Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:30]=[C:29]([O:41][CH3:42])[N:28]=3)[CH2:12]1)[C:8](=[O:43])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH3:42][O:41][C:29]1[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:43])[CH2:23]4)[CH2:12]2)[CH:32]=[C:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[N:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccc(OC)cc4)nc(OC)n3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)cc1
Yield: 35.4 %

Procedure:
A solution of the ethyl ester 16e (1.2 g, 2 mmol) in THF/MeOH 1:1 (30 ml) was treated with a 1M solution of LiOH as described in Example 13 step d. Purification by column chromatography on silica gel gave the crude title compound, (400 mg, 77%), (M+H)+565.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[OH-].[K+]>C(O)COCCO>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:12]=[C:3]([CH2:4][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[CH:15][CH:14]=1)[NH2:1]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(C(F)(F)F)cc1Cc1ccccc1

Procedure:
In the manner given in Preparation 11, 2-amino-5-(trifluoromethyl)benzophenone is refluxed with potassium hydroxide in diethylene glycol to give 4-(trifluoromethyl)-α-phenyl-o-toluidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CN([CH:19]=[O:20])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)cn1
Temperature: 0 °C
Yield: 57.2 %

Procedure:
To a solution of 2-bromo-5-chloropyridine (14.8 g, 77 mmol) in THF (38.5 mL) was added dropwise a a solution of i-PrMgCl.LiCl (14% in THF, 81 mL, 85 mmol) at 0-5° C. and the resulting mixture stirred at 0° C. for 1 h. Then DMF (7.7 mL, 100 mmol) was added dropwise at −5° C. and the temperature maintained at 0° C. for 2 h. The reaction mixture was then poured into ice cold saturated brine (500 mL) and then extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated sodiumhydrogencarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:0 to 9:1) afforded the title compound (6.24 g, 57%) which was obtained as a brown solid. MS: m/e=141.0 [M]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:27]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24]/[CH:25]=[CH:32]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:23]1)([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.43 mL, 5.0 mmol) in CH2Cl2 (30 mL) at −78° C. is added DMSO (0.52 mL, 7.0 mmol) dropwise. After gas evolution subsided (5 min), the alcohol of Example 4 (0.8 g, 3.5 mmol) in CH2Cl2 (20 mL) is added in a stream. After 20 min, (carbethoxymethylene) triphenyl-phosphorane (1.4 g, 4.0 mmol) is added. After 2 h, the reaction mixture is diluted with petroleum ether, washed with water, 5% KHSO4 and sat. NaCl, dried over MgSO4, and concentrated. Flash column chromatography (15% EtOAc in hexane) gave the title compound (0.57 g, 38%) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17]>>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=2)=[NH:10])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: CS(=O)(=O)c1ccc(C#N)cc1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(NC(=N)c2ccc(S(C)(=O)=O)cc2)cc1C
Yield: 45 %

Procedure:
The title compound was prepared from 4-methylsulfonylbenzonitrile (5.0 g, 28 mmol) and 3,4-dimethylaniline (3.36 g, 28 mmol) by following the procedure described in preparation 1 (3.75 g, yield 45%, purity 97.1% by HPLC). 1H-NMR (CDCl3):δ 2.25-2.26 (d, 6H), 3.07 (s, 3H), 4.91 (bs, 2H, D2O exchangeable), 6.71-6.73 (m, 1H), 6.78 (s, 1H), 7.12-7.14 (d, 1H), 8-8.02 (d, 2H), 8.07-8.09 (d, 2H). MS m/z:303.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:31]([Si:28]([CH3:30])([CH3:29])[O:35][C:36]1[CH:41]=[CH:40][C:39]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:10]([CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:27])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:21][CH:22]=2)=[CH:38][CH:37]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (710 mg), 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (457 mg), triethylamine (1.26 ml) and powdered 4 Å molecular sieves (700 mg) in dichloromethane (18 ml) was added copper(II) acetate (330 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [2-[4-[4-[[tert-butyl(dimethyl)-silyl]oxy]phenoxy]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (600 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([S:14]([N:17]2[C:25]3[CH:24]=[C:23]([Cl:26])[CH:22]=[C:21]4[CH2:27][CH2:28][CH:29]([CH2:30][C:31]([OH:33])=O)[C:19]([C:20]=34)=[C:18]2[C:34]([O:36][CH3:37])=[O:35])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C=O)C>[C:8]1([S:14]([N:17]2[C:25]3[CH:24]=[C:23]([Cl:26])[CH:22]=[C:21]4[CH2:27][CH2:28][CH:29]([CH2:30][C:31](=[O:33])[NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:19]([C:20]=34)=[C:18]2[C:34]([O:36][CH3:37])=[O:35])(=[O:15])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.9 %

