Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:28][CH:29]([CH3:39])[CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][OH:38])[CH:34]=[CH:35][CH:36]=1.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[OH:38][CH2:37][C:33]1[CH:32]=[C:31]([CH2:30][CH:29]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:16]4=[N:17][C:18]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:19][C:20](=[O:21])[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:39])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(N)Cc1cccc(CO)c1
Reactant: CS(=O)(=O)c1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Temperature: 100 °C

Procedure:
A mixture of 9-(2-methanesulfonyl-pyrimidin -4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (344 mg, 0.90 mmol), [3-(2-amino-propyl)-phenyl]-methanol (371 mg, 2.25 mmol), and N-methylmorpholine (8 mL) was heated to 100° C. for 20 h. Reaction was diluted with dichloromethane (15 mL) and ethyl acetate (40 mL), washed three times with water (50 mL) then saturated sodium chloride (10 mL). Organic dried over magnesium sulfate then concentrated to a oil under vacuum. Product purified on silica and isolated as a white solid. M+1=469.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.[H-].[Na+].CO.Cl>O1CCCC1.O>[C:29]1([N:13]2[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=[C:12]2[S:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reaction time: 24 h

Procedure:
170 g of 8-(1.4.5-triphenylimidazol-2-yl mercapto)-octanoic acid methyl ester are dissolved in 1.2 l of tetrahydrofurane. 42 g of sodium hydride dissolved in 700 cc. of methanol are added thereto. The mixture is stirred 24 hours at 40° to 50° C., cooled, diluted with about 2 l of water and acidified with delute hydrochloric acid. The crude acid is filtered off, dried and recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][C:7]1=[O:13].[CH3:17][NH:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:19][NH:18][CH3:17])[CH2:8][C:7]1=[O:13]
Reactant: CNN
Reactant: O=C1CCN(Cc2cccc(Cl)c2)C(=O)C1
Solvent: CCO
Product: CNN=C1CCN(Cc2cccc(Cl)c2)C(=O)C1

Procedure:
1-(3-Chlorobenzyl)piperidine-2,4-dione (1.2 g) was dissolved in ethanol (25 ml), and methylhydrazine (0.5 ml) was added. The mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:1) to give 1-(3-chlorobenzyl)-4-(methylhydrazono)piperidin-2-one (1.05 g).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:25]I>ClCCl.C(Cl)(Cl)Cl>[I:25][CH2:3][CH:2]1[CH2:1][C:4]2[C:5]3[C:6](=[N:7][CH:8]=[N:9][C:10]=3[CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[N:18]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Reactant: II
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine (0.12 g, 0.37 mmol) (from Example 15, Step E, supra) in dichloromethane (20 mL) was added I2 (0.24 g, 1.87 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.05) as eluent to give the desired 5-iodomethyl-7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 0.11 g, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].I[C:16]1([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17]1.[BH4-].[Na+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[C:20]1([S:19][C:16]2([O:1][C:2]3[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=3[CH2:4][OH:5])[CH2:18][CH2:17]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: IC1(Sc2ccccc2)CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 36 h
Yield: 52.1 %

