Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][C:41]([NH2:43])=[S:42])[CH2:4][CH2:3]2.C(N(CC)C(C)C)(C)C.Br[CH2:54][C:55](=O)[C:56]([CH3:59])([CH3:58])[CH3:57].O>CN(C=O)C>[C:56]([C:55]1[N:43]=[C:41]([NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[S:42][CH:54]=1)([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)C(=O)CBr
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(N)=S)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(Nc3nc(C(C)(C)C)cs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (150 mg, 0.249 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.217 mL, 1.244 mmol) and 1-bromopinacolone (0.056 mL, 0.373 mmol). The reaction mixture was stirred at rt overnight. After 18 h, the reaction mixture was poured into a separatory funnel containing H2O (5 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to white solid. The material was redissolved in DCM (3 mL), MeOH wash added and concentrated to remove most of the DCM. The resulting white precipitate was filtered, washed with cold MeOH, and dried in a vacuum oven to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (154.0 mg, 0.225 mmol, 91% yield) as a white solid. LC/MS: m/e 683.4 (M+H)+, 2.88 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 6.06 (s, 1H), 5.31 (d, J=4.6 Hz, 1H), 4.88 (s, 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.93 (s, 3H), 2.72 (d, J=13.7 Hz, 1H), 2.68-2.62 (m, 1H), 2.55 (dd, J=8.1, 12.7 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 2.07-1.98 (m, 1H), 1.92-1.83 (m, 1H), 1.82-1.76 (m, 1H), 1.74 (s, 3H), 1.73-1.66 (m, 2H), 1.61 (s, 1H), 1.57-1.49 (m, 3H), 1.49-1.40 (m, 4H), 1.40-1.31 (m, 3H), 1.29 (s, 9H), 1.27-1.21 (m, 1H), 1.18-1.12 (m, 1H), 1.10 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:22][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCCCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (350 mg, 15 mmol) in 1-octanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol). The mixture was stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 3-(4-fluorophenyl)-propionic acid (4.20 g, 25 mmol) in tetrahydrofuran (10 mL) was stirred on an ice bath and treated with a solution of borane in tetrahydrofuran (1.0 M, 33 mL, 33 mmol) over 15 minutes. The resulting solution was stirred at room temperature for one hour. A mixture of tetrahydrofuran (5 mL) and water (5 mL) was added over 2 minutes. After 5 minutes of additional stirring, 4 mL of additional water was added, and solid potassium carbonate was added until the aqueous phase was saturated. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to provide a colorless liquid (3.70 g, 96%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.99 (t, J=9 Hz, 2H), 3.69 (t, J=6 Hz, 2H), 2.70 (t, J=8 Hz, 2H), 1.87 (m, 2H), 1.50 (bs, 1H). Mass spec (CH4-CI) m/z 137.0 (M+H+-H2O).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:16]
Reactant: CC(C)c1cc(Cl)nc2ncccc12
Reactant: NN
Product: CC(C)c1cc(NN)nc2ncccc12
Yield: 92 %

Procedure:
A solution of chloro-4-isopropyl-1,8-naphthyridine (690 mg, 3.4 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound (620 mg, 92%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=6.74 Hz, 6 H) 3.45-3.59 (m, 1 H) 6.70 (br. s., 1 H) 7.21 (dd, J=8.06, 4.54 Hz, 1 H) 8.19 (d, J=7.62 Hz, 1 H) 8.79 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:12]1[C:11](=[O:16])[CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:17])([F:18])[F:1])=[CH:9][CH:8]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: BrBr
Reactant: O=C1CCCCC1c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
2-(4-Trifluoromethoxyl-phenyl)-cyclohexanone (53 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.4 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (65 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH2:5][O:6][CH3:7]
Reactant: COCC(C)(C)CO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(C)CO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1 g of 2,2-dimethyl-3-methoxy-1-propanol was dissolved in 20 ml of dichloromethane. The resultant solution was cooled in ice-water bath to below 5° C., and 1.65 ml of triethyl amine was added thereto. After stirring the mixture for 5 minutes, 1.29 ml of trimethylsilyl chloride was added drop-wise to the reaction mixture, and the mixture was stirred in ice-water bath for further 2 hours, and at room temperature for further 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 1.33 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([O:14]CC)=O)=[N:11][C:7]=3[C:6]=2[CH:21]=1.[NH3:23]>CO>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([NH2:23])=[O:14])=[N:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: N
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(Br)cc1-2
Solvent: CO
Product: NC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 100 %