Procedure:
A mixture of aniline (27.4 mg, 0.303 mmol), methyl 1-benzenesulfonyl-7-chloro-3-carboxymethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (120 mg, 0.275 mmol), 1-hydroxy-benzotriazole (46 mg, 0.303 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (47 mg, 0.303 mmol) in DMF (2.5 mL) was stirred for 20 h at room temperature, acidified to pH 1 by adding 1N HCl, and extracted with 1:1 toluene/ethyl acetate. The organic layer was washed successively with 1N HCl, water, saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated to give 161 mg of the title compound (quant): 1H NMR (CDCl3) δ7.95 (d, 2H, J=7.3 Hz), 7.90 (s, 1H), 7.85 (s, 1H), 7.58 (t, 1H, J=7.3 Hz), 7.52 (d, 1H, J=8.3 Hz), 7.46 (t, 1H, J=8.3 Hz), 7.30 (t, 1H, J=8.3 Hz), 7.15 (t, 1H, J=7.05 (s, 1H), 3.84 (s, 3H), 3.71 (m, 1H), 2.92 (ddd, 1H, J=17.2, 12.2, 3.6 Hz), 2.80 (md, 1H, J=17.2 Hz), 2.65 (dd, 1H, J=14.2, 4.0 Hz), 2.47 (dd, 1H, J=14.2, 9.6 Hz), 2.19 (md, 1H, J=13.6 Hz), 1.89 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Cl.[NH2:29][OH:30].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:29][OH:30])=[NH:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
1.1 g of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-benzonitrile, 247 mg of hydroxylamine hydrochloride and 430 mg of triethylamine are stirred for 48 hours at 80° C. in 25 ml of ethanol. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and crystallisation from diethyl ether yield 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine having a melting point of 144-146° C.
Reaction SMILES: O.[NH2:2][NH2:3].CCO.Cl[C:8]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:9]=1[C:10](OC)=[O:11].Cl>O>[N+:18]([C:15]1[CH:14]=[C:9]2[C:8](=[CH:17][CH:16]=1)[NH:3][N:2]=[C:10]2[OH:11])([O-:20])=[O:19]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (19 ml) was added to an EtOH (15 ml) solution containing methyl 2-chloro-5-nitrobenzoate (10 g), followed by stirring at 90° C. for 1 hour. The reaction solution was adjusted to room temperature. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution. A solid precipitate was collected by filtration and washed with water. A brown solid of 5-nitro-1H-indazol-3-ol (5.42 g) was thus obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1.[CH3:18][N:19]1[C:23]([OH:24])=[C:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]([CH3:35])=[N:20]1>C(C(C)=O)C.C(Cl)Cl>[CH3:18][N:19]1[C:23]([O:24][CH2:13][C:12](=[O:15])[C:11]2[CH:16]=[CH:17][C:8]([CH3:7])=[CH:9][CH:10]=2)=[C:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]([CH3:35])=[N:20]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: Cc1ccc(C(=O)COc2c(C(=O)c3ccc(Cl)cc3Cl)c(C)nn2C)cc1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
In a four necked flask, 2 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxy pyrazole was dissolved in 35 ml of methyl ethyl ketone, and 2 g of anhydrous potassium carbonate was added to the solution and 1.4 g of 4-methylphenacyl bromide was added dropwise to the mixture under stirring. The reaction was carried out for 2 hours under refluxing. The reaction mixture in the flask was cooled and filtered and methyl ethyl ketone was distilled off to obtain the precipitate of the reaction product. The precipitate was dissolved in methylene chloride and the solution was sequentially washed with water, an aqueous solution of sodium bicarbonate and water, and after drying over anhydrous sodium sulfate, methylene chloride was distilled off from the solution to obtain a crude product. The product was separated by a silica gel column with developing solvent (CH2Cl2 : 99.5% C2H5OH=100: 3) to obtain 1.87 g of brown oily product of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-(4-methyl benzoylmethoxy) pyrazole.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[OH-].[K+].[CH2:18](I)[CH:19]([CH3:21])[CH3:20]>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CI
Reactant: CC(C)(C)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)COc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 60.1 g (0.40 mol) 2-tert-butylphenol in 600 ml of DMSO 89.6 g (1.60 mol) of KOH and 147 g (0.80 mol) of isobutyl iodide were added. This mixture was stirred for 2 h at room temperature, then 73.6 g (0.40 mol) of isobutyl iodide was added. The resulting mixture was stirred for 1 h, and, again, then 73.6 g (0.40 mol) of isobutyl iodide was added. The formed mixture was stirred overnight at room temperature. The top layer was separated. To the bottom layer 5 liters of water was added, and some product was extracted with 2×250 ml of dichloromethane. The combined organic extract (including the separated top layer) was washed with 5×1 liter of water, dried over Na2SO4, and evaporated to dryness. The crude product (free of 2-tert-butylphenol) was obtained from the residue by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes). Further on, this crude product was distillated to give pure 1-tert-butyl-2-isobutoxybenzene, b.p. 85-95° C./4 mm Hg. This procedure gave 44.9 g (54%) of the title product.
Reaction SMILES: [N+:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=[O:7])([O-])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CCOCC>[N:1]1[O:7][C:6]([O-:8])=[C:5]2[CH2:9][CH2:10][CH2:11][N+:4]=12
Reactant: O=C(O)[C@@H]1CCCN1[N+](=O)[O-]
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-]c1on[n+]2c1CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Nitroproline (17.0 g, 118 mmol) was suspended in ether (400 ml) and cooled in ice. Trifluoroacetic anhydride (16.5 ml, 120 mmol) was then added dropwise over 30 minutes and the mixture left to warm to room temperature whilst stirring over 16 hours. The mixture was evaporated in vacuo to an oil and purified by column chromatography on silica gel using an eluant of ethyl acetate to afford the title compound, 9.8 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CCNCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCNCc2ccccc2)cc1

