Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19]C(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[C:28]([O:32][C:33]([C:35]1N=CC(Br)=[CH:37][N:36]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[C:28]([O:32][C:33]([C:35]1[N:19]=[CH:18][C:17]([O:16][C:14]2[C:8]3[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:15]=2)=[CH:37][N:36]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: CC(C)(C)OC(=O)c1ncc(Br)cn1
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cnc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 5-bromo-pyrimidine-2-carboxylic acid tert-butyl ester (171a) (497 mg, 1.92 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (426 mg, 1.92 mmol) to give a yellow oil (83 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 2 H) 7.30 (d, J=1.26 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 3.88 (s, 3 H) 2.92 (s, 2 H) 1.68 (s, 9 H) 1.50 (s, 6 H); LCMS for C21H24N2O6 m/z 345.00 (M-tBu+H+).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH:17]([C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1)=[O:18]
Reactant: O=C(O)c1csc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Br[C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.CN1C(=O)CCC1>[CH3:47][O:46][C:43]1[N:42]=[CH:41][C:40]([CH:3]=[CH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:45][CH:44]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COc1ccc(C=CC(=O)OC(C)(C)C)cn1
Temperature: 90 °C
Reaction time: 0.83 h
Yield: 98.4 %

Procedure:
A mixture of tert-butyl acrylate (98%; 137 mL; 916 mmol), triethylamine (100 mL; 720 mmol), tri-O-tolylphosphine (97%; 6.30 g; 20 mmol), Pd(OAc)2 (1.80 g; 8 mmol), and NMP (90 mL) was degassed three times. The mixture was heated to 90° C., and a solution of 2-methoxy-5-bromopyridine 1-2(50.0 g; 266 mmol) and NMP (10 mL) was added via addition funnel over 1 hour, maintaining the reaction temperature at 90° C. The reaction was heated for 12 hours after complete addition. The reaction mixture was cooled down to room temperature after completion of the reaction. To the reaction mixture was added toluene (400 mL), and the resulting solution was then passed through a pad of Solka Flok. The filter cake was washed with toluene (270 mL). The toluene solution was washed with water (3×540 mL). An aqueous solution of sodium hypochlorite (NaClO) (2.5%; 200 mL) was slowly added to the toluene solution keeping the temperature about 30° C. The reaction was aged 50 min with a vigorous stirring. The organic layer was separated, washed with water (540 mL) three times, and followed by saturated aqueous NaCl (270 mL). The organic layer was concentrated to oil. The oil was dissolved in 270 mL hexanes and loaded onto to a silica gel (90 g) pad. The silica gel pad was washed with hexanes (73 mL). The product 1-3was eluted with EtOAc:hexane (1:8; v/v) in about 730 mL. The yellow solution was concentrated to oil (126 g; 49.2 wt %; 98.4% yield). The crude oil was used for the next reaction without further purification. Authentic sample was obtained by further concentration of the oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]2[C:13]1[N:14]=[C:15]2[C:21]([C:22]([NH:24][C@@H:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[NH:31]C(=O)OC(C)(C)C)=[O:23])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]2=[N:17][CH:18]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C@@H:26]1[C@H:25]([NH:24][C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:6]4[C:5]5[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:8]([CH3:12])[N:7]=4)[N:14]=3)[NH:19][CH:20]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27]1
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)N[C@@H]1CCOC[C@@H]1NC(=O)OC(C)(C)C)cn3COCC[Si](C)(C)C)nn2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)N[C@@H]4CCOC[C@@H]4N)c3n1)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a pale yellow solution of tert-butyl (3R,4R)-4-(2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)tetrahydro-2H-pyran-3-ylcarbamate (115 mg, 176 μmol) in dichloromethane (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol, Eq: 73.6), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and most dichloromethane evaporated for solid formation, solid was separated by decantation and dried under high vacuum to give N-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (48 mg, 114 μmol, 64.6%) as an off-white solid. MS (M+H)+=422 (100% purity); 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J=2.6 Hz, 1H), 7.70 (d, J=9.1 Hz, 1H), 7.31 (dd, J=9.1, 2.3 Hz, 1H), 4.23 (td, J=7.6, 4.0 Hz, 1H), 4.14 (s, 3H), 4.08 (q, J=5.3 Hz, 1H), 3.87 (s, 3H), 3.84 (br. s., 1H), 3.52-3.72 (m, 2H), 3.38-3.51 (m, 1H), 3.15 (d, J=4.9 Hz, 2H), 2.88 (br. s., 1H), 1.85-2.07 (m, 1H), 1.70 (d, J=11.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][C:34]#[C:35][CH3:36].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][C:34]#[C:35][CH3:36])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (24.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.20 g). To the solution was added 60% sodium hydride (0.24 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1-bromo-2-butyne (0.80 ml), and the mixture was stirred at 65° C. for 4 days. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-butynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1.[H-].[Na+]>>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[CH:15]=1
Reactant: COC[C@@H]1CCCN1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-2-(methoxymethyl)pyrrolidine was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow oil. MS: 285.0, 286.9 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:31][CH3:32])[CH:3]=1.[ClH:33]>>[ClH:33].[NH2:21][CH2:20][C:19]1[CH:29]=[CH:30][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([F:1])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:17][CH:18]=1
Reactant: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CN)cc1
Yield: 90 %

