Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[C:22]1([C:28]2([NH:34][C:35](=[O:37])[CH3:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S1C=CC=C1>CC(O)C.[Pt].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:35]([NH:34][C:28]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30][N:31]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:3]2)[CH2:32][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccccc1
Agent: [Pt]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)O
Solvent: c1ccsc1
Product: CC(=O)NC1(c2ccccc2)CCN(C2CCN(C(=O)OC(C)(C)C)C(Cc3ccccc3)C2)CC1
Yield: 81.4 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 4-oxo-2-(phenylmethyl)-1-piperidine carboxylate (0.1 mol) and N-(4-phenyl-4-piperidinyl)acetamide (0.1 mol) in 2-propanol (500 ml) was hydrogenated at 50° C. with platinum (4 g) as a catalyst in the presence of titanium (IV)isopropoxide (28.5 g) and thiophene (4%; 1 ml). After uptake of hydrogen the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 40 g (74.1% ) of (±)-1,1-dimethylethyl 4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(phenylmethyl)-1-piperidinecarboxylate (intermediate 19).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[CH2:22][O:23][CH2:24][C:25]([OH:27])=O)(=[O:12])=[O:11])=[C:5]([CH3:28])[CH:4]=1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:61]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3([CH2:76][NH:77][C:78](=[O:85])[C:79]4[CH:84]=[CH:83][N:82]=[CH:81][CH:80]=4)[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]3)[CH2:66][CH2:65]2)[CH2:63][CH2:62]1>ClCCl.CN(C=O)C>[CH:61]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3([CH2:76][NH:77][C:78](=[O:85])[C:79]4[CH:80]=[CH:81][N:82]=[CH:83][CH:84]=4)[CH2:75][CH2:74][N:73]([C:25](=[O:27])[CH2:24][O:23][CH2:22][C@@H:14]4[CH2:15][C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:13]4[S:10]([C:6]4[C:5]([CH3:28])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH2:72][CH2:71]3)[CH2:66][CH2:65]2)[CH2:62][CH2:63]1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)N2CCC(CNC(=O)c3ccncc3)(N3CCN(C4CC4)CC3)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)indolin-2-yl)methoxy)acetic acid AC10 (0.282 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropyl-piperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to yield the crude product which was purified by column chromatography. Yield: 58%. MS, Rt=3.2 min, m/z=731.5 [MH]+.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[BH4-].[Na+].Br[CH2:16][CH2:17][C@@H:18]1[O:24][C@:23]([C:29]#[C:30][CH:31]2[CH2:33][CH2:32]2)([C:25]([F:28])([F:27])[F:26])[C:22]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:21]=2[NH:20][C:19]1=[O:39]>C1COCC1.C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:21]2[NH:20][C:19](=[O:39])[C@H:18]([CH:17]=[CH2:16])[O:24][C@:23]([C:29]#[C:30][CH:31]3[CH2:33][CH2:32]3)([C:25]([F:26])([F:27])[F:28])[C:22]=2[CH:34]=1
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O[C@H]1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a room temperature solution of 409 mg (1.8 mmol) of 2-nitrophenylselenocyanate in 5.0 mL of THF was added 16 mL of ethanol and 90 mg of sodium borohydride. After stirring 1 h, a solution of 260 mg of rel-(3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 8 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 2 h, at which time an additional 20 for an additional 2 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 130 mg of the title compound as a pure solid: HRMS: Calcd. for C17H14NO2F3Cl (M+H)+: 354.0508. Found: 354.0487.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>O.CN(C=O)C>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
A mixture of 2 g (13 mmol) 2-chloro-5-nitro-pyridine and 0.76 g (6 mmol) N,N-diisopropylethylamine in 21 ml water and 4 ml DMF was heated to 80° C. During 2 min 1.73 g (15 mmol) N-ethylpiperazine was added and the mixture was kept for an additional hour at 80° C. The yellow precipitate was filtered off and washed three times with 4 ml water and dried for 16 h under vacuum to yield 2.48 g (83%) of the title compound as yellow crystals. (m/e): 237.1 (MH+; 100%).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[C:13]([Li])=[CH:14][O:15][CH:16]=1>>[Br:11][C:12]1[C:13]([C:1]([C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]=2[CH3:10])([OH:3])[CH3:2])=[CH:14][O:15][CH:16]=1
Reactant: [Li]c1cocc1Br
Reactant: CC(=O)c1oc(C)nc1C
Product: Cc1nc(C)c(C(C)(O)c2cocc2Br)o1

Procedure:
Following the general method of Example 1a but using 5-acetyl-2,4-dimethyloxazole and 4-bromo-3-lithiofuran (Liebigs Ann. Chem., 1986, 625-637), the title compound was prepared.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (1.21 g, 4.95 mmol) was added thionyl chloride (5.5 mL, 74.2 mmol). The mixture was heated at 50° C. for 2 h before it was allowed to cool to room temperature and stirred at room temperature overnight. The mixture was poured into ice and stirred for 5 min before it was extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as an oil (1.16 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.63 (m, 2H), 1.69-1.77 (m, 2H), 1.82-1.90 (m, 2H), 2.05-2.13 (m, 2H), 3.37 (quintet, J=8.59 Hz, 1H), 4.58 (s, 2H), 7.46 (d, J=8.00 Hz, 1H), 7.52 (d, J=8.00 Hz, 1H), 7.61 (d, J=1.52 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:33]([S:40][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Crude 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline was dissolved in 33 mL of dioxane, was treated with Pd2(dba)3 (0.376 g, 0.411 mmol), Xantphos (0.475 g, 0.821 mmol), and n,n-diisopropylethylamine (8.61 ml, 49.3 mmol), and was heated to 60° C. Benzyl mercaptan (1.943 ml, 16.43 mmol) was added, and the reaction mixture was allowed to stir for one hour at 60° C. The reaction mixture was concentrated and was purified by silica gel column chromatography (0 to 75% EtOAc/heptane) to yield 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline (4.616 g, 10.82 mmol, 65.9% yield) with minor impurities. m/z (ESI) 427.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: FC(F)(F)c1cc(Br)cnc1Cl
Reactant: C1COCCN1
Product: FC(F)(F)c1cc(Br)cnc1N1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 260 mg (1.0 mmol) of 2-chloro-3-trifluoromethyl-5-bromopyridine (from Step B) and 3 mL of morpholine was heated at 80° C. for 1 h. The mixture was cooled and concentrated. The residue was partitioned between 50 mL of CH2Cl2 and 1.0 N NaOH and the layers were separated. The organics were dried and concentrated. Chromatography on a Biotage 40S cartridge using 19:1 v/v hexanes/ether as the eluant afforded 290 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 3.29 (app t, J=5.5, 4H), 3.82 (app t, J=5.5, 4H); 7.95 (d, J=2.0, 1H), 8.45 (d, J=2.0, 1H.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][Li].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[C:13]([O:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])[N:12]=[CH:11][N:10]=1
Reactant: CC(=O)CO
Reactant: [Li]C
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)COc1cc(Cl)ncn1
Reaction time: 1 h

Procedure:
In 20 ml of tetrahydrofuran was dissolved 1 g of 1-hydroxy-2-propanone, to which 26 ml of a 1.14 mol/l solution (diethyl ether solution) of methyl lithium was added dropwise at −78° C. The mixture was stirred at the same temperature for 1 hour. After gradually increasing the temperature up to 0° C., 4 ml of a solution containing 2 g of 4,6-dichloropyrimidine in tetrahydrofuran was added dropwise, followed by further stirring 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.66 g of 4-chloro-6-(2-hydroxy-2-methylpropyloxy)pyrimidine.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:26]1([C:32]([S:34][CH2:35][C@@H:36]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]([OH:39])=O)=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl.[CH3:49][O:50][C:51](=[O:66])[C@H:52]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[CH:57][CH:56]=1)[NH2:53].C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[CH3:49][O:50][C:51](=[O:66])[C@H:52]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[CH:59][CH:60]=1)[NH:53][C:37](=[O:39])[C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:35][S:34][C:32]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:33]
Reactant: O=C(SC[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2nccs2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](CSC(=O)c1ccccc1)Cc1ccccc1

Procedure:
A solution of hydroxybenzotriazole (0.54 g; 4 mmoles) in tetrahydrofuran (30 ml) and, subsequently, a solution of dicyclohexylcarbodiimide (0.825 g; 4 mmoles) in methylene chloride (15 ml) were added, at 0° C. under stirring, to a mixture of (2S)-3-phenylcarbonylthio-2-phenylmethylpropionic acid (1.2 g; 4 mmoles), 4-(2-thiazolyl)-L-phenylalanine methyl ester dihydrochloride (1.34 g; 4 mmoles), prepared as described in example 4, triethylamine (1.11 ml; 8 mmoles) in tetrahydrofuran (20 ml) and methylene chloride (30 ml).