Procedure:
The mixture containing [(4-nitrophenyl) ethyl]benzylamine in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield [(4-aminophenyl)ethyl]benzylamine. MS: MH+=226.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:12]1([C:15](=[O:16])[CH2:17][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1ccccn1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccccn1

Procedure:
A stirred mixture of 24 g. of ethyl picolinate, 18 g. of cyclopropylmethyl ketone and 11 g. of sodium methoxide in 250 ml. of benzene is heated under reflux for 6 hours. The mixture is diluted with 200 ml. of water and the water phase is removed. The aqueous solution is made weakly acidic with dilute hydrochloric acid. A solid precipitates and is collected by filtration. Recrystallization from cyclohexane provided colorless crystals, melting point 77°-78° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[CH2:17]Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([Br:27])=[C:25]([CH3:28])[CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20]=[C:21]2[C:26]([Br:27])=[C:25]([CH3:28])[CH:24]=[CH:23][N:22]2[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1ccnc(N)c1Br
Product: Cc1ccn2cc([C@@H]3CCCN3C(=O)OCc3ccccc3)nc2c1Br
Yield: 47.2 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (0.400 g, 1.23 mmol) and 2-amino-3-bromo-4-methylpyridine (0.2344 g, 1.25 mmol), produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (12 g SiO2, 0-50% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.239 g, 0.58 mmol, 47%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](C(=O)C)[CH2:4][CH2:3]1.[OH-].[Na+].O>C(O)C>[S:2]1(=[O:16])(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(=O)N1CCS(=O)(=O)c2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S1(=O)CCNCc2ccccc21
Yield: 76.6 %