Procedure:
Following General Procedure D-1, tert-butyl 4-(6-fluoro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (15 mg, 0.030 mmol) was reacted with HCl (2 N in diethyl ether, 1.5 mL) to afford the desired product (10 mg, 90%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=8.1 Hz, 2H), 7.58 (d, J=5.4 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.32 (d, J=12.7 Hz, 1H), 6.04 (d, J=5.4 Hz, 1H), 4.27 (s, 2H), 3.72 (s, 3H); ESI MS m/z 355 [C19H15FN2O2S+H]+; HPLC 99% (AUC), tR=10.64 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16]C3C=NC=CC=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Fc1cc(F)cc(Br)c1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=361.4 (M+H+).
Reaction SMILES: [CH2:1]1[C@H:3]2[CH:4]([OH:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][CH:4]1[C@@H:3]2[CH2:1][C@@H:2]2[C@@:19]2([CH3:20])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:5]1)(=[O:31])[CH3:30]
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Temperature: 0 °C

Procedure:
9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-ol is allowed to stand in 20 ml of pyridine and 10 ml of acetic anhydride for 20 hours at room temperature. The solution is stirred into ice water, the resultant precipitate is filtered off, taken up in diethyl ether, washed with water, and dried. After evaporation, 11 g of 3-acetoxy-1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstane is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH2:28][C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 94.4 %

Procedure:
Preparation of example 25 from the title compound of Example 7 (hydrochloride) (20 mg, 0.072 mmol), phenyl-acetic acid (11 mg, 0.08 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30 mg, 0.080 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (27 mg, 0.068 mmol) as a yellow powder in 95% yield.
Reaction SMILES: Cl[Si:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)C>[C:6]1([SiH:2]2[CH2:5][CH2:4][CH2:3]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[Si]1(c2ccccc2)CCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: c1ccc([SiH]2CCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
The 1-chloro-1-phenyl-1-silacyclobutane was reacted with lithium aluminum hydride in ethyl ether to obtain 1-phenyl-1-silacyclobutane. The 1-chloro-1-phenyl-1-silacyclobutane (8.4 g, 46 mmole) in 10 ml diethyl ether was added dropwise to 0.87 g 23 mmole of lithium aluminum hydride in 10 ml diethyl ether at ±5° C. The reaction mixture warmed gradually to room temperature. The mixture was stirred over 12 hours. The mixture was hydrolyzed with 3N hydrochloric acid. After separation, the water layer was extracted with 2×20 ml of ethyl ether. The combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent and fractional distillation gave 1-phenyl-1-silacyclobutane. b.p. 70°-72° C./20 mm Hg, 6.3 g, 92% yield was obtained. 1H NMR (δ) 1.39 (m, 4H), 2.31 (m, 2H), 5.25 (m, 1H), 7.46 (m, 3H), 7.70 (m, 2H). 13C NMR (δ) 12.71, 19.67, 127.98, 129.88, 134.35, 135.19, 29Si NMR (δ) -1.80.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18]>C(O)(=O)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:18][CH2:17][C:16]([OH:20])=[O:19])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: C=CC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCNc1ccc(C(=O)c2ccccc2)cc1

Procedure:
1.97 g of 4-aminobenzophenone (0.01 mole) and 1.44 g of acrylic acid (0.02 mole) are dissolved in 10 ml of glacial acetic acid and boiled under reflux for 2 days. The solution is evaporated to dryness in vacuo, and the residue is redissolved in 2 N sodium hydroxide solution, and the solution is extracted several times with diethyl ether. The aqueous solution is adjusted to pH 4-5 with 2 N HCl, and the precipitate is filtered off with suction and washed with water.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH2:15][CH3:16])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)C>Cl.O>[CH:17]1([N:7]2[CH2:8][CH:9]([CH2:14][CH2:15][CH3:16])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCCC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Yield: 69.5 %

