Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([N:45]2[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]2)[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH:42]6[CH2:44][CH2:43]6)[CH2:46][CH2:47]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(C2CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C3CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.038 g (0.25 mmole) of 1-cyclopropyl-piperidin-4-ylamine in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate and three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.081 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopropyl-piperidin-4-yl)-3-methoxy-benzamide (I-66) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>CO.O>[CH3:19][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3][C:2]2=[O:1]
Reactant: COS(=O)(=O)OC
Reactant: Oc1cccc2c(O)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc2c(=O)[nH]ccc12
Yield: 64 %

Procedure:
To 3.0 g (18.6 mmol) of 1,5-dihydroxyisoquinoline in 80 ml methanol and 20 ml of water was added 0.78 g of 50% sodium hydroxide (39 mmol) and 2 ml of dimethyl sulfate. The mixture was heated under reflux for two hours. An additional 4.0 ml of dimethyl sulfate and 10 ml of 50% sodium hydroxide was then added and refluxing continued for an additional hour. The mixture was diluted with 200 ml of water and concentrated to half the original volume. The resulting solid was collected and washed with water. Recrystallization from ethanol gave 2.1 g (64%) of the desired product; mp 215°-217°.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[CH3:41][O:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=3)[CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([OH:5])=[O:4])=[CH:11][CH:12]=3)[S:32][C:33]=2[CH:39]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: COc1ccc2nc(Cl)sc2c1
Product: COc1ccc2nc(N(CCc3ccc(OC(C)(C)C(=O)O)cc3)Cc3ccc(C(F)(F)F)cc3)sc2c1

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate and 2-chloro-6-methoxy benzothiazole.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH:22]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2].[C:29]1([CH3:42])[CH:34]=[CH:33][C:32]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH2:22][N:39]3[CH2:40][CH2:41][CH:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([CH3:42])=[CH:30][CH:31]=4)[CH2:37][CH2:38]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CC=O)CCCCC2)c1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(Nc4ccc(C)cc4)CC3)CCCCC2)c1
Reaction time: 0.75 h
Yield: 107.4 %

Procedure:
1,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene (synthesized in Example 32) (215 mg) and 4-(p-toluidino)piperidine (synthesized in Preparation Example 4-5) (127 mg) were dissolved in 1,2-dichloroethane (5 mL). To this was added acetic acid (0.04 mL) at room temperature. The solution was stirred for 45 minutes. Sodium triacetoxyborohydride (294 mg) was added to the solution at room temperature. The solution was stirred for 3 hours. saturated aqueous sodium bicarbonate solution was added to the solution and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give the title compound (334 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:31]([C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: CCn1nc(C)cc1C(=O)O
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.76 min; [M+H]+=469.3.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[H-].[Na+].CCOC(C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]3[C:18](=[O:20])[N:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:5]([C:6]=23)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(CCN2CCOCC2)c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Yield: 8.7 %

