Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([Cl:16])(Cl)([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH:12]([CH3:14])[CH3:13])=[O:2].Cl.[CH2:18]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH3:19].CCN(CC)CC>C(Cl)Cl>[Cl:16][P:1]([NH:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:25])[CH3:24])([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH:12]([CH3:13])[CH3:14])=[O:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cc1cc(OP(=O)(Cl)Cl)c(C(C)C)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cc(C)c(Cl)cc1C(C)C

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.098 M) of 4-chloro-2-isopropyl-5-methylphenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1.35* mixture of diastereoisomers. 31P NMR (300 MHz, CD3OD): δ 8.5 and 8.8*.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: CO
Reactant: COc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1Cl
Yield: 71 %

Procedure:
A solution of 2-chloro-5-methoxy-4-nitrobenzoic acid (1 mmol) and concentrated sulfuric acid (0.02 mmol) in methanol (200 mL) was heated to reflux for 42 hours. The solvents were evaporated under reduced pressure then the residue partitioned between EtOAc (25 mL) and water (25 mL). The separated aqueous phase was extracted with EtOAc (3×25 mL), then the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (71%) as a solid.
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH3:22])[CH2:20][O:19]1.Cl>CN(C)C=O.O>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]([OH:19])([CH:21]([N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)[CH3:22])[CH2:20][SH:1]
Reactant: COC(=O)CCS
Reactant: CC(n1cncn1)C1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(n1cncn1)C(O)(CS)c1ccc(F)cc1F
Reaction time: 0.08 h

Procedure:
Methyl 3-mercaptopropionate (0.88 ml) was added to N,N-dimethylformamide (14 ml) containing 60% sodium hydride in oil (0.32 g) under ice-cooling. After 5 minutes, a solution of 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (0.67 g) in N,N-dimethylformamide (3.5 ml) was added over 5 minutes with ice-cooling. After 15 minutes, the reaction mixture was poured into water (150 ml), neutralized with hydrochloric acid and extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (30 ml× 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×10 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether was added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of low polarity; compound 116, diastereomer B). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give 0.21 g of compound 116. The mother liquor of the above crude crystals was further subjected to silica gel chromatography (2 cm×12 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether and hexane were added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of high polarity; compound 115, diastereomer A). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give crystals of compound 115 (0.11 g). Compound 115 (diastereomer A) m.p. 112°-117° C. (colorless prism)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](N)[N:6]=[CH:5]2.C(O[N+]([O-])=O)(C)(C)C.C([O-])(O)=O.[Na+].[Cl:26]CCCl>>[Cl:26][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: ClCCCl
Reactant: Nc1ncc2cc(Cl)ccc2n1
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc2nc(Cl)ncc2c1
Temperature: 60 °C
Yield: 20 %

Procedure:
To a suspension of 6-chloro-quinazolin-2-ylamine (110) (2.8 g, 15.8 mmol) and SbCl3 (7.2 g, 32 mmol) in 1,2-dichloroethane (100 mL) was added tert-butylnitrate (6.2 ml, 52 mmol) and heated at 60° C. for 3 h under nitrogen atmosphere. To the mixture was added aqueous saturated NaHCO3 and the mixture was filtered off and filtrate was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography, using CHCl3/EtOAc (9:1, v/v) as eluent to give 2,6-dichloro-quinazoline (111) (0.65 g, 3.12 mmol, 20% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH2:35][C:36](O)=[O:37])[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:3]1[C:2]([N:1]2[C:36](=[O:37])[CH2:35][N:30]([CH3:29])[CH2:31][C:32]2=[O:33])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[N:4]=1
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))-amino]ethyl}amine, and 2 mmol of methyliminodiacetic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]-4-methylpiperazine-2,6-dione.
Reaction SMILES: [NH+]1C=CNC=1.N1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)C=CN=C1.[CH:26]([NH2:30])([CH2:28][CH3:29])[CH3:27]>>[CH:26]([NH:30][C:11]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[S:13](=[O:24])(=[O:25])[N:12]=1)([CH2:28][CH3:29])[CH3:27]
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: CCC(C)N
Agent: c1c[nH+]c[nH]1
Product: CCC(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with sec-butylamine according to the general procedure Method A to give the title compound; m.p. 287-288° C.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([F:29])[CH:4]=1.[CH3:30][C:31](C)([O-])[CH3:32].[K+]>CC(C)=O>[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH:7]=[C:31]([CH3:32])[CH3:30])=[C:5]([F:29])[CH:4]=1
Reactant: Fc1cc(Br)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
A mixture of (4-bromo-2-fluorobenzyl)triphenylphosphonium bromide (3.82 g) and potassium t-butoxide (786 mg) was stirred at room temperature for 30 minutes. Then acetone (1.0 ml) was added and the reaction mixture was heated at reflux for 40 hours. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was chromatographed on silica gel column eluting with hexane to give 1-(4-bromo-2-fluorophenyl)-2-methyl-1-propene (0.70 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20]>CN(C1C=CN=CC=1)C.ClCCl>[C:19](=[O:20])([O:21][CH3:22])[O:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(F)ccc1O
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(F)ccc1OC(=O)OC
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2-Ethyl-4-fluorophenol (2 g, 14.27 mmol) and DMAP (87 mg, 0.71 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (4 mL, 28.5 mmol), cooled to 0° C., then treated with methyl chloroformate (2.02 g, 1.65 mL, 21.40 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water, the layers separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20% ethyl acetate/hexane) provided 2-ethyl-4-fluorophenyl methyl carbonate (2.4 g, 85% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.26-7.17 (m, 2H), 7.12-7.07 (m, 1H), 5.76 (s, 1H), 3.83 (d, J=4.3 Hz, 2H), 2.54-2.48 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([CH:18]([N:25]([CH3:39])[C:26](=[O:38])[CH2:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH3:29])[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([N:25]([CH3:39])[C:26](=[O:38])[CH2:27][N:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH3:29])[CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)N(C)C(CN1CCCC1)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1cccc(-c2ccc(Cl)cc2)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure described for example 33, using 4-chlorophenylboronic acid and the intermediate from step c) above. MS (ES) m/e 532 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:16]=3[C:17](O)=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:17]([C:16]1[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:13][C:12]=1[CH2:11][C:1]12[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2)=[O:18]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Product: COC(=O)c1ccccc1NC(=O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Yield: 33.1 %