Procedure:
step d A mixture of 0.208 g (0.00065 mole) of (rac)-2-chloro-9-cyclopentyl-5-methyl-7-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-16), 0.13 g (0.00078 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.205 g of (rac)-4-(9-cyclopentyl-5-methyl-7-propyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-16) as an off-white solid.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH2:38][CH3:39])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[C:27]([CH3:40])=[CH:26]2)[CH2:24][CH2:23]1.Cl.Cl.[O:43]=[C:44]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[N:61][CH:62]=[C:63]([CH:68]=3)[C:64]([O:66]C)=[O:65])[CH:57]=2)[O:52][C:46]2([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45]1>CN(C=O)C>[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH2:38][CH3:39])[CH:30]=[C:31]([C:34]([N:49]4[CH2:50][CH2:51][C:46]5([CH2:45][C:44](=[O:43])[C:58]6[C:53](=[CH:54][CH:55]=[C:56]([C:59]7[CH:60]=[N:61][CH:62]=[C:63]([CH:68]=7)[C:64]([OH:66])=[O:65])[CH:57]=6)[O:52]5)[CH2:47][CH2:48]4)=[O:36])[CH:32]=3)[C:27]([CH3:40])=[CH:26]2)[CH2:23][CH2:24]1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Reactant: COC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1c(C)cn2C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
TEA (162 mg) was added to a mixture of EDCI (92 mg), HOBT (73.5 mg), 1-cyclopropyl-4-ethoxy-3-methyl-1H-indole-6-carboxylic acid (104 mg), and methyl 5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)nicotinate dihydrochloride (170 mg) and DMF (3 ml), and the mixture was stirred at r.t. for 5 hours. The mixture was evaporated and purified through SiO2 column chromatography (eluted with Hex-EtOAc, then MeOH—CHCl3) to give methyl ester of the title compound as a pale yellow solid. 1 ml of 1N NaOHaq was added to its solution in 3 ml of MeOH and 3 ml of THF, and the mixture was stirred at r.t. for 4 h. Then the mixture was neutralized with 1N HClaq and diluted with CHCl3-MeOH. The mixture was dried over Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc-n-hexane to give the title compound as a slightly yellowish powder. 1H-NMR (400 MHz, DMSO-d6) δ: 13.57 (1H, s), 9.08 (1H, d, J=2.0 Hz), 9.03 (1H, d, J=2.0 Hz), 8.41 (1H, dd, J=2.0, 2.0 Hz), 8.08-8.02 (2H, m), 7.26 (1H, dd, J=7.8, 1.0 Hz), 7.12 (1H, d, J=1.0 Hz), 7.00 (1H, d, J=1.0 Hz), 6.48 (1H, s), 4.36-4.14 (1H, br m), 4.08 (2H, q, J=7.0 Hz), 3.78-3.20 (4H, br m), 2.96 (2H, s), 2.33 (3H, d, J=1.0 Hz), 2.09-1.73 (4H, m), 1.37 (3H, t, J=7.0 Hz), 1.03-0.98 (2H, m), 0.89-0.85 (2H, m); MS [M+H]+=580.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.C1C=CC=CC=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1
Reactant: CC1CC(C)CC(O)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)CC(C)C1
Yield: 81.5 %

Procedure:
128 g of 3,5-dimethyl-cyclohexanol and 500 ml of benzene are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. While stirring and cooling there is now slowly added dropwise thereto a mixture of 119 g of sodium dichromate, 500 ml of water, 162 ml of concentrated sulphuric acid and 50 ml of glacial acetic acid. Thereby the temperature should not exceed +10° C. The mixture is stirred at this temperature for a further 3 hours and then the organic phase is separated. The aqueous phase is diluted with 130 ml of water and extracted with benzene. The combined organic phases are washed neutral and concentrated. The residue is distilled over a Widmer column and gives 102.7 g of 3,5-dimethyl-cyclohexanone.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:4][CH:3]=1.[CH2:18](O)[CH2:19][OH:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:5]3[S:6][CH:2]=[CH:3][CH:4]=3)[O:20][CH2:19][CH2:18][O:8]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)s1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2(c3cccs3)OCCO2)cc1

Procedure:
If one were to take 2 grams (12 mMole) of commercially available (5-chloro-thiophen-2-yl)-(4-nitro-phenyl)-methanone 1 (Reike Metals, Lincoln, Nebr.) and heat it under anhydrous conditions with an excess of ethylene glycol and catalytic amounts of toluene sulfonic acid in toluene, one would obtain the protected 2-(4-nitro-phenyl)-2-thiophen-2-yl-[1,3]dioxolane (2).