Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC=C2[C:3]=1[C:4](=O)[N:5]([CH:13]1[CH2:18]C[C:16](=O)[NH:15][C:14]1=O)[C:6]([CH3:12])=N2.[C:22](Cl)(=O)C.CCN(CC)CC.C(#N)C>O1CCCC1>[CH3:12][CH2:6][N:5]([CH:4]([CH3:3])[CH3:22])[CH:13]([CH3:14])[CH3:18].[NH:5]1[CH:13]=[CH:14][N:15]=[CH:16]1
Reactant: CC(=O)Cl
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Product: c1c[nH]cn1

Procedure:
Reaction of compound 1 with acetyl chloride and base, such as Et3N, Hunig's Base, or imidazole in either acetonitrile or tetrahydrofuran at either room temperature or 45° C. provided compound 1a.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.O.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CN
Solvent: O
Product: CNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
2-Chloromethylbenzimidazole (3.00 g, 18.01 mmol) was dissolved in aqueous methylamine (50 mL, 40 wt % in H2O) at 10° C. under N2. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 4 hours. Water was added and the mixture extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by HPLC (gradient methanol/dichloromethane) to afford 0.650 g (22%) of pure product as a tan solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2Cl)C1C=CC=CC=1.N1C2C(=CC=CC=2)C=NC1=O.C1(O)C=CC=CC=1.NC1C=CC=CC=1>ClC1C=CC=CC=1Cl>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Clc1ccnc2ccc(OCc3ccccc3)cc12
Agent: O=c1ncc2ccccc2[nH]1
Solvent: Clc1ccccc1Cl
Solvent: Nc1ccccc1
Solvent: Oc1ccccc1
Product: Oc1ccc2ncccc2c1

Procedure:
A 6-benzyloxy-4-chloroquinoline derivative or a corresponding quinazolone derivative is reacted with a phenol derivative or a corresponding aniline derivative in a suitable solvent, for example, o-dichlorobenzene, or in the absence of a solvent, for example, at 120 to 180° C. (step (i) above). Next, a 6-hydroxyquinoline derivative may be produced by reacting the resultant compound with a suitable acid, for example, methanesulfonic acid/trifluoroacetic acid (step (ii) above). The contemplated compound may be produced by reacting the 6-hydroxyquinoline derivative with an alkylating agent, for example, 1-bromo-2-chloroethane (step (iii) above).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][CH:9]([CH2:14][CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Yield: 55.1 %

Procedure:
A mixture of 0.058 g (0.00019 mole) of (rac)-2-chloro-9-cyclopentyl-7-ethyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-12), 0.038 g (0.00023 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.046 g of (rac)-4-(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-12) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34](Cl)[N:33]=[N:32][C:31]=2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:34]2[N:33]=[N:32][C:31]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:29][CH:28]=3)[CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.5 mmol, 281 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-azetidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give 6-(azetidin-3-ylmethoxy)-4-(4-benzyloxy-phenyl)-3-butyl-pyridazine dihydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH3:24]>>[CH3:13][C:9]1([CH3:12])[CH2:8][O:7][C:6]2[CH:14]=[CH:15][C:3]([C:1]#[C:2][C:21]3[CH:20]=[CH:19][C:18]([S:23][CH3:24])=[CH:17][CH:22]=3)=[CH:4][C:5]=2[O:11][CH2:10]1
Reactant: CSc1ccccc1Br
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CSc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and bromothioanisole. MS (ESI) 324.2 (M•)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:26][C:27]1[C:32]2[O:33][CH2:34][O:35][C:31]=2[C:30]([C:36]#[C:37][CH2:38][NH:39][C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:29][C:28]=1[Cl:45].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:45][C:28]1[CH:29]=[C:30]([C:36]#[C:37][CH2:38][NH:39][C:40](=[O:44])[N:41]([CH3:42])[CH3:43])[C:31]2[O:35][CH2:34][O:33][C:32]=2[C:27]=1[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Reactant: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)CC1=O
Yield: 81.4 %

