C. [α]21D =-97.7° (C=0.1 CHCl3). The free base was made from the hydrochloride salt to give an oil. GC-MS (70 eV) M=301 (100%).