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH2:16]([C:18]1[N:19]([CH3:43])[C:20]2[C:25]([N:26]=1)=[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:23]=[C:22]([S:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[N:21]=2)[CH3:17].[N+:44](C1C=C(C=CC=1OC)CBr)([O-:46])=[O:45]>CC(C)=O>[CH2:16]([C:18]1[N:19]([CH3:43])[C:20]2[C:25]([N:26]=1)=[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:23]=[C:22]([S:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([N+:44]([O-:46])=[O:45])[CH:36]=1)[N:21]=2)[CH3:17]
Reactant: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)cc3)nc2n1C
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)=O
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c([N+](=O)[O-])c3)nc2n1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Trifluoroacetic acid (40 ml) and anisole (2.7 ml, 15 mmol) were added to 8-ethyl-2-(4-methoxybenzylsulfanyl)-9-methyl-6-morpholino-9H-purine (5.0 g, 12.5 mmol), and heated and stirred at 80° C. overnight. After distilling away trifluoroacetic acid under reduced pressure, neutralization was performed by adding excess triethylamine under ice cooling. After distilling away triethylamine under reduced pressure, the residue was dissolved in acetone (50 ml) and 3-nitro-4-methoxybenzyl bromide (3.69 g, 15 mmol) dissolved in acetone (10 ml) was added. After stirring at room temperature for 2.5 hours, the reaction solution was concentrated under reduced pressure, the residue was made to have a pH of approximately 7.0 by 2N—NaOH solution, and the precipitated crystals were collected by filtration. The obtained crystals were washed sequentially with hexane and ether to obtain 3.93 g (71% yield) of 8-ethyl-9-methyl-6-morpholino-2-(3-nitro-4-methoxybenzylsulfanyl)-9H-purine.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([I:10])[C:3]=1[OH:4].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:11]([O:4][C:3]1[C:2]([I:1])=[CH:8][C:7]([OH:9])=[CH:6][C:5]=1[I:10])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:11]([O:9][C:7]1[CH:8]=[C:2]([I:1])[C:3]([O:4][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])=[C:5]([I:10])[CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1cc(I)c(O)c(I)c1
Solvent: c1ccncc1
Product: O=C(Oc1c(I)cc(O)cc1I)c1ccccc1
Product: O=C(Oc1cc(I)c(OC(=O)c2ccccc2)c(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2,6-diiodohydroquinone (0.2 g) in pyridine (10 mL) was added benzoyl chloride (0.140 mg) and the reaction mixture was stirred at room temperature for 1 hour. Following solvent removal in vacuo, purification was achieved by extraction (equal volumes ethyl acetate (EtOAc):0.01N HCl), and preparative TLC (methylene chloride) of the concentrated (in vacuo) EtOAc phases. Both the desired monoester, 4-hydroxy-2,6-diiodophenyl benzoate (Rf 0.38) and the diester, 3,5-diiodo-4(phenylmethanoyloxy)phenyl benzoate (Rf 0.96), products were formed.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:12][CH2:11][C@H:10]([CH3:9])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCC[C@@H](C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCBr
Temperature: 25 °C
Yield: 87.3 %

Procedure:
5.65 g (31.8 mmol) of N-bromosuccinimide are added portionwise while stirring to a solution of 5 g (31.6 mmol) of (R)-3,7-dimethyl-1-octanol and 9.05 g (34.5 mmol) of triphenylphosphine in 20 ml of methylene chloride. The temperature is held below 25° by occasional cooling of the reaction vessel. After 30-minutes stirring at room temperature, the solvent is removed on the rotary evaporator. The residue is washed out several times with n-hexane, then filtered and again rinsed with n-hexane. The combined n-hexane phases are concentrated on the rotary evaporator and the crude product is chromatographed on 200 g of silicagel with n-hexane. Distillation in the bulb-tube at 105°/15 Torr gives 6.1 g (87%) of (R)-1-bromo-3,7-dimethyloctane; [α]D20 = -5.0 (c = 0.82, CHCl3).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:28]=[C:29]5[CH:35]=[N:34][N:33](S(C6C=CC=CC=6)(=O)=O)[C:30]5=[N:31][CH:32]=4)[CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4S(C3C=CC=CC=3)(=O)=O)=[O:16])[N:14]=2)[CH2:3]1.[OH-:54].[Na+].Cl>C(O)(C)C>[CH:15]([OH:16])=[O:54].[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:28]=[C:29]5[CH:35]=[N:34][NH:33][C:30]5=[N:31][CH:32]=4)[CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][NH:22]4)=[O:16])[N:14]=2)[CH2:5]1
Reactant: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(-c4cnc5c(cnn5S(=O)(=O)c5ccccc5)c4)cc4c3cnn4S(=O)(=O)c3ccccc3)cs2)C[C@H](C)O1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(-c4cnc5[nH]ncc5c4)cc4[nH]ncc34)cs2)C[C@H](C)O1