Procedure:
This was prepared by the method described in example 4 but using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (140 mg, 0.38 mmol), N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (125 mg, 0.42 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 0.81 ml) in DMF (2 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (193 mg, 81%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.03 (quintet, 2H), 2.20 (s, 3H), 2.59 (t, 2H), 2.81 (s, 6H), 2.91 (s, 2H), 3.33 (t, 2H), 3.48 (t, 2H), 3.94 (s, 3H), 4.10 (d, 2H), 4.14 (t, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.16 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 624/626.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH2:19]1[O:23][C@@H:22]2[C@@H:24]([OH:27])[CH2:25][O:26][C@@H:21]2[C@@H:20]1[OH:28]>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:28][C@@H:20]2[CH2:19][O:23][C@@H:22]3[C@@H:24]([O:27][S:14]([C:11]4[CH:12]=[CH:13][C:6]([CH3:7])=[CH:9][CH:10]=4)(=[O:16])=[O:15])[CH2:25][O:26][C@H:21]23)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Triethylamine (123.2 mL, 876 mmol) was added dropwise to a stirred solution of p-toluenesulfonyl chloride (156.6 g, 822 mmol) and isosorbide (43) (40 g, 274 mmol) in dichloromethane (600 mL) over 15 minutes. The mixture was stirred at 25° C. for 16 hours then at 50° C. for 4 hours before diluting with dichloromethane (1 L). The organic layer was washed with water (2×1 L), then dried (Na2SO4), filtered then reduced in vacuo to leave a viscous oil. The oil was crystallized from hot methanol (600 mL) to obtain ditosylate (42) as a white solid (120.1 g, 97%). [α]D15+56.3° (c=11.2, CHCl3).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH3:18])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH2:17]([N:10]1[C:9]2[C:4](=[O:3])[NH:5][CH2:6][CH2:7][C:8]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:18]
Reactant: CCOC(=O)NCCc1cn(CC)c2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c2c(c3ccccc31)CCNC2=O
Yield: 9 %

Procedure:
[2-(1-Ethyl-1H-indol-3-yl)-ethyl]-carbamic acid ethyl ester (I-38e: 4.2 g, 16.09 mmol) in POCl3 (42 mL) was reacted with P2O5 (4.56 g, 32.183 mmol) at 120° C. for 1 hr to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 0.310 g of the product (9% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4](C2CCCCO2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[N:6]=2.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>CO>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:1][O:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[N:6]=2
Reactant: COc1nc2c(N)nc(OCC3CCCO3)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2c(N)nc(OCC3CCCO3)nc2[nH]1
Reaction time: 24 h

Procedure:
8-(Methoxy)-2-[(tetrahydro-2-furanyl methyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.1614 g) was dissolved in methanol (20 mL) and treated with neat trifluoroacetic acid (2 mL). The reaction mixture was stirred for 24 hours to give a white suspension. The reaction mixture was then evaporated to dryness under reduced pressure. The resultant white solid was suspended using ethyl acetate (10 mL) and then isolated by filtration, washing with ethyl acetate (2 mL). The solid was air-dried under suction and then dried further under vacuo at 50° C. This gave the title compound as a white solid (1.0602 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>ClCCl>[CH3:17][Si:18]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)Oc1ccc(F)cc1F
Temperature: 0 °C

Procedure:
In a 2.5 l sulfation flask, 260.2 g (2.0 mol) of 2,4-difluorophenol and 242.9 g (2.4 mol) of triethylamine are dissolved in 700 ml of dichloromethane and cooled to 0° C. 239 g (2.2 mol) of trimethylchlorosilane are added dropwise in the course of about 3 hours. The white suspension is allowed to react to completion for 8 hours (check using GC and TLC). The suspension is filtered, the residue is washed with a little dichloromethane, and the filtrate is evaporated on a rotary evaporator. The oil obtained is distilled at 56°-62° C. in vacuo (22 mbar). 280 g of a clear, colourless liquid are obtained.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21]([C:29]3[N:33](CCC#N)[N:32]=[N:31][N:30]=3)=[CH:22][N:23]([CH3:28])[C:24](=[O:27])[C:25]=2[CH3:26])=[C:15]([F:38])[CH:14]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21]([C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:22][N:23]([CH3:28])[C:24](=[O:27])[C:25]=2[CH3:26])=[C:15]([F:38])[CH:14]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnnn2CCC#N)cn(C)c1=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnn[nH]2)cn(C)c1=O
Reaction time: 2 h
Yield: 76.4 %

