Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH:18]1[NH2:24]>>[O:12]1[CH2:13][CH2:14][C@@H:10]([O:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:24][CH:18]3[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][CH:17]3[CH3:16])[N:4]=2)[CH2:11]1
Reactant: CC1CCCC(C)C1N
Reactant: Clc1ncc(Br)c(O[C@@H]2CCOC2)n1
Agent: Cl
Product: CC1CCCC(C)C1Nc1ncc(Br)c(O[C@@H]2CCOC2)n1

Procedure:
Using the procedure of Example 78, Step 2, (R)-5-bromo-2-chloro-4-(tetrahydrofuran-3-yloxy)pyrimidine was reacted with 2,6-dimethylcyclohexanamine HCl salt to provide the title compound. MS (ESI) m/z: Found: 370 (M++1), Calc. 369 (M+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:12]12[CH2:19][CH2:18]C(C(O)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)[CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)Cl>[CH2:7]([C:12]12[CH2:19][CH2:18][C:1]([C:2]([Cl:4])=[O:3])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Solvent: ClCCl
Product: CCCCCC12CCC(C(=O)Cl)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (505 μL, 5.79 mmol) was added dropwise to a mixture of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) in methylene chloride (10 mL). The solution was stirred at room temperature for 3 h and then concentrated in vacuo to give 4-pentylbicyclo[2.2.2]octane-1-carbonyl chloride (3-B). 1H NMR (500 MHz, CDCl3): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.45 (m, 6H); 1.88 (m, 6H) ppm.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].[C:22]1([CH2:32][CH2:33][NH2:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:34][CH2:33][CH2:32][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: NCCc1cccc2ccccc12
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNCCc1cccc2ccccc12
Temperature: 25 °C
Yield: 80.1 %

Procedure:
(2S,4S)-2-Formyl-4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (1) (1.84 g) in dichloromethane(20 ml) was added dropwise over 10 minutes to a mixture of 2-naphthalen-1-ylethylamine (1.0 g),. sodium triacetoxyborohydride(1.36 g) and 4A powdered molecular sieve (3.0 g) in dichloromethane (130 ml) cooled to −20° C. and stirred under an argon atmosphere. After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for a further 18 hours. The molecular sieves were filtered off and the fitrate stirred with saturated aqueous sodium bicarbonate solution( 100 ml) for 5 minutes. The mixture was separated, the organic phase dried over magnesium sulphate and applied to a silica flash column which was then eluted with 1.Ethyl acetate/Hexane(50:50), 2.Ethyl acetate/Hexane(80/20), 3.Ethyl acetate to give (2S,4S)-4-BOCsulfanyl-2[(2-naphthalen-1-ylethylamino)-methyl]pyrrolidine-1-carboxylic acid allyl ester (2) (2.2 g) as a colourless gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[C@@H:21]([NH:26][CH3:27])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[C@@H:21]([N:26]([CH3:27])[C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=2[N+:9]([O-:11])=[O:10])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN[C@H]1CN(Cc2ccccc2)CC[C@H]1C
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc(N)c1[N+](=O)[O-]
Yield: 89.8 %

Procedure:
In a microwave reaction vessel 4-chloro-3-nitro-2-pyridinamine (125 mg) and (3R,4R)-1-benzyl-N,4-dimethyl-3-piperidinamine (314 mg) were suspended in 2-propanol (6.25 mL). To the mixture was added N,N-diisopropylethylamine (0.63 mL). The vessel was sealed and reacted in the microwave reactor at 135° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-3-nitro-2,4-pyridinediamine (230 mg) as a yellow amorphous.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([C:15]#[CH:16])#[N:14]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:15]([C:13]#[N:14])[CH:16]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC#N
Solvent: c1ccccc1
Product: N#Cc1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
6.0 g (0.04 mole) of 3-diazooxindole and 2.2 g (0.045 mole) of cyanoacetylene are taken up in benzene (250 ml) and refluxed overnight under N2. The mixture is cooled and the beige-colored precipitates are filtered off. The crude product is dried in a vacuum oven at room temperature for 3 hours. Yield: 5.2 g, m.p. 302°-304°. Percent yield: 65.6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[C:8](Cl)=[N:9][C:10](Cl)=[N:11][CH:12]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[C:8]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:9][C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cccnc1
Reactant: Nc1ccccc1
Product: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cccnc1
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester (326 mg, 1.0 mmol) (from Example 10a supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester as a brown solid which was used in the next step without further purification. (Yield 60 mg, 13.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:20]=[C:21]2[NH:27]C(=O)O[C:23](=[O:24])[C:22]2=[CH:29][CH:30]=1)([O-:18])=[O:17]>>[NH2:27][C:21]1[CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:30]=[CH:29][C:22]=1[C:23]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:24]
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1cccc(OCc2ccccc2)c1
Yield: 75.1 %