Procedure:
2-Adamantan-1-ylmethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (Example 1, step c) (335 mg, 1.00 mmol) was reacted with 2-amino-benzoic acid methyl ester (1.51 mg, 1.00 mmol) according to the procedure of Example 1, step d to afford the product as a pale yellow solid (155 mg, 33%). 1H NMR (300 MHz, d6-DMSO) 11.32 (1H, s), 11.24 (1H, s), 8.67 (1H, d), 8.00 (1H, d) 7.60 (3H, m), 7.40 (2H, m), 7.25 (1H, t), 7.12 (1H, t), 6.83 (1H, s), 3.92 (3H, s), 2.86 (2H, s), 1.88 (3H, s), 1.55 (12H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([CH3:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39](N1C=CN=C1)=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:32])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([CH3:24])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:31])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1)=[O:40]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
The amine from above (230 mg, 0.50 mmol), and imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (300 mg, 1.0 mmol) were combined in DMF (2.5 mL) and treated with DIPEA (0.52 mL, 3.0 mmol). The solution was stirred at 75° C. for 3 hours and then concentrated under reduced pressure. This afforded, after column chromatography with silica gel (50:1:0.2 CH2Cl2:MeOH:NH4OH), COMPOUND 309 (180 mg, 65%). 1H NMR (CDCl3): δ 1.17 (q, 2H, J=12.3 Hz), 1.55 (d, 2H, J=12.3 Hz), 1.61 (s, 6H), 2.29 (s, 3H), 2.53 (m, 3H), 3.36 (s, 2H), 3.64 (s, 2H), 4.08 (d, 2H, J=12.9 Hz), 6.68 (s, 2H), 7.00 (d, 2H, J=7.5 Hz), 7.08 (m, 1H), 7.19 (m, 3H), 7.36 (s, 1H), 7.85 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.48 (br d, 1H, J=3.3 Hz). 13C NMR (CDCl3) δ 18.87, 28.30 (2C), 31.29 (2C), 42.88, 44.58 (2C), 54.13, 55.33, 58.30, 121.67, 126.02 (2C), 126.32, 128.88 (2C), 130.40, 134.13, 135.41, 137.73, 143.49, 144.91 (2C), 145.48, 146.91 (2C), 149.84, 155.60, 156.53, 158.59. ES-MS m/z 559 (M+H). Anal. Calcd. for C31H36N7OCl.0.3CH2Cl2: C, 64.42; H, 6.32; N, 16.80; Cl, 9.72. Found: C, 64.26; H, 6.35; N, 16.64; Cl, 9.47.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[I-].CS[C:15]1[S:16][CH2:17][C@@H:18]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:20][N+:19]=12>N1C=CC=CC=1>[CH:7]1[C:8]2[C:3](=[C:2]([N:1]=[C:15]3[N:19]4[CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[CH2:27][C@H:18]4[CH2:17][S:16]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1cccc2cnccc12
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cccc4cnccc34)N1C2
Temperature: 5 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
5-Aminoisoquinoline (10.8 g.) is added to a solution of (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g.) in pyridine (500 cc.). After 5 hours at a temperature of about 20° C., solution is complete and the reaction is allowed to continue for 10 hours. The solution is concentrated to dryness under reduced pressure (25 mm.Hg) at 60° C. The residue is dissolved in a mixture consisting of N sodium hydroxide solution (250 cc.) and methylene chloride (250 cc.). The organic phase is decanted, washed with water (2 × 100 cc.), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (50 mm.Hg) at 40° C. Isopropanol (150 cc.) is added to the residue obtained; the mixture is brought to the boil and is filtered hot. After cooling to 5° C., the crystals formed and filtered off and washed with isopropanol (3 × 10 cc.). After drying at 60° C., under reduced pressure (0.1 mm.Hg), (S)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b] isoquinoline (13.0 g.) is obtained in the form of white crystals melting at 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:5]Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([O:26]C)=[O:25])[CH:19]=[CH:20][C:21]=1[OH:22]>CO.O>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)COc1ccc(CCl)cc1Cl
Solvent: CO
Solvent: O
Product: CC(C)COc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1Cl