Procedure:
To a solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (240 g, 1.0 mol) in ethanol (1.0 L) was added sodium hydroxide (200 g, 5.0 mol) and water (700 mL). The mixture was refluxed overnight and then concentrated in vacuo. The residue was extracted by ethyl acetate (1500 mL×4). The combined organic layers were extracted by hydrochloric acid (2000 mL, 3 N). The acidic aqueous layer was washed with ethyl acetate (1500 mL×2), then basified with a saturated aqueous solution of sodium bicarbonate to pH >7, and extracted with ethyl acetate (1500 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 151 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (yield was 76%), MS obsd. (ESI+) [(M+H)1] 198, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=1.2, 7.6 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.47 (t, J=7.6 Hz, 1 H), 7.42 (d, J=7.6 Hz, 1 H), 4.04 (s, 2 H), 3.32-3.30 (m, 2 H), 3.30-3.25 (m, 2 H), 2.64 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[Cl:42][C:43]1[CH:44]=[N:45][NH:46][CH:47]=1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:45]3[CH:44]=[C:43]([Cl:42])[CH:47]=[N:46]3)=[CH:29][CH:30]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cn[nH]c1
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-n3cc(Cl)cn3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 4-chloro-1H-pyrazole.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH:10]=[CH2:1]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(F)cccc1Cl

Procedure:
Under an argon atmosphere, to a suspension (1.1 L) of methyltriphenylphosphonium bromide (90 g) in dry tetrahydrofuran was added a solution (264 mL) of 1 mol/L-potassium tert-butoxide in tetrahydrofuran with stirring under ice-cooling, and the mixture was stirred at the same temperature for 30 min. Then, a solution (165 mL) of 2-chloro-6-fluorobenzaldehyde (34.5 g) in tetrahydrofuran was added to the mixture, and the mixture was stirred for 30 min. The insoluble material was removed with celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and, after triturating, the crystals were collected by filtration and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane) using NH-silica gel (manufactured by Fuji Silysia Chemical Ltd.) to give the title compound as a colorless oil (yield: 20.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]1[O:23][C@H:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: c1ccc([C@H]2CO2)cc1
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](O)c2ccccc2)CC1
Yield: 99.3 %

Procedure:
2-Methoxyphenylpiperazine (17.4 g, 0.0906 m) in dry acetonitrile (150 ml) was refluxed 24 hrs with (S)-styrene oxide (10.84 g, 0.09 m). The residue on evaporation was treated by acid-base extraction to remove unreacted styrene oxide to leave 28 g of the crude alcohol as a mixture of regioisomers which was purified by chromatography on silica, using 1:1 hexane ethylacetate, to give 16.5 g of the pure isomer, [α]23D +56° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3].[O:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]1[C:18]1[C:19]([NH2:35])=[N:20][CH:21]=[C:22]([C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:28]=2)[CH:23]=1>N1C=CC=CC=1>[NH2:35][C:19]1[N:20]=[CH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3])[CH2:31][CH2:30]3)[CH:28]=2)=[CH:23][C:18]=1[C:10]1[O:9][C:17]2[C:12]([N:11]=1)=[N:13][CH:14]=[CH:15][CH:16]=2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Reactant: COCCOC(=O)Cl
Solvent: c1ccncc1
Product: COCCOC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methoxyethyl chloroformate (0.035 ml) at 25° C. was added over a period of 5 minutes under argon to a stirred mixture of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and pyridine (5 ml). The resulting suspension was stirred at 25° C. for 2 hours. The solvent was evaporated. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-methoxyethyl 4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]piperidine-1-carboxylate (75 mg) as a solid. NMR Spectrum: (CDCl3): 1.95-2.07 (m, 2H), 2.17-2.26 (m, 2H), 3.01 (bs, 2H), 3.40 (s, 3H), 3.63 (t, 2H), 4.28 (bs, 2H), 4.29-4.44 (m, 3H), 7.02 (bs, 2H), 7.35 (dd, 1H), 7.69 (s, 1H), 7.79 (s, 1H), 7.90 (dd, 1H), 8.41 (d, 1H), 8.42 (d, 1H), 8.59 (dd, 1H); Mass spectrum: M+H+ 464.