Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N+]=[N-])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:1]([O:11][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a solution of 25.0 g (164 mmol) of D-mandelic acid in 200 ml of ethyl acetate was added 38.9 g (164 mmol) of diphenyldiazomethane under stirring at room temperature. The completeness of reaction was monitored by TLC and the reaction mixture was concentrated. The residue was recrystallized from ether-petroleum ether to give 47.7 g of the aimed product D-5 in 91% yield.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13]CC)=O)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.[NH3:25]>CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:25])=[O:13])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2cccs2)Sc2ccccc21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2cccs2)Sc2ccccc21
Reaction time: 24 h

Procedure:
In 300 ml of methanol is dissolved 8 g of ethyl trans-3-amino-4-oxo-2-(2-thienyl)-2,3,4,5-tetrahydro-1,5 -benzothiazepine-5-acetate, and ammonia gas is under ice-cooling blown into the solution until being saturated with ammonia gas. The reaction temperature is slowly elevated to room temperature, and the mixture is left standing for one day. Thereafter, the reaction mixture is concentrated under reduced pressure. Isopropyl alcohol is added to the obtained residue to crystallize. The crystals are collected by filtration to give 7 g of trans-3 amino-4-oxo-2-(2-thienyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 207°-210° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.[C:23](Cl)(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:23]([O:15][CH2:14][C:3]1[CH:4]=[C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[O:6][C:2]=1[CH3:1])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1cc([Si](CC)(CC)CC)oc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyl-2-triethylsilyl-4-furylmethanol (208 mg. 0.92 mmol) and triethylamine (121 mg, 1.20 mmol) in tetrahydrofutan (10 ml) at 0 degrees under argon was added lauroyl chloride 302 mg, 1.38 mmol). This solution was allowed to warm gradually to room temperature and quenched with a 10% aqueous HCl solution. The organics were extracted into hexanes and the combined fractions were washed with a saturated aqueous solution of sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15](O)[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Solvent: CN(C)c1ccccc1
Product: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol (Int-5e, 11.7 mmol) was charged to 250 mL round-bottom flask. To this flask was added 4 mL N, N-dimethylaniline, followed by 40 mL POCl3. This suspension was sonicated to break up the starting material and stirred at room temperature for 18 hours. After 18 hours, all starting material had dissolved. The solution was reduced in vacuo and cooled to 0° C. in an ice bath. The reaction was then quenched with sat. NaHCO3(aq) and extracted with DCM (x3). The combined organics were dried over Na2SO4 and the solvent was removed in vacuo. The resulting oil was purified via silica gel column with a 20% to 100% ethyl acetate in hexanes gradient to yield 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine (Int-5f) (2.65 grams, 77% across 2 steps) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCC(N)c1nc(-c2cccc(Br)c2)c[nH]1
Reactant: O=C1CCCCC1
Product: CC(C)CCCC(NC1CCCCC1)c1nc(-c2cccc(Br)c2)c[nH]1
Yield: 38 %

Procedure:
This compound is obtained according to an operating method similar to that of Stage 35.3 of Example 35 using as starting amine, 1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine (obtained in Stage 7.3; 0.8 g; 0.0019 mol) and as ketone, cyclohexanone (0.32 ml; 0.0023 mol). A white-coloured powder is obtained with a yield of 38%. Melting point: 236-238° C.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:12]1([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][C:19](=[O:20])[CH2:18][CH2:17][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC1CCCC1
Reactant: Nc1cccc2ncccc12
Product: O=C(CCC1CCCC1)Nc1cccc2ncccc12
Yield: 24.1 %

Procedure:
Prepared according to the method of example 18, using 5-quinolinamine (250 mg) and cyclopentanepropanoic acid (270 mg). Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) followed by recrystallisation from methanol/ethyl acetate gave the title compound as a colourless solid (112 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)(=[O:27])=[O:26])=[O:18])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)(=[O:26])=[O:27])=[O:18])[C:13](=[O:15])[NH:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a room temperature mixture of (S)-3-(4-isopropoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid (96.0 mg, 0.177 mmol) (prepared according to the method described for the preparation of compound 17e, HOBT (29.0 mg, 0.215 mmol), 4-aminotetrahydropyran (19.6 mg, 0.194 mmol), methylene chloride (2 mL), and water (2 mL) was added EDCI (39.0 mg, 0.203 mmol) in one portion. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with methylene chloride, washed with water, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate to afford 77.1 mg (69%) of the title compound as an amorphous white solid. mp: 78.6° C. Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [F-:1].[K+].Br[CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]>C(#N)C>[F:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: [F-]
Reactant: O=C(O)c1cccc(CBr)c1
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1cccc(CF)c1
Yield: 84.9 %

