Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:11])[C:8]=1[O:9][CH3:10])[NH2:5].[Br:12]Br>C(Cl)Cl>[Br:12][C:3]1[C:2]([Br:1])=[C:8]([O:9][CH3:10])[C:7]([Br:11])=[CH:6][C:4]=1[NH2:5]
Reactant: BrBr
Reactant: COc1c(Br)cc(N)cc1Br
Solvent: ClCCl
Product: COc1c(Br)cc(N)c(Br)c1Br
Reaction time: 0.75 h

Procedure:
3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[C:11]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([NH:26][C:27](=[O:37])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[NH2:36])[CH:25]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>C(O)(=O)C>[C:11]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([N:26]2[C:27](=[O:37])[C:28]3[C:29](=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:36]=[CH:1]2)[CH:25]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(=O)n(-c3cc(NC(=O)c4ccccc4)ccc3Cl)cnc2c1

Procedure:
Triethyl orthoformate (0.189 ml) was added to a stirred mixture of N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide (0.15 g), ethanol (10 ml) and glacial acetic acid (0.022 ml) and the resultant mixture was heated to 70° C. for 16 hours. The mixture was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated and the residue was triturated under a mixture of ethyl acetate and diethyl ether. The material so obtained was further purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.054 g); NMR Spectrum: (DMSOd6) 3.92 (s, 3H), 7.12–7.22 (m, 2H), 7.48–7.6 (m, 3H), 7.68 (d, 1H), 7.88–8.0 (m, 3H), 8.04–8.12 (m, 2H), 8.28 (m, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 406 and 408.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[C:22]([CH3:27])=[N:23][O:24][C:25]=1[CH3:26]>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[N:13]=1
Reactant: Cc1noc(C)c1CCl
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1c(C)noc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (10 ml, 15.5 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2.85 g, 15.5 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 4- chloromethyl-3,5-dimethylisoxazole (2.34 g, 16 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 4/1, silica gel).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH:38]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:39]1([N:44]([CH3:46])[CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C.C(O)C(N)(CO)CO>C(Cl)Cl.CN1CCCC1=O>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:37][CH:38]([C:39]1([N:44]([CH3:46])[CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:6]
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN(C)C1(C(NC(=O)c2c(Cl)cccc2Cl)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 2,6-dichlorobenzoic acid (20 mg; 0.105 mmol) in DCM (2 ml) and N-methylpyrrolidinone (0.1-0.5 ml) was added 1-hydroxybenzotriazole (18 mg; 0.11 mmol) and PL-dicyclohexylcarbodiimide (88 mg; 0.14 mmol; Polymer Labs 1.59 mmol/g). The mixture was shaken at room temperature for 1 hour and then 1-[amino(phenyl)methyl]cyclopentyl}dimethylamine dihydrochloride D2 (20 mg; 0.07 mmol) and PS-diisopropylethylamine (82 mg; 0.21 mmol; Polymer Labs 2.59 mmol/g) were then added and shaking continued overnight at room temperature. An excess of PS-Trisamine was then added and after shaking for a further 4 h, the mixture was filtered and the resins washed well with DCM and methanol. The filtrate was reduced in volume by evaporation in vacuo and loaded onto an SCX cartridge (500 mg). Washing with DCM, then methanol followed by elution with 1M ammonia in methanol afforded the title product (22.8 mg). 1H NMR (CDCl3) δ: 0.98 (1H, m), 1.26 (1H, m), 1.40 (2H, m), 1.68 (2H, m), 1.85 (2H, m), 2.22 (6H, s), 5.08 (1H, bs), 7.27 (7H, m), and 7.47 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 391 (MH+). C21H2435Cl2N2O requires 390. Ret. time 1.88 min.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[N+:13]([CH2:16][C:17]([CH3:19])=O)([O-:15])=[O:14].[NH2:20][C:21]1[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=1.C(O)(=O)C>C(O)(C)C.CS(C)=O>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]1[C:22]2[C:23](=[O:27])[NH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:17]([CH3:19])=[C:16]1[N+:13]([O-:15])=[O:14])[C:7]#[N:8]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1C1C([N+](=O)[O-])=C(C)Nc2cc[nH]c(=O)c21