Procedure:
The procedure of Example (1) (e) was repeated wherein 3-chloro-4-isobutyoxybenzyl chloride was reacted with methyl 3-chloro-4-hydroxyphenylacetate to yield 3-chloro-4-(3'-chloro-4'-isobutoxybenzyloxy) phenylacetic acid (52.4yield), m.p. 127.5°-129° C. (methanol-water).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]#[N:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[O:30]1C[CH2:33][CH2:32][CH2:31]1.OCC(=O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][NH:27][C:28]3[O:30][CH:31]=[C:32]([CH3:33])[N:29]=3)[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1coc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)n1
Reaction time: 2 h
Yield: 6 %

Procedure:
To a stirred mixture of 1.95 parts of [2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-cyanamide, 45 parts of tetrahydrofuran and 50 parts of water was added a solution of 3.7 parts of 1-hydroxy-2-propanone in water (=50%). 5 Parts of a sodium hydroxide solution 2N were added dropwise. Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.3 parts (6%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(4-methyl-2-oxazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 178.1° C. (compound 84).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[C:4]=1[C:5](OC)=[O:6].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>O1CCCC1.CN(C=O)C>[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:6])[N:15]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[CH2:2]2)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1c(C#N)cccc1CBr
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C#N)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 6C (300 mg) in tetrahydrofuran (2 mL) and N,N′-dimethylformamide (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (320 mg,) in N,N′-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) at −40° C. The solution was warmed to ambient temperature over 2 hours, and stirred for 16 hours. The solvent was removed, and the concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 80% ethyl acetate in hexanes.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1([N:25]2[C:29](=[S:30])[N:28]=[N:27][NH:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C@@H:38]1[CH2:40][C@H:39]1[CH2:41]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C@@H:38]1[CH2:40][C@H:39]1[CH2:41][S:30][C:29]1[N:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:26]=[N:27][N:28]=1
Reactant: OC[C@@H]1C[C@H]1c1ccccc1Cl
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1[C@@H]1C[C@H]1CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
DIAD (87 μL, 0.44 mmol) was added dropwise to a solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (84.0 mg, 0.37 mmol), trans-2-(2-chlorophenyl)cyclopropanemethanol (80.5 mg, 0.44 mmol), and PPh3 (116 mg, 0.44 mmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to give the title compound (81 mg, 56% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC=CC=1>[CH:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:16])[N:3]=[C:2]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: Cc1nc(Cl)c2cccc(OC(C)C)c2n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1nc(-c2ccccc2)c2cccc(OC(C)C)c2n1

Procedure:
To a stirred mixture of 4-chloro-8-isopropoxy-2-methyl-quinazoline (35) (0.58 mmol), phenylboronic acid (0.62 mmol), 2 N Na2CO3 (7.2 mL), EtOH (1.2 mL) and benzene (6 mL) was added, under a blanket of argon, Pd(PPh3)4 (20 mg). The mixture was stirred under reflux for 16 h, cooled, and concentrated. Subsequent column chromatography (ethyl acetate/hexane) provided 8-isopropoxy-2-methyl-4-phenyl-quinazoline (36) as a solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br>CN(C)C=O>[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:8]([CH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH3:14])[CH:12]=1)[OH:9]
Reactant: NO
Reactant: Cc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CN(O)Cc2cccc(C)c2)c1
Yield: 49.4 %

Procedure:
The procedure of Example 1 is repeated using 21.2 g of sodium carbonate, 3.47 g of hydroxylamine hydrochloride and 18.51 g m-methylbenzyl bromide in 75 ml of dimethylformamide. Recrystallization from ethanol affords 5.95 g of the title hydroxylamine as a white solid, mp 70°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=3)[NH2:16])=[CH:10][N:4]2[N:3]=1.C(#N)C.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[CH:17]=3)=[CH:10][N:4]2[N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
A 40 mL vial is charged with 5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-aniline (0.85 g, 3.28 mmol), acetonitrile (14 mL) and pyridine (0.450 mL). The mixture is added trimethylacetyl chloride (0.628 mL, 0.0051 mol) and stirred for 20 min at 80° C. The mixture is concentrated, taken up in EtOAc (35 mL) and washed once with HCl (20 mL, 1M) and then NaOH (20 mL, 1M). Organic layer is dried, concentrated and purified on silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (1.05 g, 94% yield). LCMS m/z=343.5 [M+H]+, tR=2.39 min. (compound same as Example 118)