Procedure:
2.945 g (11.15 millimoles) of 1,4,7,10,13,16-hexanona-cyclooctadecane (18-Crown-6) are dissolved in 30 ml anhydrous acetonitrile, whereupon 6.48 g (111.54 millimoles) of anhydrous potassium fluoride are added. The mixture is stirred for half an hour and 12 g (55.77 millimoles) of 3-bromomethyl benzoic acid are added. The reaction mixture is stirred at 50° C. for 3 hours, whereupon it is filtered and the filtrate is evaporated in vacuo. The residue is taken up in 100 ml of ethyl acetate and the suspension is washed with 15 ml of water, 15 ml of a saturated sodium chloride solution, dried over sodium sulfate, filtered and the organic solvent is distilled off in vacuo. Thus 7.3 g of the title compound are obtained, yield 85%.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([NH:18][C:19]([C:21]1([NH:26][C:27](=[O:36])[CH:28]([S:32]C(=O)C)[CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO.O>[SH:32][CH:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C:21]1([C:19]([NH:18][CH:5]([CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[C:4]([OH:37])=[O:3])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:36]
Reactant: CCOC(=O)C(Cc1ccc(-c2ccccc2)s1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(S)C(=O)NC1(C(=O)NC(Cc2ccc(-c3ccccc3)s2)C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 mg (0.101 mmol) of 2-{[1-(2-Acetylthio-3-methyl-butanoylamino)-cyclopentanecarbonyl]-amino}3-(5-phenyl-thien-2-yl)-propionic acid ethyl ester is dissolved in 2 mL of MeOH. 0.41 mL of 1N NaOH is added, and the solution is stirred at room temperature for 3 h. The reaction mixture is diluted with water, and MeOH is removed in vacuo. The residue is partitioned between water and Et2O. The aqueous phase is extracted twice with Et2O, acidified with 0.41 mL of 1N HCl, and then extracted with EtOAc. The EtOAc phase is concentrated to furnish the product; mp 154-155° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: OC1CCNCC1
Product: COc1cc(N2CCC(O)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 79 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 4-hydroxy-piperidine instead of thiomorpholine to the title compound (SiO2, dichloromethane:methanol=100:0 to 90:10, 197 mg, 79%) which was obtained as an off-white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O>[Cl:15][CH2:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc(F)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1cccc(F)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-fluoroaniline (10 g, 90.00 mmol) in acetone (40 ml) was added pyridine (18 g, 227.56 mmol) and 3-chloropropanoyl chloride (13.73 g, 108.14 mmol) and the reaction was stirred for 3 h at 55° C. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 3-chloro-N-(3-fluorophenyl)propanamide as a yellow solid (13.21 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[C:7]2[C:11]=1[O:10][CH:9]=[CH:8]2.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([O:14][CH3:20])=[O:13])=[C:7]2[C:11]=1[O:10][CH:9]=[CH:8]2
Reactant: COc1ccc(C(=O)O)c2ccoc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c2occc12

Procedure:
7-Methoxybenzofuran-4-carboxylic acid (0.50 g) was dissolved in methanol (10 ml), and sulfuric acid (0.6 ml) was dropwise added thereto under ice-cooling, followed by heating under reflux for one hour. Sulfuric acid (0.2 ml) was further added to the mixture followed by heating under reflux for 30 minutes. After being allowed to stand for cooling, the solvent was distilled off, and the residue was poured into a 1N aqueous solution of sodium hydroxide. The precipitate was collected by filtration and dried to give Compound IIw-a (0.53 g, 99%) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1([B:24]([OH:26])[OH:25])C=CC=CC=1.C1(C)C=CC=CC=1.Cl>CCOCC>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([B:24]([OH:26])[OH:25])=[CH:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc(-c2ccccc2)c2ccccc12
Reactant: OB(O)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OB(O)c1ccc(-c2ccccc2)c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 14 g of 1-bromo-4-phenylnaphthalene synthesized in accordance with a conventional process or by the reaction of 1-bromo-4-iodo-naphthanlene and phenylboronic acid, 130 ml of anhydrous ether and 50 ml of anhydrous toluene were added, and the reaction system was purged with argon and cooled at −40° C. To the cooled mixture, 37 ml of a 1.6 M hexane solution of normal-butyllithium was added dropwise, and the resultant mixture was stirred for 1 hour. After the obtained mixture was heated to −5° C. and then cooled to −40° C., a solution obtained by diluting 34 ml of boronic acid triisopropyl ester with ether was added dropwise, and the resultant mixture was stirred for 3.5 hours and then left standing for one night. After the resultant mixture was acidified with a 10% dilute hydrochloric acid, the reaction mixture was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was removed using an evaporator. The obtained white solid substance was washed with methylene chloride and dried, and 10 g of 1-phenylnaphthalene-4-boronic acid was obtained as white crystals (the yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C([BH3-])#N.[Na+]>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20]([CH:36]5[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]5)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC(C)CN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC(C)CN(C2CN(C(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C