Procedure:
Using the procedure described in Example 91, Part B, 3-benzyloxyaniline (4.4 mmol) and 4-nitroisatoic anhydride (4.8 mmol) yielded 1.2 g (81%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Chloro-3-iodobenzene (10.0 g, 41.9 mmol) was dissolved in 100 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The desired product was obtained as a light yellow oil (7.38 g, purity ˜70%, yield ˜59%).
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(C)(C)C)=O.[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:19](N)=[C:18]([Cl:24])[CH:17]=1>C(#N)C.ClCCl>[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:19]([CH2:4][C:5](=[O:6])[CH3:7])=[C:18]([Cl:24])[CH:17]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: C=C(C)OC(C)=O
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)Cc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
In a 50 ml three-neck flask equipped with mechanical stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetonitrile (10 ml), were added cuprous oxide (1.5 g, 0.018 mol), isopropenyl acetate (13.6 ml, 0.125 mol) and tert-butyl nitrite (1.7 ml, 0.0125 mol). The resulting red suspension is stirred for 15 min at ambient temperature. A solution of 4-bromo-2,6-dichloroaniline (2.0 g, 0.0083 mol), dissolved in acetonitrile (15 ml) was added dropwise over a period of 20 minutes. During the addition, bubbling was observed. The mixture was stirred at 40° C. for 20 hours. The red crude mixture was passed through celite to remove solid particles and concentrated under reduce pressure to give a brown solid. The residue was dissolved in dichloromethane (120 ml) and washed with water (2×50 ml) and brine (40 ml). Organics were dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(4-bromo-2,6-dichloro-phenyl)-propan-2-one (2.3 g) as a dark brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.Cl.NO.[N:41]1C=CC=CC=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([C:13]#[N:41])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 90 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (950 mg), hydroxylamine hydrochloride (150 mg), pyridine (1 mL) and ethanol (20 mL) was refluxed for 3 hrs. After concentration of the reaction mixture, dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in acetic anhydride (20 mL), and the mixture was refluxed for 5 hrs. After concentration of the reaction mixture, the residue was subjected to silica gel column chromatography to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbonitrile (850 mg, yield 90%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from acetone-hexane. melting point: 174-175° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([F:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([F:8])=[CH:6][N:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Yield: 33 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-fluoropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave −20° C., 24 hours) to afford 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 33% yield. Mp: 225° C. (dec); MS: 281.23 (M+H); 1H NMR (chloroform-d): δ 11.78 (br s, 1H), δ 8.80 (d, J=8 Hz, 1H), δ 8.11 (s, 1H), δ 7.60 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.15 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.06 (dd, J=2.5 Hz, 3H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH:17][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)CCN
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzenesulfonyl chloride (500 mg, 2.83 mmol) in pyridine (10 mL) is added 3-amino-propionic acid ethyl ester (672 mg, 8.49 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using a gradient of 10-50% heptane/EtOAc to afford 3-benzenesulfonylaminopropionic acid ethyl ester. MS 258.3 (M+1); 1H-NMR (400 MHz, CDCl3); δ ppm 1.24 (t, 3H), 2.53 (t, 2H), 3.21 (q, 2H), 5.22 (m, 1H), 7.51-7.61 (m, 3H), 7.87 (d, J=7.20Hz, 2H).
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]2[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[N:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])C=CC=CC=1.CSC>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]1[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[N:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:1]
Reactant: O=[O+][O-]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ozone was passed through a -78° C. methylene chloride (100 mL) solution of compound 34 (8.2 g, 12 mmol) until the solution retained a blue color. Dimethyl sulfide (10 mL) was added. The solution was warmed to room temperature and allowed to stand for 16 h. The solution was concentrated to afford the title product which was not purified but used directly in Step B.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:24][CH:25]([CH2:27][CH3:28])[CH3:26])=[C:11]2[C:17](C)=[N:16][N:15](C3OC=CC=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[C:1]([C:9]1[C:10]([NH:24][CH:25]([CH2:27][CH3:28])[CH3:26])=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)Nc1c(C(=O)c2ccccc2)cnc2c1c(C)nn2-c1ccco1
Agent: O=S(=O)(O)O
Product: CCC(C)Nc1c(C(=O)c2ccccc2)cnc2[nH]ncc12