Procedure:
688 mg (4.26 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 440 mg (4.26 mmol) of 1-nitroacetone, 470 mg (4.26 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 367 μl (6.40 mmol) of acetic acid in 10 ml of isopropanol and heated under reflux under argon for 12 h. After cooling, DMSO (5 ml) is added and the reaction solution is purified directly by preparative HPLC. 41 mg (2% of theory) of the title compound are obtained as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[O:12])=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)cc1)N[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 3-(4-hydroxyphenyl)propionic acid 7 (0.48 g, 2.9 mmol), amine 5 (0.50 g, 2.9 mmol), EDC (0.67 g, 3.5 mmol), and HOBT (0.39 g, 2.9 mmol) in DMF (5 mL) was stirred under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between H2O (25 mL) and EtOAc (50 mL). The organic layer was washed with H2O, 3N HCl (25 mL), H2O (25 mL), and saturated NaCl (25 mL). After drying (Na2SO4), concentration under reduced pressure gave (a) trans-3-(4-hydroxyphenyl)-N-(4-phenylcyclohexyl)propionamide (0.65 g, 69%) which was used without further purification: 1H NMR (300 MHz, CD3OD) δ 7.28-7.06 (m, 5H), 3.74-3.60 (m, 1H), 2.80 (t, J=4 Hz, 2H), 2.51-2.36 (m, 3H), 1.97-1.82 (m, 4H), 1.67-1.51 (m, 2H), 1.40-1.21 (m, 2H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14]C(C(O)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.[C:19](Cl)(=O)[C:20]([Cl:22])=[O:21].C(Cl)[Cl:26]>CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][C:19]([C:20]([Cl:22])=[O:21])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:26])=[O:8])=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Yield: 93 %

Procedure:
A solution of biphenyl-4.4′-dicarboxylic acid (200 mg. 0.8 mmol) in 15 mL of CH2Cl2 was stirred with oxalyl chloride 0.8 mL. 9 mmol) and 1 drop DMF under Ar for 18 h. Removal of solvents in vacuo afforded 211 mg (93%) of biphenyl-4,4′-dicarbonyl dichloride as a yellow solid. Spectral data matches the referenced spectral data. IR (CH2Cl2) 1781 (C═O) cm; H NMR (CDCl3), 360 MHz) δ 8.2 (d, J=8.2 Hz, 4H(C═O)ArH), δ 7.7 (d. J=8.7 Hz, 4H, ArH); 3C NMR (CDCl3, 90 MHz) δ 167.9, 145.8, 133.2, 132.1, 127.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:22][CH3:23])(=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:23][O:22][C:11](=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([O:18][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[C:14]([O:15][CH3:16])[CH:13]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)c(OC)c1
Yield: 42.4 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with methyl vanillate (3.64 g, 20 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 4-(4-bromo-2-formyl-phenoxy)-3-methoxy-benzoic acid methyl ester as a white solid (Yield 3.1 g, 92%).
Reaction SMILES: FC(F)(F)C(OCC)=O.O.NN.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21](Cl)[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.[F:30][C:31]([F:38])([F:37])[C:32]1[NH:36][N:35]=CN=1>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)[C:32]([C:31]([F:38])([F:37])[F:30])=[N:36][N:35]=2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ncn[nH]1
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CCOC(=O)C(F)(F)F
Agent: NN
Solvent: CO
Solvent: O
Product: FC(F)(F)c1nnc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
Ethyl trifluoroacetate (2.9 g) was added to hydrazine hydrate (1.1 g, 99-100%) in methanol (20 ml) at 5°-10° and stirred for 15 min. N-(4-chlorophenyl)-4-chlorobenzimidoyl chloride (5.7 g) was added keeping the temperature below 5°for 3 hr and then at reflux for 1 hr 3,4bis 4-chlorophenyl)-5-trifluoromethyl-1,2,4-triazole crystallized on cooling (4.1 g, 57.8%) m.p. 184°. (Found: C, 50.54%; H, 2.40%; Cl, 19.6%; F, 15.8%; N, 11.54%. C15H8Cl2F3N3 requires: C, 50.30%; H, 2.25%; Cl, 19.8%; F, 15.9%; N, 11.73%) δ (CDCl3); 7.43 (m).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.1 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10 g, 0.0543 mol) and N,N-diisopropylethylamine (14.2 mL, 0.0814 mol) in dry dichloromethane (200 mL) at 0° C. under nitrogen was added dropwise a solution of 4-bromobenzenesulfonyl chloride (10.4 g, 0.0407 mol) in dry dichloromethane (80 mL) over 10 minutes. The ice bath was removed and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was then washed with 1 M hydrochloric acid (2×250 mL), 0.5 M sodium hydroxide (250 mL) and water (250 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a purple syrup (17.91 g). Purification by flash chromatography using a solvent gradient of 5 to 10% ethyl acetate in hexane afforded a tan solid (3.21 g) that was recrystallized from ethyl acetate/hexane to afford the title compound (2.55 g, 16%) as a tan crystalline solid, m.p. 128-129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.C(N(CC)CC)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1.Cl>O1CCCC1>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.1 %