Procedure:
tert-Butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (75 mg, 0.15 mmol) was stirred in 4 N HCl in dioxane (5 mL) and evaporated. The residue was stirred in methanol (4 mL) and tert-butyl 3-oxoazetidine-1-carboxylate (110 mg, 0.61 mmol) was added. Sodium cyanoborohydride (86 mg, 1.4 mmol) was added and the mixture was warmed to 60° C. overnight and evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The reactions were purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers (peak #1 and 2): Peak #1 (Example 26): LCMS calculated for C26H34ClFN7O3 (M+H)+: m/z=546.2; found: 546.2 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.38 (m, 1 H), 6.32 (m, 1 H), 4.11 (m, 1 H), 3.95 (m, 2 H), 3.78 (m, 2 H), 3.50 (m, 2 H), 2.92 (m, 2 H), 2.65 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.42 (s, 9 H), 1.38 (m, 3 H). Peak #2 (Example 27): LCMS calculated for C26H34ClFN7O3 (M+H)+: m/z=546.2; Found: 546.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[Li]CCCC.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH3:24]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:18]1([S:23][CH2:24][CH2:9][C:7](=[O:8])[CH2:6][C:5]([O:4][CH3:3])=[O:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: CSc1ccccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CCSc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
To a suspension of NaH (60%) (815 mg, 20.39 mmol) in THF-HMPA (20 ml, 5 ml) was added methylacetoacetate (2.0 g, 18.5 mmol) in THF (5 ml) at 0° C. The mixture was stirred for 10 min. at 0° C. under nitrogen atmosphere. BuLi (12.3 ml, 20.39 mmol) was dropwise added and the red mixture was stirred for 15 min. at 0° C. Then a solution of chlorothioanisole (2.7 ml, 20.39 mmol) in THF (5 ml) was added to the mixture at 0° C. The mixture was stirred for 1 h at -5° C. The mixture was quenched with H2O, then extracted with AcOEt (100 ml×2). AcOEt layer was washed with H2O (10 ml×2) and brine (10 ml), then dried over MgSO4 and evaporated. The residue was purified by a silica gel column chromatography (150 g, hexane :AcOEt=6:1) to give a colorless oil (1.0 g, 22.7%).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7](I)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC1
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nn2C1CCC1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg, 0.190 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (64.4 mg, 0.194 mmol), Na2CO3 (50.5 mg, 0.476 mmol), and Pd(PPh3)4 (13.7 mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixture was heated under nitrogen to 80° C. (bath temp.) for 17 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated and chromatographed on an SCX column (1 g/6 mL barrel). The amine-containing fraction was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-11)→1% MeOH in CH2Cl2 (12-28)→2% MeOH in CH2Cl2 (29-46)], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (mc, 2H), 2.86-2.98 (mc, 2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H), 7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.49-8.52 (m, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.99 (−), 29.91 (2C, −), 50.61 (+), 98.68 (Cquart), 119.59 (+), 126.53 (+), 126.97 (Cquart), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +), 129.00 (+), 129.53 (+), 134.83 (Cquart), 136.53 (+), 139.14 (Cquart), 143.40 (Cquart), 148.22 (Cquart), 154.00 (Cquart), 155.53 (+), 157.92 (Cquart), 158.18 (Cquart). MS (ES+): m/z 393.1 (53) [MH+]. HPLC: tR=3.1 min (OpenLynx, nonpolar—5 min), 3.6 min (OpenLynx, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:20]1(N)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC1C=CC(C(C)C)=CC=1>[CH:20]1([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC1CCCCC1
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)cccc21
Yield: 92.1 %

Procedure:
25.3 g of 1-nitroanthraquinone (99% pure) in 120 ml of p-cymene are boiled together with 29.8 g of cyclohexylamine (molar ratio 3:1) for 2 hours under reflux. After cooling the reaction mixture, 150 ml of petroleum ether are added, the mixture is filtered and the residue is washed with petroleum ether and dried. 28.1 g (94% of theory) of cyclohexylamino-anthraquinone are obtained. No further starting material can be detected by means of thin layer chromatography.
Reaction SMILES: C[Si](C)(C)[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Cl[Si:11]([Cl:14])(Cl)Cl>C(Cl)Cl.CN(C)C(=O)N(C)C>[Cl:14][Si:11]([O:3][Si:4]([CH3:5])([CH3:6])[CH3:7])([O:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: CN(C)C(=O)N(C)C
Product: C[Si](C)(C)O[Si](Cl)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 21 h
Yield: 27 %

Procedure:
About 4.6 g (0.2% by weight) of tetramethylurea and 183.4 g of a 25% solution of phosphonitrile chloride in methylene chloride are added to a mixture containing 1707 g (10.5 mol) of hexamethyldisiloxane and 595 g (3.5 mol) of tetrachlorosilane with stirring in a 4 liter multineck flask fitted with internal thermometer, stirrer and a reflux condenser. The reaction temperature is kept at 45° C. by cooling. After 21 hours, the volatile components of the reaction mixture are removed by distillation at 200 mbar and 100° C. The crude distillate contains 56% of 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane, 29% of 3,3-dichlorohexamethyltrisiloxane and 16% of 3,3-bis(trimethylsiloxy)hexamethyltrisiloxane. The crude distillate is fractionally distilled, and gives, at 20 mbar and 83° to 87° C., 313 g (27% of theory) of 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane in a purity, determined by gas chromatography, of 97%.