Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:12])[C:6](=[CH2:11])[NH:7][C:8](=[O:10])[CH3:9].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](S)=[CH:17][CH:16]=1.COC(=O)C(CC1C=CC(SOC)=CC=1)NC(=O)C.O[O:42][S:43]([O-:45])=O.[K+]>CO.O.C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:12])[CH:6]([CH2:11][S:43]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)(=[O:45])=[O:42])[NH:7][C:8](=[O:10])[CH3:9]
Reactant: COc1ccc(S)cc1
Reactant: O=S([O-])OO
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: COSc1ccc(CC(NC(C)=O)C(=O)OC)cc1
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(CS(=O)(=O)c1ccc(OC)cc1)NC(C)=O
Reaction time: 2 h
Yield: 65 %

Procedure:
Part A: To a stirred degassed (N2) solution of (20 g, 139 mmol) of N-acetyl-dehydroalanine methyl ester in 400 mL of methanol was added (19.5 g, 139 mmol) of 4-methoxythiophenol followed by 14.0 g, 140 mmol) of triethylamine and the resulting solution stirred for 2 hours. The resulting N-acetyl-β-(4-methoxythio-phenyl)-D,L-alanine methyl ester was oxidized in situ by the addition of 800 mL of methanol, 160 mL of water followed by (250 g, 417 mmol) of OXONE®. The suspension was stirred for 3 hours and then filtered through a fritted glass buchner funnel. The filtrate was concentrated by rotary evaporation and the concentrated material was partitioned between ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a white solid which was triturated with cold ethyl acetate and filtered to yield 28.5 g of N-acetyl-β-(4-methoxyphenylsulfonyl)-D,L-alanine methyl ester.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]([NH2:24])([CH3:23])[CH3:22]>>[CH3:20][C:21]([NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)([CH3:23])[CH3:22]
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)Nc1nccc(-n2cnc3ccccc32)n1
Temperature: 40 °C

Procedure:
The title compound was prepared from 2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine according to the procedure described in EXAMPLE 1, Step C except using 1,1-dimethylethylamine as the solvent and heating at 40° C. Mass Spectrum (CI): m/e 268.3 (M+1). ). 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H); 8.40 (d, J=5.5 Hz, 1H); 8.07 (d, J=7.3 Hz, 1H); 7.88 (m, 1H); 7.40 (m, 2H); 6.81 (d, J=5.2 Hz, 1H); 5.40 (br s, 1H); 1.54 (s, 9H).
Reaction SMILES: [O:1]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:12]([CH3:14])[CH3:13])[N+:20]([O-:22])=[O:21]
Reactant: CC(C)C(Oc1ccccc1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(C)C(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 68.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.47 g of 2-phenoxy-3-methylbutyric acid and 0.40 g of 2-nitroxyethylamine nitrate, 0.46 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13](Cl)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(OCC)(=O)C.O>[Cl-].[Na+].O>[CH2:1]([NH:8][C:9](=[O:24])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 5.0 g (14.8 mMol) of N-benzyl-6-chloro-4-o-tolyl-nicotinamide and 25 ml morpholine was heated to 100° C. for 3.5 hours. After cooling to room temperature, extractive work-up with ethyl acetate, water and brine gave 5.7 g (100%) N-benzyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide as a yellow powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31]
Reactant: Cc1ccn2cc(-c3ccc(CCCCO)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccn2cc(-c3ccc(CCCCOS(C)(=O)=O)cc3)nc2c1
Temperature: 0 °C
Yield: 125.6 %

Procedure:
The product of Step A (0.33 g) in dichloromethane (20 mL) was treated with triethylamine (0.36 g) and cooled to 0° C. The cold solution was treated with methanesulfonyl chloride (0.338 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with water (50 mL), saturated sodium bicarbonate solution (25 mL), water (50 mL), dried over sodium sulfate, filtered and evaporated to give the crude title compound (0.53 g). The crude product was used, Step C, without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Product: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Yield: 77.7 %

Procedure:
1.0 g (2.93 mmol) of 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide and 1.18 g (2.93 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Example 1 to obtain 1.43 g (yield 78%) of benzyl 2-{[(3-benzyloxycarbonylamino-4-chlorobenzene sulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 5.19 (2H, s), 5.36 (2H, s), 7.21 (1H, dd), 7.34-7.48 (10H, m), 7.72-7.76 (2H, m), 7.97 (1H, d), 8.25 (1H, d), 8.30 (1H, d), 9.53 (1H, s), 10.30 (1H, s). 1.38 g (2.20 mmol) thereof was dissolved in 50 ml of THF, then 200 mg of palladium-carbon (10%) was added and the mixture was stirred under a hydrogen flow for 2 hours. The reaction mixture was filtered with Celite to remove the palladium-carbon, then the filtrate was concentrated in vacuo to obtain a carboxylic acid. The product obtained was suspended in 50 ml of THF, then 356 mg (2.20 mmol) of CDI was added under ice cooling and the resultant mixture was treated in the same way as Example 1 to obtain 560 mg (yield 66%: 2 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.00 (2H, s), 7.12 (1H, s), 7.26 (2H, t), 7.48 (1H, d), 7.66 (1H, s), 7.86 (1H, d), 11.76 (1H, br).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:15])[C:3]=1O.[C:17]([O-:20])([O-])=O.[K+].[K+].[CH3:23]I>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:15][CH3:23])[C:3]=1[O:20][CH3:17]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc2c(Br)c(O)c(O)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c([N+](=O)[O-])cccc2c(Br)c1OC
Temperature: 50 °C

