Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)[C:3]=1[OH:58].C([O-])([O-])=O.[K+].[K+].[CH2:65](Br)[CH:66]=[CH2:67]>CC(C)=O.C([O-])(O)=O.[Na+]>[CH2:67]([O:58][C:3]1[C:2]([Br:1])=[C:7]([Cl:8])[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[CH:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:22]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:20]1)[CH:66]=[CH2:65]
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccc(OCC)cc2)c(Cl)c1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2-bromo-3-chloro-4-(4-ethoxybenzyl)-6-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenol (500 mg, 0.579 mmole) in acetone (15 mL) were added K2CO3 (120 mg, 0.869 mmole) and allyl bromide (75 μL, 0.869 mmole) continuously. The resulting solution was stirred at 60° C. overnight, diluted with a saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (325 mg, 62%) as a colorless gum.
Reaction SMILES: [BH4-].[Na+].[Br-].[Li+].[NH2:5][C:6]([C:28](OCC)=[O:29])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)[C:7](OCC)=[O:8].O>C(O)C>[NH2:5][C:6]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)([CH2:28][OH:29])[CH2:7][OH:8]
Reactant: CCCCCCCCc1ccc(CCC(N)(C(=O)OCC)C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69.8 %

Procedure:
A suspension of sodium borohydride (0.60 g) and lithium bromide (1.66 g) in ethanol (17 ml) was stirred at room temperature for 25 minutes. Ethyl 2-amino-2-ethoxycarbonyl-4-(4-octylphenyl)butyrate (1.24 g) was dropwise added thereto over 3 minutes and the mixture was stirred at room temperature for 5 hours. Water (40 ml) was added to the reaction mixture and the mixture was stirred for 40 minutes. The crystals precipitated was collected by filtration and dried to give 0.68 g of the subject compound, melting point=125-126° C. Treatment of the subject compound with hydrochloric acid-ethanol gives the corresponding hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([O:9][CH2:10][C:11]([OH:13])=[O:12])[N:5]=1
Reactant: CCOC(=O)COc1nc(C)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)nc(OCC(=O)O)n1

Procedure:
2g (9.5mmol) of the ethyl ester prepared in Example 7 were dissolved in 20ml of ethanol. 25ml of an aqueous solution (10% by vol) of sodium hydroxide were then added to the solution. The reaction mixture was refluxed for 4 hours. After the reaction was complete, as confirmed by thin layer chromatography, the ethanol was evaporated off, the aqueous residue cooled, acidified to a pH of 2 and the product extracted into chloroform. Following drying first over anhydrous sodium sulphate and then by evaporation, 0.6g (yield 35% by weight) of a reddish oil were obtained which oil crystallised on standing.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].F[C:9]1[C:10]([C:19]#[C:20][Si](C)(C)C)=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=1)[C:13]#[N:14].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([N:1]1[C:9]2[C:10](=[C:11]([C:17]#[N:18])[C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[CH:19]=[CH:20]1)[CH3:7]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Reactant: C[C@H](N)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](n1ccc2c(C#N)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
An oven-dried vial was charged with (S)-3-amino-2-methylbutan-2-ol (Example 21G) (0.064 g, 0.622 mmol), 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (0.126 g, 0.518 mmol), and K2CO3 (0.143 g, 1.036 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 30 min, the vial was sealed with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 15 min. The mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0659 g, 50% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.7 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 4.47 (q, J=7.0 Hz, 1H), 1.63 (d, J=7.0 Hz, 3H), 1.53 (s, 1H), 1.34 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[C:5]([O:9][CH3:10])(=[O:8])[CH:6]=O.CO.C(OC(=O)C)(=O)C>N(CC(O)=O)C>[CH:1](/[C:2](/[CH3:3])=[CH:6]\[C:5]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: CCC=O
Reactant: COC(=O)C=O
Agent: CNCC(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: COC(=O)/C=C(/C)C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
688 g (11.9 mol) of propionaldehyde were added within 45 min to a mixture of 968 g (11 mol) of methyl glyoxylate, 352 g (11 mol) of methanol and 9.6 g (0.11 mol) of sarcosine at 50° C. After the addition was complete, the mixture was stirred at 80° C. for 1 h and then 2805 g (27.5 mol) of acetic anhydride were added. Distillation was carried out under atmospheric pressure with a column until the top temperature was 105° C., to remove some of the methyl acetate/acetic acid, and then up to 125° C. to remove a mixture of methyl acetate, acetic acid, acetic anhydride and methyl 3-formylcrotonate. Distillation was then continued under 250 mbar up to 105° C. and then under 30 mbar until the top temperature was 90° C. The combined distillates were redistilled to give 1184 g (9.3 mol) of methyl 3 -formylcrotonate, corresponding to a yield of 84% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C[C:12]([N:14](C)C)=O>CCOC(C)=O>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:12]#[N:14])[C:3]=2[CH:10]=[CH:9]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccnc2[nH]ccc12
Temperature: 150 °C