Procedure:
Silver carbonate (4.82 g, 17.5 mmol) was added to a solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (2.0 g, 9.7 mmol) and (1-iodocycloprop-1-yl)phenylsulfide (Cohen T. and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (5.48 g, 17.5 mmol) in toluene (25 mL) and the mixture was stirred at 40° C. for 36 h., then at room temperature for 16 h. The mixture was diluted with ethyl acetate and filtered, washing well with ethyl acetate. The mixture was washed with aqueous sodium hydroxide (1M, 6×75 mL) and brine (75 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, (15 mL), cooled to 0° C. and sodium borohydride, (0.74 g, 19.6 mmol), was added. The mixture was stirred at room temperature for 1 h., poured into water and extracted into ethyl acetate (3×100 mL). The combined organic fractions were dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (97:3 increasing to 70:30), to give the title compound as a yellow oil (1.8 g, 53%). 1H NMR (250 MHz, CDCl3) 1.41-1.44 (2H, m), 1.46-1.51 (2H, m), 1.84 (1H, t, J 6.5 Hz), 4.58 (2H, d, J 6.5 Hz), and 7.18-7.48 (8H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]#[N:6].[OH-].[Na+].C([OH:33])(C)(C)C.CO>OO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]([NH2:6])=[O:33]
Reactant: CC(C)(C)O
Reactant: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-chloro-4-[4-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-1-piperazinyl]benzonitrile (Example 29; 0.122 g), NaOH (0.063 g), 30% hydrogen peroxide (2 drops), and tert-butanol (2 mL) is stirred at 80° C. for 4 h, after which it is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The solids remaining suspended in the aqueous layer are collected, washed with water, dried under reduced pressure, and combined with the solids obtained from concentration of the organic layers. The solids are taken up in dichloromethane and methanol with warming and filtered through a cotton plug to remove insolubles. The filtrate is then concentrated and the residue is crystallized from dichloromethane/hexane to give 0.0745 g of the title compound; mp 254-256° C.; MS m/z 403, 405; IR (mineral oil) 1413, 1235, 1597, 800, 1328 cm-1. 1H NMR (DMSOd6) δ2.64, 3.05, 3.69, 7.17, 7.25, 7.37, 7.55, 7.79, 7.84, 7.89, 7.96, 8.80.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH2:9]SC)[C:5]([F:12])=[C:4]([F:13])[CH:3]=1>C(O)C.[Ni]>[F:12][C:5]1[C:6]([CH3:9])=[C:7]([CH:2]=[CH:3][C:4]=1[F:13])[NH2:8]
Reactant: CSCc1c(N)c(Br)cc(F)c1F
Agent: [Ni]
Solvent: CCO
Product: Cc1c(N)ccc(F)c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 117.7 %