Procedure:
A solution of ethyl 9-bromo-8-fluoro-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (80 mg, 0.22 mmol) in methanolic ammonia (10 mL of a 7M ammonia solution in methanol) was warmed to 40° C. for 3d in a pressure tube. Evaporation of the reaction mixture in vacuo furnished the title compound (77 mg, 0.22 mmol, 100%) as a colorless solid: 1H NMR (500 MHz, d4-methanol) δ 1.62-1.69 (m, 2H), 2.92-3.01 (m, 2H), 3.45-3.50 (m, 1H), 3.65-3.72 (m, 1H), 6.97-7.02 (m, 1H), 8.42-8.50 (m, 1H); M+1=336/338.
Reaction SMILES: P([O-])(O)(O)=O.[K+].[OH-].[Na+].[C:9]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(OC)(C)C>[C:9]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C@@:25]([OH:31])([CH3:30])[C:26]([F:27])([F:28])[F:29])=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1)C(F)(F)F
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: C[C@](O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 38 °C
Reaction time: 24 h

Procedure:
5 mM potassium dihydrogen phosphate solution (50 mL) was adjusted to pH 7.1 with 0.1 N sodium hydroxide solution (2 mL), porcine pancreatic lipase (Biocatalysts, Treforest, UK) (0.2 g) added and the pH again adjusted to 7.1 with 0.1 N sodium hydroxide solution (2 mL). Racemic butyric ester derived from N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1 g) was dissolved in MTBE (10 mL) and added to the reaction, washing in with further MTBE (2 mL). The reaction was stirred at 38° C. under pH control initially set at 7.05 max/7.00 min. After 24 hr., further porcine pancreatic lipase (0.8 g) was added and the pH adjusted to 7.55 max/7.50 min and left for a further 42 hours when a total of 10 mL of 0.1 N sodium hydroxide had been added. The reaction mixture was acidified to pH 3.5 with 2 N HCl (2 mL), stirred for 15 min., then ethyl acetate (30 mL) was added and the mixture was stirred for a further 10 min. The mixture was then filtered and the residue washed with ethyl acetate (20 mL). The aqueous phase was separated and extracted with ethyl acetate (30 mL). The combined organic extracts were washed with 50% brine (20 mL), filtered and evaporated to an oil which partly crystallized. Yield: 0.95 g. The product was a mixture of the (R)-alcohol (99% enantiomeric excess) and ester.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCc3ccncc3C2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.88 mmol) in 3.0 mL CH2Cl2 at rt was added 3-(trifluoromethyl)benzoyl chloride (0.041 mL, 0.277 mmol) and the reaction stirred for 15 min at rt. The reaction was evaporated, then partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, and dried with anhydrous Na2SO4. The EtOAc solution was filtered past a silica gel plug, rinsed with EtOAc, and evaporated to a yellow solid. The solid was recrystallized from EtOAc/hexane to give the title compound as a light tan solid (83 mg, 83%). 1H NMR (DMSO-d6) δ: 10.28 (s, 1H), 8.44 (s, 1H), 8.32 (d, J=5.0 Hz, 1H), 8.23-8.30 (m, 2H), 7.95 (d, J=7.9 Hz, 1H), 7.74-7.80 (m, 1H), 7.61-7.68 (m, 2H), 7.19 (dd, J=5.0, 0.6 Hz, 1H), 7.03-7.09 (m, 2H), 4.40 (s, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.93 (t, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:21])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:14]2)[CH3:11])=[O:21])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)Oc1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, the trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 390 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:23])=[O:24]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=C(O)c1ccc(CNS(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 72 %