Procedure:
To a solution of 75 mg of 1-bromo-2,3-dihydroxy-5-nitronaphthalene in 3.0 ml of DMF was added K2CO3 and Methyl iodide. The resulting solution was heated at 50° C. overnight after which the reaction mixture was diluted with water and extracted with ethyl acetate. Column chromatography using 30% ethyl acetate in hexane afforded the product, 1-bromo-5-nitro-2,3-dimethoxynaphthalene as a yellow solid. (Yield: 60 mg; 1H NMR (CDCl3) δ 3.99 (s, 3H), 4.04 (s, 3H), 7.45-7.53 (m, 1H), 7.98 (s, 1H), 8.21 (dd, J=6.0 Hz, 1.2 Hz, 1H), 8.51 (dd, J=6.0 Hz, 1.2 Hz, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([Li])CCC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.CCCCCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3](=[O:11])[CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1COc2ccccc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1COc2ccccc2N1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Under an anhydrous atmosphere, a solution of 10 mmol of 2H-1,4-benzoxazin-3-one in 50 ml of tetrahydrofuran is cooled to −78° C. At that temperature, 11 mmol of a 1.6M solution of n-butyllithium in hexane are added dropwise. After being in contact for 30 minutes at −78° C., 11 mmol of phenyl chloroformate are added dropwise and stirring is carried out for a further 2 hours. After returning to ambient temperature, the solution is hydrolysed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated. After purification by chromatography over silica gel (petroleum ether/ethyl acetate: 8/2), the expected product is isolated.
Reaction SMILES: C[Si](CC(N)=O)(C)C.[NH2:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41](Cl)=[O:42])[N:39]=1)=[O:33].O>C(Cl)Cl>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:42])[N:39]=1)=[O:33]
Reactant: CON=C(C(=O)Cl)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 40 °C
Yield: 93.9 %

Procedure:
N,N-Dimethylformamide (3 drops) was added to a suspension of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 23 g.), and stirred at 60° C. for 5 minutes. After concentrating the solution in vacuo, benzene was added to the residue. The precipitates were collected by filtration, washed with benzene (30 ml.) three times and diethyl ether in turn to give 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 18 g.). On the other hand, trimethylsilylacetamide (46 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (16.8 g.) in methylene chloride (168 ml.), and stirred at 40° C. for an hour. To the suspension was gradually added 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 13.6 g.) at -5° to 0° C., and stirred at the same temperature for an hour. Water (150 ml.) was added to the resultant solution and stirred for 15 minutes. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (anti isomer, 25.7 g.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([C:25]#[N:26])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=2[O:27][CH:28]([CH3:30])[CH3:29])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.C(C(C1C=CC(OC)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)C)#N>>[C:25]([C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:27][CH:28]([CH3:30])[CH3:29])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:24])[CH3:23])#[N:26]
Reactant: CC(C)Oc1ccc(C(C)(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 42 in the same manner of Compound 19.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:29][C:30]([O:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:31])[C:11]([NH:13][CH:14]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH:10]([NH:29][C:30]([O:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:31])[C:11]([NH:13][CH:14]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCNc1cccc(C)n1)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(NCCOC(=O)NC(COCc2ccccc2)C(=O)NC(CC(=O)O)c2cc(Cl)cc(Cl)c2)n1