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (10.13 g, 66.4 mmol) was dissolved into DMAC (100 mL). This solution was filtered to remove insoluble particles. N2 was purged into the solution while adding the following reagents: 4.68 g Zn(CN)2, 1.476 g dppf, 0.519 g Zn, and 1.227 g Pd2(dba)3. The greenish brown mixture was heated to 150° C. for 4 h. After cooled to RT, the mixture was filtered through a pad of Celite® and silica to remove Zn and Pd. The pad was washed with EtOAc and CH2Cl2. The filtrate was concentrated and the residue was taken into 500 mL EtOAc. This organic solution was washed with 10% NH4OH (500 mL) and sat'd NaCl (500 mL), dried over Na2SO4, filtered and concentrated to afford a dark residue, which was taken into 100-200 mL of EtOAc and resulting precipitate of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile was collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([OH:20])=[C:6]([CH2:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=2[OH:19])[CH:7]=1.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[NH2:16][C:11]1[C:10]([OH:19])=[C:9]([CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([NH2:21])[C:5]=2[OH:20])[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cc2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(Cl)cc(Cc2cc(Cl)cc(N)c2O)c1O
Reaction time: 4 h
Yield: 56.5 %

Procedure:
To a suspension of 36.3 g (0.1 mole) of 1,1-bis(5-chloro-2-hydroxy-3-nitrophenyl)methane of Example 19 in 300 ml of methanol-water (1:1) was added 145 g (0.4 mole) of sodium dithionate. The mixture was stirred for 4 hours and then filtered. The solid was dissolved in 22 g of ethyl acetate and washed with water, dried over magnesium sulfate and concentrated to yield 16.9 g of product of m.p. 212°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:19][N+:16]([O-:18])=[O:17])[CH2:9][C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CC(C[N+](=O)[O-])CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (6.2 g, 30 mmol) in nitromethane (64.5 g, 1.06 mol) under an atmosphere of nitrogen was added DBU (4.59 g, 30.2 mmol). The reaction mixture was stirred overnight at room temperature. The product mixture was concentrated under vacuum. The residue was purified using column chromatography on silica gel eluting with 50%-100% ethyl acetate in hexanes. Collection and concentration of appropriate fractions provided the title compound as pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 7.01 (t, J=8.7 Hz, 2H), 4.64 (d, J=14.6 Hz, 1H), 4.48 (d, J=14.5 Hz, 1H), 4.34 (m, 2H), 3.27 (m, 2H), 2.23 (dd, J=17, 10.6 Hz, 1H), 2.0 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:13][C:10]3[CH:11]=[CH:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:8]([CH3:14])[CH:9]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(O)ccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-phenyl-3-methyl-phenol (1 eq), 4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 eq) and PPh3 (1.5 eq) in dry THF (3 mL) is added 1,1′-(azodicarbonyl)-dipipperidine (1.5 eq) in THF (1 mL). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by silica gel chromatography (10% EtOAc in hexanes) to give 4-[4-(4-phenyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=O)=[CH:25][CH:24]=1.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:25][CH:24]=1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=CCCc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2ccc(F)cc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(4-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 0.88 g (64.2%, yellow oily substance) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[C:5]([F:16])[CH:4]=1.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH:19]1C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][CH:19]2[CH2:20][CH2:21][CH2:22][C:18]2=[O:17])[CH:4]=[C:5]([F:16])[C:6]=1[CH:10]([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C1CCCC1=O
Reactant: COC(=O)C(C)c1c(F)cc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(=O)O)c1c(F)cc(CC2CCCC2=O)cc1F
Yield: 80.3 %