Procedure:
To a solution of 100 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26 and 0.1 ml of triethylamine in 5 ml tetrahydrofuran was added 55 mg of nicotinic acid chloride hydrochloride, and the mixture was stirred at room temperature for two days. After the completion of the reaction, the reaction mixture was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 62 mg of the title compound as a colorless powder.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[CH:22][CH:21]=3)[C:14]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[CH:22][CH:21]=3)[C:14]([CH2:16][CH2:17][CH:18]=[O:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Nc1ncnn2cc(CCCO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2cc(CCC=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Yield: 99.1 %

Procedure:
To a solution of THF (5 mL) was added N-{4-[4-amino-6-(3-hydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (55 mg, 0.11 mmol) followed by Dess-Martin Periodinane reagent (0.29 mL, 0.14 mmol, 15% wt in CH2Cl2). The reaction was stirred until HPLC indicated completion of reaction (2 h). The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3/Na2S2O3 1:1 (3×). The aqueous layer was back extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give a crude yellow solid (53 mg, 96%) that was used without further purification. 1H-NMR (DMSO-d6) δ 9.35 (s, 1H), 8.98 (s, 1H), 8.62 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.62 to 7.28 (m, 6H), 2.71 (t, J=7.5 Hz, 2H), 2.41 (t, J=7.4 Hz, 2H); MS [M+H]+=487; LCMS RT=2.62 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1>C(O)CCC>[OH2:12].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:17])[CH2:23]2)[N:3]=1.[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:17])[CH2:23]2)[N:3]=1
Reactant: CC1CNCCN1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCCCO
Product: COc1cc2nc(N3CCNC(C)C3)nc(N)c2cc1OC
Product: O
Yield: 42.9 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (8.05 g.) and 2-methylpiperazine (10 g.) were heated under reflux in butanol for 15 hours. The reaction was then evaporated in vacuo and the residual oil was taken up in chloroform (200 ml.), washed with water (4×50 ml.), dried (Na2SO4) and evaporated in vacuo. The residual oil (13 g.) was recrystallized from isopropanol to give 4-amino-6,7-dimethoxy-2-(3-methylpiperazin-1-yl)quinazoline hemihydrate (3.0 g.), m.p. 185°-187° C.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].C(O)(=O)C.[CH3:16][S-:17].[Na+].[Cl-].[Na+]>O.C(#N)C>[C:6]1([S:3]([CH2:1][CH2:2][S:17][CH3:16])(=[O:4])=[O:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CSCCS(=O)(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 6.5 h
Yield: 90 %

