Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCC)C.[Li]CCCC.[Br:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17].CN([CH:21]=[O:22])C>C1COCC1.CCCCCC>[Br:11][C:12]1[S:13][C:14]([CH:21]=[O:22])=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccsc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: CCCCCC
Product: Cc1cc(C=O)sc1Br
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was added at −40° C. under nitrogen a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol) in hexane. After addition, the solution was stirred at −40° C. under nitrogen for 30 minutes, cooled to −78° C. and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450 mL). The reaction solution was stirred at −78° C. for 30 minutes and treated with anhydrous DMF (100 mL). The mixture was allowed to warm to ambient temperature and was quenched with IN aqueous hydrochloride solution (1 L). The solution was extracted with ethyl acetate (3×450 mL) and the extracts washed with water, brine and dried (MgSO4). After removal of solvent in vacuo, the title compound was obtained as a white solid (46 g, 88.3%). A sample of the product was crystallized from hexane: mp 63-65° C.; IR (KBr) 1654 cm−1. 1H-NMR (CDCl3) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206 (M+). Anal. Calc. For C6H5BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7]O)[C@@H:4]([OH:5])[C@H:2]1[OH:3].[N-:20]=[N+:21]=[N-:22].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>>[N:20]([CH2:7][C@H:6]1[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[N+:21]=[N-:22]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.17 h

Procedure:
Inosine (890 mg, 3.0 mmol) was dried under reduced pressure for 1 hour. Thereto was added 1.02 g (21 mmol) of lithium azide, and the mixture was further dried for 1 hour. Distilled DMF (40 ml) was added to the reaction vessel, and the pressure was reduced for about 10 minutes with stirring. Further, 2.20 g (8.4 mmol) of triphenylphosphine was added and, after confirmation of the dissolution of triphenylphosphine, 2.78 g (8.14 mmol) of carbon tetrabromide was added to initiate the reaction. On that occasion, the solution turned yellow. After 8 hours, the completion of the reaction was confirmed by TLC, and the reaction was quenched with methanol. The solution was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase MeOH:CHCl3=1:5) to give 5′-azido-5′-deoxyinosine. Isolation yield 775 mg, 88%.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][C:9](=[N+:13]=[N-:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(CCC#N)CCCC([CH:32]=[O:33])C2=O)C=CC=CC=1>>[CH3:32][O:33][C:5]1[CH:6]=[C:1]([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][C:9](=[N+:13]=[N-:14])[C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=1
Reactant: N#CCCC1(c2ccccc2)CCCC(=[N+]=[N-])C1=O
Reactant: N#CCCC1(c2ccccc2)CCCC(C=O)C1=O
Product: COc1cccc(C2(CCC#N)CCCC(=[N+]=[N-])C2=O)c1

Procedure:
Similarly prepared was 2-phenyl-2-(2-cyanoethyl)-6-diazocyclohexanone from 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[S:19][CH2:18][CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.O>O1CCCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([CH:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][OH:8])[CH:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:18][S:19]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
4-[3-(t-butyldimethylsilyloxymethyl)phenyl]-7-methoxy-3-(4-methoxyphenyl)thiochroman (480 mg, 0.947 mmol) was dissolved in tetrahydrofuran (40 ml), and added 3N hydrochloric acid solution (2.7 ml) thereto. The reaction mixture was stirred at room temperature for 4 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographied on silica gel (n-hexane:ethyl acetate=1:1) to obtain 358 mg (yield: 96%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[N:6][CH:5]=1.[C:13]([O:17][C:18](=[O:40])[NH:19][C:20]1([C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH:31](Br)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C(O)(C)C.C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]2[N:6]([C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]4([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:40])[CH2:23][CH2:22][CH2:21]4)=[CH:29][CH:28]=3)[N:11]=2)[CH:5]=1)=[O:12].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Agent: COC(=O)c1cnc(N)c(Cl)c1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(Cl)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1