Procedure:
To a 0° C. mixture of 7-bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.065 g, 0.20 mmol) from Example 1, step 4 and 4-(2-chloroethyl)morpholine hydrochloride (0.12 g, 0.63 mmol) in DMF (1 mL) was added NaH in mineral oil (0.048 g, 1.2 mmol). The reaction mixture was stirred over a weekend. EtOAc and water were added. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated to dryness to give an orange oil. The crude was purified by LCMS (C18 column eluting with a gradient MeCN/H2O containing 0.15% NH4OH at 5 mL/min.) and gave a white solid (7.7 mg, 9% yield). 1H NMR (400 MHz, CD3OD/CDCl3): d 7.31 (3H, m); 7.18 (3H, m); 6.65 (1H, d); 5.19 (1H, m); 4.61 (1H, m); 4.43 (1H, m); 3.99 (2H, m); 3.6 (4H, m); 2.65 (2H, m); 2.51 (4H, m). LCMS calc. for C26H29N4O4 (M+H)+: m/z=. found: 444.1, 446.1.
Reaction SMILES: C(O)C.C(Cl)(Cl)Cl.[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:26])[C:10]=1[C:27](=O)[CH2:28][CH3:29].[Cl:31][CH:32]=[CH:33][CH2:34][O:35][NH2:36].Cl>C(O)C>[Cl:31][CH:32]=[CH:33][CH2:34][O:35][N:36]=[C:27]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=2)[CH2:14][C:9]=1[OH:8])[CH2:28][CH3:29]
Reactant: NOCC=CCl
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCC(=NOCC=CCl)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into 40 ml of mixture solvent of ethanol-chloroform (1:1) was dissolved 2 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 10 ml of ethanol containing 10% of 3-chloroallyloxyamine at room temperature. The mixture was kept for 3 hours and it was poured into ice water. The mixture was acidified with hydrochloric acid and the oil separated was extracted with chloroform. The chloroform solution was dried with anhydrous magnesium sulfate and the chloroform was removed from it under reduced pressure and 1.5 g of the desired crude compound was obtained. It was purified by column chromatography and trans-cis mixture which was pale pink crystal having a melting point of 125°-127° C. was obtained.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1cccc(F)c1N
Product: Cc1cccc(F)c1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2-fluoro-6-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 2.07 (s, 3H), 2.11 (s, 3H), 2.23 (s, 3H), 4.29 (s, 2H), 6.88 (t, J=9.1 Hz, 1H), 6.97 (t, J=5.9 Hz, 2H), 7.13 (m, 1H), 7.26 (t, J=7.3 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 8.34 (d, J=5.0 Hz, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: C(OCC)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.C1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.Cl>O1CCCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
100 ml (0.11 mol) of a diethyl ether solution of 1 M 4-methoxyphenylmagnesium bromide was dropwise added to a tetrahydrofuran solution (200 ml) of 14.81 g (0.10 mol) of phthalic anhydride at −78° C., and stirred overnight at room temperature. Aqueous 1 N hydrochloric acid solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, then the reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain 25.63 g (yield: 100%) of 2-(4-methoxyphenyl)-benzoic acid as a yellow oily substance.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCC(n3ccc4ccccc43)CC2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2ccc3ccccc32)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of 1-N-(1-benzyl-piperidin-4-yl)-indole (100 g, 0.344 mol) in methylene chloride (1 L) was added ethyl chloroformate (99.2 mL dropwise with stirring. The mixture was refluxed for 48 hours, cooled to room temperature, and concentrated. The residue was crystallized from i-propanol to give the title compound as colorless crystals (50 g, 53% yield). M.Pt.: 127° C.
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13]C)=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=O)C.Br>C(O)(=O)C>[OH:4][C:5]1[C:12]([OH:13])=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1OC(C)=O
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc([N+](=O)[O-])c(O)c1O
Temperature: 150 °C
Yield: 90.5 %

Procedure:
43 (2.5 g, 10.5 mmol) was added to a solution of acetic acid (62.5 mL) and hydrobromic acid 48% (70 mL) and the reaction mixture was heated at 150° C. for 4 h. The reaction mixture was then cooled to rt and evaporated to dryness. The residue was diluted in hot CH2Cl2 (40 mL) and filtered. The filtrate was evaporated to dryness to give 44 (1.74 g, 91%) which was used as such in the next step:
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[C:35]([O:36]C)=[CH:34][C:10]2[C@H:11]([N:18]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)C(=O)OC(C)(C)C)[C@@H:12]([OH:17])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].B(Br)(Br)Br.O>ClCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[C:35]([OH:36])=[CH:34][C:10]2[C@H:11]([NH:18][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:12]([OH:17])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=1)(=[O:4])=[O:5]
Reactant: COc1cc2c(cc1NS(=O)(=O)CCl)OC(C)(C)[C@H](O)[C@H]2N(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)Oc2cc(NS(=O)(=O)CCl)c(O)cc2[C@H](NCCc2ccccc2)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of t-butyl(3R*,4S*)-7-{[(chloromethyl)sulfonyl]amino}-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl(2-phenylethyl)carbamate (400 mg, 0.72 mmol) in dichloromethane (4.0 mL), 1 mol/L solution of boron tribromide in dichloromethane (3.61 mL, 3.61 mmol) was added below freezing point, and the resulting mixture was stirred at 0° C. for 1 hour. Water was added, and the resulting mixture was further stirred for 30 minutes. The resulting solid was filtered off, washed with water and then with chloroform. The solid was dried at 60° C. for 3 hours under reduced pressure, and the aimed product was quantitatively obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([C@@H:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]2[CH2:16][OH:17])=[C:8]([O:18][CH3:19])[CH:7]=[C:6]([O:20][CH3:21])[C:5]=1[C:22](=[O:24])[CH3:23]>CN(C)C=O>[OH:3][C:4]1[C:9]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH:11]2[CH2:16][OH:17])=[C:8]([O:18][CH3:19])[CH:7]=[C:6]([O:20][CH3:21])[C:5]=1[C:22](=[O:24])[CH2:23][C:22]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=1[O:20][CH3:21])=[O:24]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)CC(=O)c1c(OC)cc(OC)c(C2CCN(C)C2CO)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a suspension of 50% sodium hydride in mineral oil (1.39 g, 29.1 mmol) in N,N-dimethylformamide (60 mL) maintained under nitrogen atmosphere and cooled to 0° C., (±)-trans-1-[2-hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4,6-dimethoxyphenyl]-ethanone (3 g, 9.7 mmol) was added portionwise and stirred for 15 mins. At the end of 15 mins., 2-methoxy methylbenzoate (4.8 g, 29 mmol) was added dropwise and the reaction stirred at 0° C. for 1 hr. Excess sodium hydride was destroyed by careful addition of methanol. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 9. The reaction mixture was concentrated under reduced pressure and dried under vacuum to yield 1-[2-hydroxy-3-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-4,6-dimethoxyphenyl]-3-(2-methoxyphenyl)-propane-1,3-dione as an oil (1.4 g). This β-diketone was dissolved in conc. HCl (50 mL) and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 10. The aqueous layer was extracted with chloroform (50×3 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.1% ammonia as eluent to yield the compound, (±)-trans-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-(2-methoxyphenyl)-chromen-4-one.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: C1COCCN1
Product: O=C(C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1)N1CCOCC1
Yield: 16 %