Procedure:
To a three-neck 50 mL round bottom flask equipped with a temperature probe, magnetic stirring, and bleach scrubber was charged in sequence 3.43 g (20.39 mmol) phenyl vinyl sulfone followed by 5 mL of acetonitrile, and the mixture was then cooled in an ice-water bath. To this mixture was then added 2.53 g (42.13 mmol) of glacial acetic acid in one portion. To this mixture was con-added 10 g (21.40 mmol) of a 15 wt % sodium thiomethoxide in water solution over a 17 min period. The internal reaction temperature rose from 14° C. to 17° C. during the sodium thiomethoxide addition. The ice-water bath was removed and the reaction mixture was heated to 50-60° C. for 3.5 h at which time liquid chromatography (LC) analysis indicated about 42% (relative area) of starting phenyl vinyl sulfone in the reaction mixture. Another 4.76 g (10.19 mmol) of a 15 wt % sodium thiomethoxide in water solution was added over a 9 min period. The reaction mixture was then stirred an additional 6.5 h at 50-60° C., and then cooled to ambient temperature and allowed to stir overnight. At this time LC analysis indicated about 7% (relative area) of starting phenyl vinyl sulfone in the reaction mixture. To the reaction mixture was added 1.37 g (23.44 mmol) of sodium chloride and the reaction phases were allowed to separate. The organic layer was concentrated on a rotary evaporator to give 3.96 g of methyl 2-phenylsulfonylethyl sulfide as a yellow oil (yield was ˜90% based on theoretical yield). 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 3H), 2.78 (m, 2H), 3.35 (m 2H), 7.1 (m, 2H), 7.7 (m, 1H), 7.9 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 15.5, 26.4, 56.0, 127.9, 129.4, 134.1, 138.6.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:32][C:33]([O:35]C)=[O:34].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:32][C:33]([OH:35])=[O:34]
Reactant: COC(=O)CC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-3-phenylpropanoate (0.22 g, 0.39 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.033 g, 0.78 mmol) in water (1 mL). After stirring at room temperature for 24 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.080 g, 37%); 1H NMR (DMSO-d6): δ 1.45 (d, 1H, J=13.2 Hz), 1.55 (d, 1H, J=13.2 Hz), 1.81 (t, 2H, J=6.8 Hz), 2.33 (t, 2H, J=6.8 Hz), 2.48-2.50 (m, 2H), 2.57-2.68 (m, 4H), 3.07-3.10 (m, 2H), 3.84 (t, 2H, J=6.8 Hz), 4.37 (d, 1H, J=5.2 Hz), 4.70 (d, 1H, J=5.2 Hz), 5.52 (t, 1H, J=7.2 Hz), 6.75 (t, 1H, J=7.2 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=3.2 Hz), 7.16-7.24 (m, 3H), 7.29-7.32 (m, 1H), 7.37 (d, 4H, J=4 Hz), 10.80 (s, 1H), 11.50 (br, 1H); MS for C32H35N5O4 m/z 554.05 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:28]([Cu])#[N:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:28]#[N:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 530 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:28]2[N:37]=[CH:36][C:35]3[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=3)[C:29]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=2)[C:15](=[O:26])[N:14]([CH3:27])[N:13]=1)(=O)C.O.[OH-].[Li+]>CC(O)C.O1CCCC1>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=4)[C:15](=[O:26])[N:14]([CH3:27])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nn1C
Temperature: 30 °C
Reaction time: 2 h
Yield: 18.4 %

Procedure:
To a solution of 127c (176 mg, 0.30 mmol) in propan-2-ol (4 mL), tetrahydrofuran (4 mL), and water (1.0 mL) was added lithium hydroxide (72 mg, 3.0 mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 127 (30 mg, 18%) as a white solid. MS-ESI: [M+H]+ 544.8. 1H NMR (500 MHz, MeOD) δ 8.66 (d, J=5.0 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.88 (s, 1H), 7.76-7.72 (m, 2H), 5.97 (s, 1H), 4.68 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H), 2.29 (s, 3H), 1.47 (s, 9H)