Procedure:
A mixture of 6-amino-5-chloronicotinic acid methyl ester (0.588 g, 3.15 mmol), {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (2.00 g, 70% purity by UPLC-MS, 3.15 mmol) and powdered activated 3 Å molecular sieves in isopropanol (9.7 mL) was heated at reflux for 20 hours. On cooling, the mixture was diluted with DCM and water, filtered through Celite and the organic extract washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel (gradient elution: hexane-hexane/ethyl acetate 1:1) to give the title compound contaminated with 6-amino-5-chloronicotinic acid methyl ester. Further purification was achieved by acid extraction of a solution of the crude product in ethyl acetate with dilute aqueous hydrochloric acid (1 M). The organic extract was washed with brine, dried and concentrated in vacuo to give the title compound;
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[SH:30][C:31]1[CH:32]=[C:33]([C:37]2([OH:43])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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]>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][N:13]=1)=[CH:3][C:2]([S:30][C:31]1[CH:32]=[C:33]([C:37]2([OH:43])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)=[CH:11][CH:10]=3
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Reactant: OC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccccn6)n54)c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
5k (201 mg, 0.54 mmol) was suspended in 1,4-dioxane (4.5 mL) and degassed with N2 for 5 minutes. iPr2NEt (0.19 mL, 1.08 mmol) was added, followed by 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (51, 131 mg, 0.60 mmol) in 1,4-dioxane (1 mL). Pd2dba3 (13 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.03 mmol) were added, and the reaction was sealed and heated to 90° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (20-100% EtOAc in hexanes, followed by 0-10% MeOH in EtOAc) to obtain the desired product, 5p. Further purification by preparative HPLC was required, followed by standard aqueous workup of the combined fractions using EtOAc and saturated aqueous NaHCO3 to give clean product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=O)[CH3:8])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][NH2:21].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH3:8])[N:20]([C:14]2[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:21]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNc1c(Cl)cccc1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
Into a 2000 mL flask was weighed 35.33 g (223.5 mmol) of 2,4-dioxopentanoic acid ethyl ester, 50 g (234.7 mmol) of 2,6 dichlorophenyl hydrazine, 400 mL of acetic acid and 400 mL of ethanol. The resulting solution was heated at 80° C. for 18 h and was then cooled and was washed into a separatory funnel with 1.0 M aq. NaOH and ethyl acetate. The organic layer was separated, washed with sat. aq. NaHCO3, brine, dried over Na2SO4, and was concentrated in vacuo. The residue was recrystallized from EtOH-heptanes to afford 1-(2,6-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (44.6 g, 60%); 1H NMR (400 MHz, DMSO-d6): δ 7.67 (d J=7.67 Hz, 2H), 7.57 (m, 1H), 4.17 (q, J=7.07 Hz 2H), 1.97 (s, 3H); 1.18 (t, J=7.07 Hz 3H), MS (ES): 321 [M+Na]+.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]1([C:37]2[NH:41][N:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35]1>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:41]3[C:37]([CH:34]4[CH2:36][CH2:35]4)=[CH:38][CH:39]=[N:40]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: c1cc(C2CC2)[nH]n1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2nccc2C2CC2)cc1

Procedure:
The title compound was prepared by the method of Preparation 23b using (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid and 5-cyclopropyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][CH2:18][N:19]([CH2:29][CH2:30][Cl:31])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.C1C2C(=NC3C(C=2NC2C=C(C=C(CO)C=2)N)=CC=CC=3)C=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:16][CH2:17][CH2:18][N:19]([CH2:29][CH2:30][Cl:31])[C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Reactant: CN(C)CCC(=O)Nc1cccc(N)c1
Agent: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)CCC(=O)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(3-aminophenyl)-3-(dimethylamino)propanamide (1.15 g, 5.5 mmol) in dry DMF (20 mL) containing TEA (1.6 mL) was added a solution of N,N-bis(2-chloroethyl)-4-isocyanatoaniline [7, freshly prepared from N1,N1-bis-(2-chloroethyl)benzene-1,4-diamine hydrochloride 6 (3.4 g, 11 mmol) and triphosgene in chloroform] in dry DMF (5 mL)) at room temperature. After being stirred overnight at room temperature, the solid was filtered and washed with dry DMF. The filtrate was evaporated to dryness in vacuo and the product was purified by column chromatography using CHCl3/MeOH (100:10 v/v) as an eluent. The fractions containing main product were combined and evaporated to dryness under vacuum to afford compound N-(3-(3-(4-(bis(2-chloroethyl)amino)-phenyl)ureido)phenyl)-3-(dimethylamino)-propanamide (BO-2091), 2.2 g (62%); mp 88-90° C. The HCl salt of BO-2091 was prepared by treating the compound with HCl/EtOAc in a mixture of EtOAc:MeOH (10:1, v/v, 50 mL) under argon atmosphere during 30-40 min at room temperature. Solvent was then evaporated to dryness to give HCl salt of BO-2091. 1H NMR (DMSO-d6) δ: 2.77 (6H, s, CH3), 2.84-2.87 (2H, t, J=7.1 Hz, CH2), 3.32-3.35 (2H, t, J=6.7 Hz, CH2), 3.68-3.70 (8H, m, CH2), 6.71-6.73 (2H, d, J=8.6 Hz, Ar—H), 7.27-7.29 (2H, d, J=8.8 Hz, Ar—H), 7.36-7.38 (2H, d, J=8.8 Hz, Ar—H), 7.48-7.50 (2H, d, J=8.8 Hz, Ar—H), 7.95 (1H, brs, NH), 8.82 (1H, brs, NH), 9.02 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 30.50, 41.00, 42.10, 52.52, 52.58, 112.95, 117.95, 119.74, 120.02, 130.64, 132.64, 135.77, 140.96, 152.85, 167.25. HRMS [ES+]: calcd for C22H29Cl2N5O2, 466.4040 [M+H]+. found 466.1771. HPLC 98.7%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].ClC(N(C)C)=C(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([C:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=3)[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CC#N>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:34]([C:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=3)[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.3 %