Procedure:
3.7 g. of 5-benzoyl-4-sec.butylamino-1-(2-furanyl)-methyl-1H-pyrazolo[3,4-b]pyridine are stirred in 20 ml. of conc. sulfuric acid for 3 hours at 50°. The mixture is decomposed with 30 ml. of water and filtered. The filtrate is made alkaline with 30% aqueous ammonia and the white precipitate of 5-benzoyl-4-sec.butylamino-1H-pyrazolo[3,4-b]-pyridine is filtered off, yield 1.7 g. (58%), m.p. 186°-187°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[CH:15][N:14]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccnc(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloropyridin-4-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:31])[F:32])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (1.78 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.1 mmol) in acetonitrile (20.2 mL) was heated at 50° C. overnight. After cooling, the solvent was removed under reduced pressure. The residue was used in the next step without further purification. LCMS cacld. for C24H28BF5N5O3 (M+1)+: m/z=540.2. Found: 540.1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=1)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 3.88 g, 96.98 mmol) was added portionwise to a stirring solution of ethyl 5-bromo-1H-indole-2-Carboxylate (20.0 g, 74.6 mmol) in DMF (140 mL) at 0° C. under a nitrogen atmosphere over a period of 10 min. The mixture was then warmed to room temperature. After the reaction mixture was stirred at room temperature for one hour, 4-methylbenzyl bromide (14.2 g, 74.6 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate. This mixture was concentrated to give a semi-solid contained 0.8 mole equivalent DMF. Mass spectrum (ESI, [M+H]+) m/z 372. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H, J=7.94 Hz), 7.55 (d, 1H, J=9.01 Hz), 7.40 (dd, 1H, J=8.85 and 1.98 Hz), 7.32 (s, 1H), 7.04 (d, 2H, J=7.96 Hz), 6.90 (d, 2H, J=7.94 Hz), 5.79 (s, 2H), 4.28 (q, 2H), 2.20 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: [Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]([CH:13]([OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:27][CH:13]([C:11]#[CH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(Cl)Cl
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(OC(=O)C1C(C)(C)C1(Cl)Cl)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2-dichloro-3,3-dimethylcyclopropanoyl chloride (2.7g), alpha-ethynyl-3-phenoxybenzyl alcohol (3.0g) and triethylamine (3.0g) were dissolved in toluene (65 ml) at 10° C and the solution was stirred at room temperature for 16 hours. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was purified by chromatography on silica gel using toluene as eluant to give the desired product as an oil nD20 1.5660.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:11]([NH2:13])[CH3:12]>C1COCC1>[CH2:11]([NH:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cccc(C#N)c1
Reaction time: 5 h
Yield: 73 %

Procedure:
3-(Bromomethyl)benzonitrile (20.0 g, 0.1 mol) was added portion wise into a 2M solution of ethylamine in THF (150 mL) at 0° C. After 5 hours, the reaction mixture was concentrated under vacuum. The residue was taken up with water and extracted with DCM. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound as yellow liquid (12 g, 73%). 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.67 (d, 2H), 7.50 (m, 1H), 3.71 (s, 2H), 2.46 (m, 2H), 0.99 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:33](=[O:35])[CH3:34])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CC(=O)Cl
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(C)=O
Yield: 73 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.40 g (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.17 g (2.2 mmol) of acetyl chloride as a reaction reagent (XII) were added. The resultant mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate, and its organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=1:2) to give 0.33 g (yield 73%) of 4-methoxy-5-methyl-6-(1-ethyl-5-acetoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51) as an end compound which comes under the general formula (XI). Table 18 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).