Product: O=CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
2-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (99 mg, 0.129 mmol) was suspended in Isopropanol (1 mL) and Sodium hydroxide (1 ml, 2.0 mmol) was added. The mixture was stirred at room temperature for 18 h then neutralised with 2 M HCl (aq.) and the solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (2 ml) (insoluble salt was filtered off through a filter tube) and the samples (2×1 ml injections) were purified by mass directed autoprep HPLC (Method F). The product-containing fractions were concentrated under a stream of nitrogen to give the title compound as a white solid (18 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:6]=[C:5]2[CH2:17][C:18]([O:20]CC)=O)[CH2:3][CH2:2]1.C[Al](C)C.[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH2:31][NH:32]2.CO>C1(C)C=CC=CC=1.O1CCCC1>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH2:31][N:32]2[C:18](=[O:20])[CH2:17][C:5]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:6]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C1CC1
Reactant: Clc1cccc2c1CCN2
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)n1C1CC1)N1CCc2c(Cl)cccc21
Temperature: 90 °C
Yield: 32.1 %

Procedure:
2 ml of toluene, 90 mg of ethyl (1-cyclopropyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and, finally, dropwise, 0.55 ml of a 2M solution of trimethylaluminum in toluene are successively added to a solution of 113 mg of 4-chloroindoline in 4 ml of tetrahydrofuran. The reaction mixture is heated at 90° C. for 4 hours, and then cooled to ambient temperature, and 5 ml of methanol are added. After the addition of 10 g of silica, the reaction mixture is concentrated under reduced pressure. After purification by silica column chromatography (solid deposit), elution being carried out with a mixture of dichloromethane and methanol (100/0 then 98/02 V/V), 39 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-cyclopropyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([CH:4]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].[ClH:18]>O>[Cl:18][C:6]1([Cl:13])[CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:10][CH2:9][NH:8][C:7]1=[O:11]
Reactant: CC(C)C1CCNC(=O)CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cl
Solvent: O
Product: CC(C)C1CCNC(=O)C(Cl)(Cl)C1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
5-Isopropyl-azepan-2-one (39.5 g, 254.4 mmol) was dissolved in xylenes (1.1 liter) and phosphorus pentachloride (159.0 g, 763.3 mmol) was added and the reaction mixture slowly warmed to 90° C. HCl(g) accompanied the slow dissolution of phosphorus pentachloride and after 30 min a clear yellow solution resulted. After a further 90 min at 90° C. the reaction mixture was allowed to cool (ice-water bath) and water (500 ml) was added dropwise. The emulsion was stirred for a further 90 min at r.t and the aqueous layer was washed with CHCl3 (3×). The xylene fraction was concentrated under reduced pressure and the residue was dissolved in CHCl3. The combined organic fractions were washed with water (3×), brine and dried (MgSO4) filtered and evaporated under reduced pressure. The crude brown oil was purified over silica gel (ethyl acetate/n-heptane 1:2): white solid 39.8 g (58%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:10].[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:10]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Clc1cncc(Cl)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: [O-][n+]1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 15 grams (0.1 mole) of 2,6-dichloropyrazine in 120 milliliters of concentrated sulfuric acid, maintained at 5° C, was gradually added 30 grams (0.11 mole) of potassium persulfate. The reaction mixture was stirred overnight at room temperature and thereafter poured into 400 milliliters of ice water. The resulting solution was thoroughly extracted with chloroform and the extract washed with both a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. The chloroform was thereafter removed by evaporation leaving the 2,6-dichloropyrazine-1-oxide as a white solid residue. The product was recrystallized from methanol and was recovered in a yield of 10.2 grams (62 percent of theoretical). The product melted at 120°-123.5° C, and upon analysis was found to have carbon, hydrogen, nitrogen and chlorine contents of 29.20, 1.42, 17.01 and 42.40 percent, respectively, as compared with the theoretical contents of 29.09, 1.21, 16.97 and 43.03 percent, respectively, calculated for the above-named compound.