Procedure:
3.8 g (25 mmol) of 4-(aminomethyl)benzoic acid were reacted with 2-naphthalenesulfonyl chloride by the method of procedure 4b, affording 6.1 g (72%) of the product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[Br:7][CH:8]([CH3:16])[C:9](=O)[CH2:10][C:11](OC)=[O:12]>>[Br:7][CH:8]([C:9]1[N:6]=[C:2]2[S:1][CH:5]=[CH:4][N:3]2[C:11](=[O:12])[CH:10]=1)[CH3:16]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: Nc1nccs1
Product: CC(Br)c1cc(=O)n2ccsc2n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of polyphosphoric acid (73.8 g, 677 mmol), 1,3-thiazol-2-amine (12.3 g, 123 mmol), and methyl 4-bromo-3-oxopentanoate (34.8 g, 166 mmol) was stirred at 110° C. overnight. After cooling, an ice-cold 10% aq. NaOH solution was slowly added to adjust the pH to 7. The mixture was filtered, and the collected precipitate was air-dried to give crude product which was directly used in next step. LCMS calculated for C8H8BrN2OS (M+H)+: m/z=259.0. Found: 259.0.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=2[C:19]=1[CH3:28])=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25]([NH:13][C:12]3[C:7]([O:6][C@H:3]4[CH2:4][CH2:5][O:1][CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:20]=2[C:19]=1[CH3:28])=[O:17]
Reactant: Nc1cccnc1O[C@H]1CCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c2c1C

Procedure:
Prepared analogously from 2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamine and 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:17])=[CH:10][CH:9]=1
Reactant: NCC(=O)O
Reactant: COc1ccc(CCC(=O)Cl)cc1
Product: COc1ccc(CCC(=O)NCC(=O)O)cc1

Procedure:
Prepared in analogy to example 2.1 from glycine and 3-(4-methoxy-phenyl)-propionyl chloride (CA [15893-42-2]). MS (m/e): 236.1 (MH−, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[C:35]([O:36][CH3:37])[CH:34]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC)c(OC)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3,4-dimethoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.28 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH2:30])(=[O:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].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>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:4]2[CH:3]=[C:2]([NH:30][C:27](=[O:29])[CH3:28])[CH:7]=[CH:6][CH:5]=2)=[N:9]1
Reactant: CC(N)=O
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sccc2-3)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of the corresponding intermediate 6-(3-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), acetamide (0.15 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give N-{3-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-acetamide as brown solid in 75% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (800 mg, 2.49 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.031 g, 7.47 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (510 mg, 2.74 mmol) in DMF (25 ml) was stirred at 80° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate removed in vacuo. The residue was purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product recrystallised from ethanol to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline (510 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N)ccc(C#N)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(NC[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7B (730 mg, 2.21 mmol) in 10% DMF in CH2Cl2 (5.5 mL) at rt was added 4-amino-2-chloro-3-methyl-benzonitrile (400 mg, 2.4 mmol) followed acetic acid (200 μL) and sodium triacetoxyborohydride (730 mg, 3.5 mmol). The reaction was stirred for 24 h at rt. The reaction was then extracted with EtOAc and washed with saturated aqueous NaHCO3. The organic extracts were dried over MgSO4 filtered and concentrated. Purification by flash chromatography (silica gel, 0-20% EtOAc in hexanes) provided impure (2R,3S)—N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(3-chloro-4-cyano-2-methyl-phenylamino)-methyl]pyrrolidine as a light brown residue. This residue was taken up in 10% TFA in CH2Cl2 (20 mL) and stirred for 2.5 h at rt. Toluene (10 mL) was added and solvents were removed under vacuum. Purification by preparative HPLC (separated into 4 injections, YMC C18 5 μm 30×100 mm, 0-100% B, 10 min grad., 2 min. hold, 25 mL/min.: A=10% MeOH/Water+0.1% TFA, B=90% MeOH/Water+0.1% TFA) provided the title compound (267 mg). MS (ES) m/z 380.23 [M+1]+
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].CC(C)([O-])C.[K+]>C1COCC1>[CH:11]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([O:23][C:2]2[C:7]([CH2:8][CH3:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: CCc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 4,6-dichloro-5-ethyl-pyrimidine (1 g, 5.65 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (1.05 g, 5.65 mmol) in dry THF under nitrogen at 0° C., potassium tert-butoxide (1M solution in THF, 6.78 mL) was added dropwise. The reaction was stirred at rt for 30 min. The mixture was quenched with water and extracted with EtOAc (3×). The organic layer was washed with water, sat. NH4Cl and brine, followed by drying over sodium sulfate and concentration under vacuo. The resulting oil was purified by HPLC to afford 4-(6-chloro-5-ethyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (0.74 g, 39.8%) as a colorless oil. Exact mass calculated for C15H22ClN3O3 327.13, found 328.2 (MH+).