Procedure:
Compound (32b) (2.2 g, 7.5 mmol), methyl 2-oxocyclopentane-carboxylate (1.3 mL, 11.3 mmol), and anhydrous potassium carbonate (1.9 g, 13.6 mmol) in acetone (100 mL) were allowed to react in the same manner as in Example 15. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional decarboxylation and hydrolysis to give 1.7 g (64%) of compound (33b) of interest as clear yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[S:13][C:12]([CH:14](O)[C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[S:13][C:12]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(C(O)c2cc(OC(C)C)cc(C(=O)O)c2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(Cc2cc(OC(C)C)cc(C(=O)O)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[5-(diethoxy-phosphoryl)-thiophen-2-yl]-hydroxy-methyl}-5-isopropoxy-benzoic acid (700 mg, 1.64 mmol) in CH2Cl2 (10 ml) was added TFA (1.1 ml), followed by triethylsilane (0.92 ml, 5.72 mmol). The reaction mixture was then stirred at r.t. for 30 min, concentrated down, re-dissolved in water, extracted with EtOAc. The EtOAc layer was separated, dried over MgSO4, filtrated, and concentrated to afford the crude product 3-[5-(diethoxy-phosphoryl)-thiophen-2-ylmethyl]-5-isopropoxy-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9]Br.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(=S)=S>[F:1][C:2]1[CH:7]=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: S=C=S
Solvent: O
Product: Oc1ccc(Br)cc1F
Reaction time: 8 h

Procedure:
2-Fluorophenol (56.03 g) was dissolved in carbon disulphide (100 ml). A solution of bromine (87.89 g) in carbon disulphide (30 ml) was added dropwise over a period of 5 hours with vigorous stirring. The mixture was allowed to stand overnight at room temperature, then was poured into water (80 ml). A saturated solution of sodium thiosulphate (200 ml) was added and the mixture shaken. The organic layer was separated, washed with saturated sodium bicarbonate solution (100 ml) and water (150 ml). The organic layer was dried over anhydrous sodium sulphate, then was evaporated to leave 2-fluoro-4-bromophenol as an orange oil. This was distilled at about 14 mm Hg pressure. The fractions distilling at 89°-92° C. (65 g 98% pure by g.l.c.) and 92°-96° C. (10 g 97% pure by g.l.c.) were collected.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([SH:20])=[N:18][N:17]=[N:16]2)[CH:12]=[CH:13][CH:14]=1)(=O)CCCCC.[ClH:21]>C(O)C>[ClH:21].[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([SH:20])=[N:18][N:17]=[N:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCC(=O)Nc1cccc(-n2nnnc2S)c1
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-n2nnnc2S)c1
Temperature: 25 °C

Procedure:
In 450 ml of ethanol was dispersed 150 g (0.51 mol) of 1-(3-hexaneamidophenyl)-5-mercaptotetrazole, and 300 ml of concentrated hydrochloric acid was added to the resulting dispersion while stirring at room temperature. They were further reacted at room temperature for 3 hours and, thereafter, cooled with ice. The thus-precipitated crystals were filtered off and washed with acetone to obtain 110 g of a 1-(3-aminophenyl)-5-mercaptotetrazole hydrochloric acid salt. This amine hydrochloric acid salt was dispersed in 750 ml of acetonitrile, and 485 ml of triethylamine was added thereto. Thereafter, 125 g of butyl isocyanate was added dropwise at room temperature. They were further reacted at room temperature for 6 hours. At the end of the time, 2,200 ml of water was added, and the pH of the resulting solution was adjusted to 2 with hydrochloric acid. The thus-precipitated crystals were filtered off, and recrystallized from ethanol to obtain 69 g (yield, 46%) of the desired compound, m.p. 171°-172° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.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:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)c2cc(-c3ccccc3-c3ccccc3)ccc21