Procedure:
The compound (97 mg, 0.28 mmol) prepared in Example 42 and morpholine instead of ethylamine were reacted according to the same procedure as Example 89 to give the title compound (19 mg, Yield 16%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C@@H:13]3[C@@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46](O)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:46]([O:19][C@H:18]1[C@@H:13]2[N:14]([N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:12]2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:16][CH2:17]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN3CC[C@@H](OC(=O)c4ccccc4)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (80 mg, 0.235 mmol) in THF (3 mL) were added PPh3 (123 mg, 0.470 mmol), benzoic acid (58 mg, 0.470 mmol) and DIAD (0.09 mL, 0.470 mmol) and the reaction mixture was stirred at room temperature for 3 h. Then it was diluted with ethyl acetate and washed with saturated NaHCO3 solution, water, and brine, then dried over Na2SO4 and concentrated to get the crude product which was used in the next step without purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].[CH2:16]=[O:17]>O>[CH2:16]=[O:17].[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc2ccccc2c1
Agent: C=O
Solvent: O
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 160 °C

Procedure:
A charge of 64 g (0.5 mole) of naphthalene was heated to 160° C. and 75 g (0.75-0.765 mole) of 98-100% strength sulfuric acid was added. The reaction mixture was maintained for 2 hours at 160° C. under constant stirring, was then cooled to 100° C. and 20 g of water added. Then 40 g of 37% by weight formaldehyde solution and 80 g of water were added and the reaction mixture maintained at 100° C. for 4 hours to obtain a naphthalene sulfonic acid formaldehyde condensate solution. The condensate solution was added to a milk of lime mixture containing 37 g of lime and 56 g water, to which was then added 166 g of crystalline aluminum sulfate dissolved in 300 grams of water. Calcium sulfate was filtered off and a 20% by weight solution of the aluminum salt of the naphthalene sulfonic acid formaldehyde condensate obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[NH:24][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:23]=[CH:22][C:17]4[NH:18][C:19](=[O:21])[S:20][C:16]=4[CH:15]=3)[C:7]=2[CH:6]=1.C(O)C>[Pd].O1CCCC1>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:24][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:23]=[CH:22][C:17]4[NH:18][C:19](=[O:21])[S:20][C:16]=4[CH:15]=3)[C:7]=2[CH:6]=1
Reactant: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(C#CCO)cc34)cc2s1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(CCCO)cc34)cc2s1
Yield: 4.5 %

Procedure:
A mixture comprising 262 mg (777 μmol) 6-{[6-(3-hydroxyprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 11), 15 mL ethanol, 5 mL tetrahydrofuran and 41.3 mg palladium on charcoal (10%) were stirred at 23° C. under an atmosphere of hydrogen overnight. After filtration and removal of the solvents the crude product was purified by chromatography and crystallization to give 12 mg (4%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH3:19][NH:20][CH2:21]/[CH:22]=[CH:23]/[C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:18].[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]#[C:24]/[CH:23]=[CH:22]/[CH2:21][N:20]([CH2:12][C:11]1[CH:14]=[C:15]([CH3:17])[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:19]
Reactant: Cc1cc(CBr)cc(OCc2ccccc2)c1
Reactant: CNC/C=C/C#CC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C)C/C=C/C#CC(C)(C)C)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
3-Benzyloxy-5-methylbenzyl bromide (118 mg) and 76 mg of (E)-N-methyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride were dissolved in 25 ml of dimethylformamide, and 67 mg of potassium carbonate was added. The mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure, and the residue was purified by preparative thin-layer chromatography [thin layer plate: Kieselgel 60F254, Art. 5715 (a product of E. Merck Co.); developing solvent: hexane/ethyl acetate=4/1]. The purified compound was then converted into a hydrochloride using HCl methanol solution. Treatment with a mixture of tetrahydrofuran and hexane gave 102 mg (yield 60.9%) of the captioned compound as a colorless crystalline powder having a melting point of 180° to 186° C.