Procedure:
50.00 mg of ethyl 3-{3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionate are reacted with 2 ml of ethanol and 0.50 ml of 1 molar sodium hydroxide solution for 2 hours with stirring, acidified using 0.5 ml of glacial acetic acid and evaporated to dryness, giving 3-{3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:21][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
To the solution of 10 g ethyl 4-nitrophenylacetate in 400 ml dimethyl formamide-toluene (1:1), 2.5 g 50% sodium hydride are added portionwise during 15 minutes while stirring and cooling with ice, after which the solution of 9.6 g cyclopropylmethyl bromide in 50 ml toluene is added dropwise and the mixture stirred overnight at room temperature. It is diluted with 200 ml water, extracted with diethyl ether, the extract dried, evaporated, the residue distilled and the fraction boiling at 132°-138°/0.25 mm Hg collected, to yield the ethyl α-(4-nitrophenyl)-β-cyclopropylpropionate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:18][CH:17]3[O:19][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:11][N:8]1[C:6]2=[N:7][C:2]([C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=3)=[N:3][C:4]([N:12]3[CH2:18][CH:17]4[O:19][CH:14]([CH2:15][CH2:16]4)[CH2:13]3)=[C:5]2[CH:10]=[N:9]1
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reactant: OB(O)c1cccc(O)c1
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: Cc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3cccc(O)c3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (95 mg, 0.34 mmol), 3-hydroxyphenylboronic acid (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (39 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified with 1 M aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined extracts were washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The extracts were then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 90% acetonitrile to provide, after concentration, 3-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol. MS (ES+): 338.0 (M+H)+
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:13]I>CN(C=O)C>[I:13][C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:1][N:2]=1
Reactant: c1n[nH]c2c1CCCCC2
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2c1CCCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of 1,4,5,6,7,8-hexahydrocycloheptapyrazole (500 mg, 3.67 mmol) in DMF (8 ml) at room temperature was added powdered potassium hydroxide (618 mg, 11.0 mmol) and iodine (1.86 g, 7.34 mmol). The maroon reaction mixture was stirred at room temperature for 1 h then quenched with aqueous 10% Na2S2O3, diluted with water, and extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography with 20% to 50% EtOAc/hexanes to afford 600 mg (62%) of 3-iodo-1,4,5,6,7,8-hexahydrocycloheptapyrazole as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 2.75-2.84 (m, 2H), 2.46-2.55 (m, 2H), 1.80-1.91 (m, 2H), 1.63-1.77 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:26]([O:36][CH2:37][CH2:38][OH:39])=[C:25]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)[CH:24]=1)C>C1COCC1>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:24]=[C:25]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)[C:26]([O:36][CH2:37][CH2:38][OH:39])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71.6 %

Procedure:
To a flamed dried round bottom flask with dodecyl amine (0.519 g, 2.80 mmol) and THF (8 mL) cooled to 0° C. was added n-BuLi (1.12 mL, 2.5 M in hexane, 2.80 mmol) dropwise over a 5 min. period. The resulting solution was stirred at this temperature for 40 min. and then cooled to −45° C. To this solution was added dropwise a solution (at 0° C.) of 3,5-bis-(m-chlorophenyl)4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.302 g, 0.700 mmol) in THF (8 mL) over 5 min. This final mixture was stirred and warmed to room temperature over 30 min. At this point, the reaction mixture was quenched with H2O (3 mL) and diluted with EtOAc (40 mL). The organic layer was washed with 1 N HCl (3×7 mL), brine (7 mL), and H2O:brine (1:1, 14 mL) and then dried (Na2SO4). After concentration, the residue was purified by flash chromatography (0 to 15% EtOAc/hexane gradient) to afford the product (0.286 g, 72%) as an oily white solid; 1H NMR (DMSO-d6) δ0.86 (t, J=7.7 Hz, 3H), 1.20-1.37 (m, 18H), 1.46-1.57 (m, 2H), 3.13 (dd, J=6.9, 11.5 Hz, 2H), 3.20-3.33 (m, 4H), 4.46 (t, J=6.2 Hz, 1H), 7.43-7.57 (m, 4H), 7.59-7.63 (m, 2H), 7.68-7.73 (m, 2H), 7.89 (s, 2H), 8.67 (t, J=6.2 Hz, 1H); mass spectrum [(+) APCI], m/z 570 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:13](O[K])C.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C(O)C>[CH2:7]([O:6][Si:5]([O:9][CH2:10][CH3:11])([CH3:12])[CH2:4][CH2:3][CH2:2][S:1][CH2:13][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([F:17])[CH:23]=1)[CH3:8]
Reactant: CCO[Si](C)(CCCS)OCC
Reactant: Fc1ccccn1
Reactant: CCO[K]
Solvent: CCO
Product: CCO[Si](C)(CCCSCc1ccnc(F)c1)OCC
Reaction time: 0.08 h
Yield: 78 %

Procedure:
10 mmole of 3-mercaptopropylmethyldiethoxysilane was dissolved in 10 ml ethanol, then 10 mmole EtOK was added, and stirred for 5 minutes. 10 mmole of 2-fluoropyridine in 10 ml ethanol was added to the solution, and stirred for 30 minutes. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The product was purified with a short Si gel column. The solvent was 1:3 ethyl acetate:hexane by volume. 1H NMR (CD3Cl): δ(ppm) 0.03 (3H, s), 0.60 (2H, m), 1.15 (6H, m), 1.55 (2H, m), 2.40 (2H, m), 3.65 (4H, m), 6.85 (1H, s), 7.09 (1H, d, JH-H=5.02), 8.08 (1H, d, JH-H=5.02. Yield: 78%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]2=[O:18].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]2=[O:18]
Reactant: CC(C)(C)N
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1CC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CC(F)(F)F
Yield: 85.5 %

Procedure:
8-Bromo-2-(tert-butylamino)-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (501d, 505 mg, 86%) as an off-white solid was prepared according to the procedures described for 408 using 8-bromo-2-chloro-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (534 mg, 1.562 mmol, 501c), tert-butylamine (4.9 mL, 46.9 mmol), and NMP (0.5 mL). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87-8.00 (2H, m) 7.06 (1H, t, J=7.73 Hz) 6.44 (1H, s) 5.22 (2H, q, J=9.00 Hz) 1.55 (9H, s). m/z (ESI, +ve) 379.9/381.0 (M+H)+.