Procedure:
A suspension of 101 mg (0.741 mmol) 4-cyano-1H-pyrrole-2-carboxylic acid (Canadian J. Chem. 59: 2673 (1981)) in 20 mL CH3CN was treated with 116 μL (0.741 mmol) (1-chloro-2-methyl-propenyl)-dimethylamine at RT for 20 min. The mixture was added to a solution of 220 mg (0.617 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH3CN, stirred at RT for 20 h and the solvents evaporated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 25-gm column with 10-25% EtOAc-hexane afforded 36.0 mg (12%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C24H27N4O3, 419.2 (M−C4H9+2H), found 419.1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.[CH2:20]=O.Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:20])=[CH:18][CH:19]=1
Reactant: C=O
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Agent: Cl
Solvent: O=CO
Product: CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
N-[2-(4-Chlorophenoxy)ethyl]-3-(imidazol-1-yl)propylamine (1.50 g) was added dropwise to 98% formic acid (1.0 ml) at 0° C. Formaldehyde (0.96 ml of a 37% aqueous solution) was added and the mixture heated at 95° C. for 6 hours. On cooling, concentrated hydrochloric acid (1.6 ml) was added. The mixture was evaporated to dryness and the residue dissolved in water, basified with 5M sodium hydroxide solution and extracted with ethyl acetate to give N-[2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)-N-methylpropylamine as an oil.
Reaction SMILES: CS(C1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[C:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7]C=1)(=O)=O.BrC1C=CC(C(=C2CC(C)(C)CC(C)(C)C2)C2C=CC([OH:49])=CC=2)=CC=1.O1C=CC(B(O)O)=C1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1COCC1>[O:49]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[C:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:33])([CH3:34])[CH2:26]3)[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7]1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccoc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccoc3)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 69 %

Procedure:
The Suzuki protocol described for (163) was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.270 g, 0.676 mmol), PdCl2(PPh3)2 (0.048 g, 0.068 mmol), 3-furanylboronic acid (0.152 g, 1.35 mmol), aqueous 2 M Na2CO3 (1.4 mL, 0.144 g, 1.35 mmol) solution, and 4:1 THF:H2O mixture (10 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 6 h. Reaction mixture was cooled to room temperature, diluted with Et2O (10 mL) and filtered. The filtrate was diluted with EtOAc (60 mL), washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 chromatography using hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.180 g (69%) of the title compound (234) as white solid. mp 128° C.-129° C. 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.45 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 6.68 (br s, 1H), 4.66 (s, 1H), 2.00 (s, 2H), 1.99 (s, 2H), 1.29 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 385.31 (M−H)−.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][N:6]=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])(=[O:11])=[O:10])[N:4]=1.[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:7]2[N:6]=[C:5]([NH:8][S:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[Cl:19])(=[O:10])=[O:11])[N:4]=[C:3]2[N:2]=1
Reactant: Nc1nc(NS(=O)(=O)c2cc(Cl)ccc2Cl)n[nH]1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(NS(=O)(=O)c3cc(Cl)ccc3Cl)nc2n1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 4.60 g (13.3 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2,5-dichlorobenzenesulfonamide hydrochloride and 4.0 g (40 mmol) of 2,4-pentanedione in 60 ml of glacial acetic acid was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and poured into 500 ml of ice water to separate a solid. The solid was collected by filtration and dried to yield 4.53 g (92 percent) of the desired product as a white solid, m.p. 216.5°-218.5° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)[CH:51]=1>CN(C=O)C>[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([C:60]2[CH:61]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=2)[CH:51]=1
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnc5ccccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 59.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 59% yield: LCMS (ESI) m/z 423 (MH+).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27]C(OC)=O)[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].O.Cl>CO>[ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([OH:27])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (259 mg, 0.54 mmol), (prepared as described for the starting material in Example 12), in methanol (15 ml) containing 1M sodium hydroxide (1.6 ml) was stirred at ambient temperature for 1 hour. After addition of water (15 ml), concentrated hydrochloric acid (1 ml) was added and the mixture was stirred at ambient temperature for 15 minutes. After evaporation of methanol, the precipitate was filtered, washed with water and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-hydroxy4-methylanilino)-6-methoxyquinazoline hydrochloride (192 mg, 80%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1>[Pd].C(O)C>[CH3:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[CH2:8][CH2:9][Cl:10]
Reactant: Cc1nc(Cl)sc1CCCl
Agent: [Pd]
Solvent: CCO
Product: Cc1ncsc1CCCl
Yield: 90.9 %

Procedure:
To a solution of 63 g (0.32 moles) of 2-chloro-4-methyl-5-(2-chloroethyl)-thiazole in 630 cm3 of a 96% ethanol 9 g of a wet palladium on charcoal catalyst (palladium content: 8%) are added. The mixture is hydrogenated at atmospheric pressure. The termination of the reaction is indicated by the cease of the hydrogen consumption. After filtering off the catalyst the solution is evaporated, the residue is dissolved in water and the solution is neutralized with sodium hydrogen carbonate (pH 7). The separated oil is shaken out with chloroform. The residue after the evaporation of the chloroform solution is distilled under reduced pressure. 47 g (91%) of 4-methyl-5-(2-chloroethyl)-thiazole are obtained. Its boiling point is 105° C. at a pressure of 0.93 KPa, nD20 =1.5430. Its active agent content is 98.8%, determined by gas chromatography.