Procedure:
Into a solution of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (6.00 g) in ethanol (120 ml) is suspensed Raney nickel (70 ml), and the mixture is stirred at 50° C. for 30 minutes. After removing Raney nickel by filtration, the filtrate is concentrated to give 3,4-difluoro-2-methylaniline (3.77 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17]>S(Cl)(Cl)=O.C(Cl)(Cl)Cl>[C:16]([NH:19][NH:20][C:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:15])(=[O:18])[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CC(=O)NN
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)NNC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 111.5 g (0.5 mole) of 5-(p-chlorophenyl)furoic acid in 500 ml of thionyl chloride was heated at reflux for 1-11/4 hr. After slight cooling, the reaction mixture was filtered and the filtrate was concentrated in a water bath at reduced pressure to a creamy solid. The solid was dissolved in 400 ml of chloroform. To this chloroform solution under stirring at room temperature was added a suspension of 74 g (1 mole) of acetyl hydrazine in 900 ml of chloroform. Addition was completed in about 20 min. White creamy solid separated fairly readily while the temperature rose to about 45°. The mixture was allowed to stir at ambient temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C-]#N.[Na+].[CH3:15][N:16](C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1cccc(Cl)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(Cl)n1
Temperature: 170 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of 2-chloro-6-methylsulfonylpyridine (13.0 g, 67.8 mmol), sodium cyanide (6.69 g, 136 mmol) and DMF (150 ml) was stirred at 170° C. for 18 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v) to give 2-chloro-6-cyanopyridine (6.67 g, 71%) as crystals (mp. 82.9-83.1° C.).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1>CO>[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccccc1-c1ccc2c(c1)CCC2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
Sodium borohydride (1.03 grams, 27 mmol) was added to a mixture of 2-(1-oxo-indan-5-yl)-benzonitrile (3.2 grams, 13.6 mmol) in methanol (MeOH) (130 mL) at ) 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. After cooling to 0° C., the reaction mixture was quenched with saturated aqueous ammonium chloride (NH4Cl) (25 mL). EtOAc (500 mL) was added and the organic layer was separated and washed with saturated aqueous NaCl (3×100 mL), dried (Na2SO4) and concentrated in vacuo to yield 2.9 grams of a brown oil. 1H NMR (250 MHz, CDCl3): d 7.78 (d, 1 H), 7.65 (t, 1 H), 7.50 (m, 5 H), 5.32 (t, 1 H), 3.15 (m, 1 H), 2.92 (m, 1 H), 2.55 (m, 1 H), 2.0 (m, 1 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=O)[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10](=[O:12])[CH3:11].[NH2:24][C:25](=[CH:27][C:28](=[O:30])[CH3:29])[CH3:26]>CO>[C:10]([C:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:27]([C:28](=[O:30])[CH3:29])=[C:25]([CH3:26])[NH:24][C:8]=1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:12])[CH3:11]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCBr
Reactant: CC(=O)C=C(C)N
Solvent: CO
Product: CC(=O)C1=C(C)NC(CCCCCCBr)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
45 g (0.14 mol) 1-bromo-8-(3-nitrophenyl-methylene)-7,9-decanedione and 28 g (0.28 mol) 2-amino-2-penten-4-one are boiled under reflux in 300 ml methanol for 24 h. The mixture is concentrated and the residue is prepurified by chromatography with toluene/acetone=99/1. The product thus obtained is chromatographed again over silica gel with toluene/ethyl acetate=8/2The title compound is obtained as a yellow oil. Yield: 10.3 g (16%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2=[N:44][CH:45]=[N:46][C:47](Cl)=[C:42]2[CH:41]=[N:40]1>C1COCC1>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2[N:44]=[CH:45][N:46]=[C:47]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])[C:42]=2[CH:41]=[N:40]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Reactant: Clc1cccc(Br)c1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.875 g, 21.87 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (3.0 g, 7.29 mmol) in anhydrous THF (35 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then a solution of 1-(2-bromo-6-chlorophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BO2) (2.507 g, 7.29 mmol) in anhydrous THF (20 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 10minutes and then allowed to warm to ambient temperature for 6 hours.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25]>>[C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18]([Cl:25])=[CH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A suspension of 3.0 g (8.94 mmol) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of POCl3 was heated at reflux for 45 min. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 100 ml of CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 19:1) of the residue yielded 3.0 g (94%) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as pale yellow crystals, m.p. 163-165° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COc1cccc2c1cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 4-methoxy-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 330.1 ([M−H]−).
Reaction SMILES: C1C(Cl)=CC=C(Cl)C=1.C(OCC1OC1)(=O)C(C)=C.[C:19]1([C:25]([CH2:27]C(C2C=CC=CC=2)(C)C)=[CH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:27][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:26].[CH3:27][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:26]
Reactant: C=C(CC(C)(C)c1ccccc1)c1ccccc1
Agent: C=C(C)C(=O)OCC1CO1
Solvent: Clc1ccc(Cl)cc1
Product: C=C(C)c1ccccc1
Temperature: 190 °C
Reaction time: 0.71 h
Yield: 8760.3 %

Procedure:
Using the same procedure and equipment as in Example 1, the flask was charged with brominated styrene monomer (1004.2), dichlorobenzene (492 g), glycidyl methacrylate (5.11 g, 0.0359 mol), 2,4-diphenyl-4-methyl-1-pentene (20.13 g, 0.0851 mol) (α-methyl styrene dimer) and VAZO-52™ (1.03 g, 4.15 mmol). The solution was heated to about. 90° C. until exotherm. It then reached a peak temperature of 141° C. after which the mixture was heated to 190° C. over 5-10 min and held at 190° C. for 40-45 min. Heating was halted; the solution (1509.3 g) was transferred to a 2-liter bottle, and cooled to room temperature. The material was split into four parts. Each part was precipitated into a 5-liter flask of 3400 mL acetone and 400 mL methanol. The precipitate was filtered over frit, dried at ambient temperature for about 14 h and oven dried at 110° C. for 8 h. A white powder (881 g) was isolated.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1.C(OCC)C>ClCCl>[C:1]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CN(C(=O)OCc2ccccc2)CC1O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
3.24 g acetic anhydride was added to 7.1 g benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate in 100 mL dichlormethane at 0-5° C. The mixture was stirred 2 h at RT, 100 mL diethylether was added and the mixture was stirred for 15 min. The precipitate was filtered to give 7.6 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>CCO>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH:1][C:2]2[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and 5-bromo-2-fluoronitrobenzene, m.p. 76°-78° C. EtOH).
Reaction SMILES: [C:1]([N:8](C)[C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.Cl>C(OCC)(=O)C>[NH:8]([CH3:1])[C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Yield: 64 %