Procedure:
Under the atmosphere of argon, 3.4 g (14 mmole) of 2-chloro-anthraquinone, 5 g (17 mmole, 1.2 eq) of 2-biphenylylboronic acid, 0.32 g (0.35 mmole; 5% by mass Pd) of tris(dibenzylideneacetone)dipalladium(0) and 14 g (43 mmole; 2.5 eq) of cesium carbonate were suspended in 40 ml of anhydrous dioxane. Then, 1.1 ml (25% by mass; 0.98 mmole; 1.4 eq to Pd) of a toluene solution of tricyclohexylphosphine was added, and the resultant mixture was stirred at 80° C. for 10 hours.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:26])[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CNC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(c1ccc(F)cc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
2,5-Difluoronitrobenzene (2.69 ml, 24.84 mmol), 1-benzyl-4-methylaminopiperidine (EXAMPLE 9, 5.00 g, 24.84 mmol), and potassium carbonate (4.12 g, 29.81 mmol) are refluxed in acetonitrile for 21 hr. The mixture is then poured into water and extracted with chloroform. The extract is dried over sodium sulfate, filtered and concentrated. The concentrate is chromatographed (silica gel; ethyl acetate/hexane) to give the title compound, NMR (300 MHz, CD3OD) 7.45, 7.37, 7.29, 3.46, 2.99, 2.87, 2.64, 1.98 and 1.67δ.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ncnc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccccc12
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
A mixture of 4-hydroxyquinazoline (2.56 g, 17.5 mmol) and POCl3 (8.0 mL, 88 mmol) was stirred at 140° C. (oil bath) for 10 min. The homogeneous light amber solution was then allowed to cool to rt before concentrating under reduced pressure at 70° C. The translucent residue was dissolved in DCM (25 mL), and the homogeneous yellow solution was partitioned with ice and 1 M NaHCO3 to pH ˜6 (paper) (˜20 mL aq layer). The organic layer was dried twice (Na2SO4), filtered through a 0.22 micron filter, and concentrated under reduced pressure (bath <40° C.) to provide the title compound as a yellow solid (2.53 g, 88%). 1H-NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.30 (ddd, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[O:34])=[CH:28][CH:27]=3)[C:14]([C:16]3[O:17][CH2:18][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=3)=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.CO.C(Cl)Cl>[NH2:6][C:7]1[C:12]2=[C:13]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[O:34])=[CH:28][CH:27]=3)[C:14]([C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=3)=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)C1COC(c2cn3ncnc(N)c3c2-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)=N1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1coc(-c2cn3ncnc(N)c3c2-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of THF (2 mL) and DCM (2 mL) cooled in an ice/water bath was added ethyl 2-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)-4,5-dihydro-1,3-oxazole-4-carboxylate (Example 236) followed by DBU (24 μL, 0.16 mmol) and BrCCl3 (16 μL, 0.16 mmol). The solution was allowed to stir under N2 for 1 h and then the solution was left to warm to rt while stirring for 17 h. The reaction mixture was evaporated in vacuo and then purified by flash chromatography 50:45:5 v/v/v DCM/EtOAc/MeOH resulting in the isolation of 16 mg of the title compound as a white solid (0.028 mmol, yield 65%). 1H-NMR (DMSO-d6) δ 9.35 (s, 1H), 8.96 (d, J=2.8 Hz, 1H), 8.69 (s, 1H), 8.62 to 8.60 (d, J=9.3 Hz, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.58 to 7.56 (d, J=8.4 Hz, 2H), 7.52 to 7.47 (m, 1H), 7.40 to 7.37 (m, 3H), 4.27 to 4.23 (q, J=6.3 Hz, 2H), 1.28 to 1.24 (t, J=7.1 Hz, 3H); MS [M+H]+=570.1; LCMS RT=3.16 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.O1CCCC1.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(C)c1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Ethyl 2-(3-methyl-4-nitrophenyl)propanoate (1.2 g, 5.05 mmol) was dissolved in methanol and tetrahydrofuran (1:1, 15 mL). 10% Pd/C (180 mg, 10%) was added to it. The resulting mixture was stirred at room temperature for 3 h under H2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure. The crude was purified by column chromatography to give ethyl 2-(4-amino-3-methylphenyl)propanoate (944 mg, 90%).