Procedure:
DBU (0.030 mL, 0.21 mmol) was added to a solution of 3-{5-[4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl]-tetrazol-1-yl}-propionitrile (30 mg, 0.069 mmol) in methylene chloride (1.5 mL). After 2 hours, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Trituration with diethyl ether gave clean desired product (20 mg, 77%); MS APCI (−) m/z 377, 379 (M−, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.29 (dd, 1H), 7.13 (dd, 1H), 6.63 (t, 1H), 3.65 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)CCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Mix 4-cyanophenol (1.2 g, 10 mmol), 1-bromo-3,3-dimethylbutane (5.3 g, 32 mmol), powdered potassium carbonate (4.14 g, 30 mmol), and powdered potassium iodide (166 mg, 1 mmol) in acetone (60 mL). Stir under inert atmosphere and heat at reflux for 48 h. Cool the reaction mixture to ambient temperature. Dilute with acetone, filter and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1.0 and 9:1) to obtain the desired intermediate (1.8 g, 89%). MS (ES+) m/z: 221 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12](SCC)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2[N:28]=[N:29]C(S)=CC=2C1)=O)C.C(Br)C>>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12]([NH:28][NH2:29])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Reactant: CCOC(=O)N1CCc2nnc(SCC)cc2C1
Solvent: CCBr
Product: CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-ethylmercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 41(b), from 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and ethyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:22]O)[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[N:7]2.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:22][Cl:26])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[N:7]2
Reactant: OCc1cc2c(Cl)cccc2nc1-c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: FC(F)(F)c1ccccc1-c1nc2cccc(Cl)c2cc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (5-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol (2.180 g, 6.455 mmol) in 22 mL of CHCl3 was treated with thionyl chloride (2.348 mL, 32.27 mmol) dropwise, and the reaction mixture was stirred at room temperature. After 1.5 hr, the mixture was concentrated under reduced pressure and co-evaporated three times with CH2Cl2 to give 5-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline hydrochloride as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.86 (1 H, d, J=0.6 Hz), 7.99-8.05 (1 H, m), 7.94 (1 H, dd, J=7.4, 1.0 Hz), 7.88-7.92 (1 H, m), 7.81-7.87 (2 H, m), 7.74-7.81 (1H, m), 7.61-7.66 (1 H, m), 4.77 (2 H, d, J=79.0 Hz); LC-MS (ESI) m/z 356.0 and 358.0 [M+H]+ (Exact Mass of neutral form: 355.014). The yellow solid was carried on crude without purification for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([CH3:12])=[CH:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5])[CH3:2].[ClH:20]>C(OCC)(=O)C>[ClH:20].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([CH3:12])=[CH:9][CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(C)=CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC(C)=CCN1
Reaction time: 2 h

Procedure:
A stirred, ice-cooled solution of the product from (g) above (3.13 g, 11.62 mmol) in ethyl acetate (30 ml) was saturated with hydrogen chloride over 0.5 hour and then stood at room temperature for a further 2 hours. The solvent was evaporated under reduced pressure and the residue crystallised from a mixture of ether and ethanol to afford the title compound (2.20 g) as white crystals, m.p. 108°-109° C. Rf 0.35 (SS 3), [α]D25 106.5° (c=1.0, CH3CH2OH). Found: C,52.49; H,7.90; N,6.70. C9H15NO2 ; HCl requires C,52.55; H,7.84; N,6.81%.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:29]1([P:35](Cl)(Cl)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.C1CCCCC1>[C:29]1([P:35]2(=[O:36])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: O=P1(c2ccccc2)c2ccccc2CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.0 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of dibenzylamine (11.8 g, 0.06 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -76° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to 0° C. The reaction mixture was allowed to cool to -76° C., after which time the reaction mixture was stirred for 0.25 hours. The solid carbon dioxide-acetone bath was then removed and the reaction mixture was stirred for an additional 2 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed on a rotary evaporator, and the resulting residue partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried and concentrated in vacuo to yield an orange glass. The orange glass was distilled at 220° C. and 0.25 torr and the resulting solid residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was crystallized from diethyl ether and petroleum ether to yield 1-phenyl-2-(phenylmethyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (6.15 g, 32% yield) as a white solid having a melting point of 99°-101° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1)[C:5]([NH2:7])=[O:6].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:17]=1)[C:5]([NH2:7])=[O:6]
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2)c(Cl)c1
Yield: 96.9 %

Procedure:
Use 3-chloro-4-(4-formyl-phenoxy)-benzamide (0.20 g, 0.71 mmol), 2-thiophen-2-yl-ethylamine (0.075 mL, 0.64 mmol), sodium borohydride (0.049 g, 1.29 mmol) and methanol (8 mL) in a procedure and purification similar to that of Example 1, to obtain the product (0.24 g, 94%), 2137632. Mass spectrum (ion spray): m/z=387.1 (M+1); 1H NMR (CDCl3) 7.93 (d, J=2.1 Hz, 1H), 7.62 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.14 (d, J=5.2 Hz, 1H), 6.97 (d, J=8.3 Hz, 2H), 6.93 (dd, J=3.4 Hz, 5.1 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.1 Hz, 1H), 6.11 (bs, 2H), 3.81 (s, 2H), 3.05 (t, J=6.7 Hz, 2H), 2.95 (t, J=6.7 Hz, 2H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([C:67](Cl)=O)=[CH:63][CH:62]=2)=[CH:57][CH:56]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]4[N:4]=[C:54]([C:55]5[CH:60]=[CH:59][C:58]([C:61]6[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=6)=[CH:57][CH:56]=5)[O:1][N:2]=4)=[CH:44][CH:43]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:31])([F:30])[F:32])[CH:23]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Prepared using General Procedure 20: To a stirring solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (104 mg, 0.169 mmol) and DIEA (47.0 μL, 0.254 mmol) in dioxane (4 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (39.0 mg, 0.169 mmol) in dioxane (1 mL). After stirring at room temperature for 30 min, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature then diluted with NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 54 mg (40%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-34. LCMS-ESI (m/z) calculated for C45H41F3N4O6: 791; no m/z observed, tR=1.70 min (Method 10).