Procedure:
Methylation of BocLeuOH (12.5 g.) using sodium hydride and methyl iodide gave BocMeLeuOH in 73% yield. Condensation of BocMeLeuOH (3.7 g.) and HMetNH2 hydrochloride salt (2.8 g.) by the mixed anhydride method using isobutyl chloroformate gave BocMeLeu-MetNH2 in 56% yield. De-t-butoxycarbonylation of BocMeLeu-MetNH2 (3.3 g.) using hydrogen chloride in ethyl acetate gave MeLeu-MetNH2 in 64% yield.
Reaction SMILES: [F:1][C:2]([F:30])([CH2:25][C:26]([F:29])([F:28])[F:27])[C:3]([F:24])([F:23])[O:4][CH2:5][C:6]1([CH2:10][O:11][C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][O:8][CH2:7]1.[BrH:31]>>[Br:31][CH2:7][C:6]([CH2:10][O:11][C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[CH2:14][C:15]([F:18])([F:17])[F:16])([CH2:5][O:4][C:3]([F:24])([F:23])[C:2]([F:30])([F:1])[CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:9][OH:8]
Reactant: FC(F)(F)CC(F)(F)C(F)(F)OCC1(COC(F)(F)C(F)(F)CC(F)(F)F)COC1
Reactant: Br
Product: OCC(CBr)(COC(F)(F)C(F)(F)CC(F)(F)F)COC(F)(F)C(F)(F)CC(F)(F)F
Yield: 89.1 %

Procedure:
In a manner similar to that described above, 3,3-bis(heptafluorobutoxymethyl)oxetane (250.0 g, 0.52 mole) was reacted with 48% HBr (131.7 g, 0.78 mole) to give 260.9 g (89.1%) of 3-bromo-2,2-bis(heptafluorobutoxymethyl)-1-propanol, a clear oil: 1H NMR (CDCl3) 3.49 (s, 2H), 3.65 (s, 4H), 3.69 (s, 2H), and 3.95 (t, J=13.3 Hz, 2H); Anal. Calcd for C13H13BrF14O3 : C, 27.72; H, 2.33; Br, 14.19; Found: C, 27.73; H, 2.27; Br, 14.09.
Reaction SMILES: Cl.CC1(C)CO[C:6]2([CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)[O:5]C1>CC(C)=O>[O:5]=[C:6]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)COC2(CCC(Oc3ccc(C#N)cn3)CC2)OC1
Agent: Cl
Solvent: CC(C)=O
Product: N#Cc1ccc(OC2CCC(=O)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Combine hydrochloric acid (1.0M aq., 20 mL) with a solution of 6-(3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yloxy)-nicotinonitrile (2000 mg, 6.61 mmol) in acetone (25 mL). Stir at room temperature for 2 h then at 40–50° C. for 1 h. Concentrate the reaction mixture. Partition the residue between EtOAc/hex (25 mL) and K2CO3 (aq. sat. 20 mL). Wash the organic layer with water, brine, and dry it over sodium sulfate, filter and concentrate. Triturate the residue with EtOAc/hexanes (1/4) to provide a white solid which is further purified by flash chromatography (EtOAc/Hexanes 1/4) to give 1010 mg (71% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[C:29]([F:30])[CH:28]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)c(F)c4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3,4-difluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2,3′,4′-trifluorobiphenyl-5-yl)-imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (6 mg, 3%): m/z (ES+) 401 [MH+].