Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.CN(C)C1C=CN=CC=1>[C:26]([O:11][CH2:10][CH2:9][O:8][C:4]1[C:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(OCCO)c(C(=O)OC(C)(C)C)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCOc1nn(C)c(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 5-amino-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-4-carboxylate (Preparation 11) (60 g) in tetrahydrofuran (500 ml), under nitrogen and at room temperature, was added triethylamine (41.7 ml), 4-dimethylaminopyridine (400 mg) followed by acetic anhydride (28.6 ml) dropwise. The reaction was stirred at room temperature overnight and was then concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 ml) and washed with brine (2×100 ml). The organics were dried with magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as white solid (71 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].[OH-].[Na+].O>CS(C)=O.[Cu]I>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:29][N:28]=2)([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)(CC2CCCC2)c2ccc(Br)cn2)cc2cccnc21
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 43.1 %

Procedure:
To a mixture of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(5-bromo-pyridin-2-yl)-2-cyclopentyl-ethanol (0.28 g, 0.53 mmol), sodium methanesulfinate (82 mg, 0.8 mmol), and copper (I) iodide (10 mg, 0.05 mmol) in dimethylsulfoxide (5 mL) was added sodium hydroxide (4 mg, 0.106 mmol). The resulting mixture was heated at 95° C. After stirring for 12 h, the mixture was poured into water (10 mL), extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-ethanol (0.12 g, 43%): LC/MS m/e calcd for C26H27N3O5S2 [M+H]+ 526.65, observed 526.3.
Reaction SMILES: C1CO[CH:3]([CH2:4][CH2:5][CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[O:2]1.O1CCCC1.Cl>O>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(CCCC2OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCCC=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.5 %

Procedure:
A mixture of 2.8 g of p-(4,4-ethylenedioxybutyl)benzonitrile, 56 ml of tetrahydrofuran and 56 ml of 10% hydrochloric acid was stirred for 3 hours at room temperature and then left to stand overnight. Thereafter, the reaction mixture was diluted with water and extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. There were obtained 2.6 g of 4-(p-cyanophenyl)butyraldehyde which was processed without additional purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([CH2:29][CH3:30])[C:17]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:8]([O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:22]([F:27])[CH:23]=2)[N:18]([CH2:29][CH3:30])[C:17]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCNCC1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 84.9 %

Procedure:
4-Methylpiperazine (0.08 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and DBU (0.09 mL, 0.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 100 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of a solid. The solid was purified by column chromatography (chloroform/methanol 99:1). The appropriate fractions were combined to give 0.14 g of the title compound as a solid, mp 134-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:6]=2[CH:22]=1.[C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[C:24]([CH3:26])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:26])[CH2:9][N:8]=[C:7]([C:14]3[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=3[F:20])[C:6]=2[CH:22]=1
Reactant: CC(=O)C(=O)OC(C)(C)C
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Product: CC(=NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1)C(=O)OC(C)(C)C

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can be stirred with tert.-butyl pyruvate to give 7-chloro-2-[[1-(t-butyoxycarbonyl)ethylidene]hydrazino]-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.O.[NH2:23][NH2:24]>C1COCC1>[C:8]([C:7]1[C:2]([NH:23][NH2:24])=[N:3][CH:4]=[CH:5][C:6]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)#[N:9]
Reactant: NN
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1Br
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1NN
Temperature: 160 °C
Yield: 88.7 %

Procedure:
To a solution of compound D6 (0.5 mg, 1.461 mmol) in THF (4 ml), was added hydrazine monohydrate (0.366 g, 7.305 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 15 min. After cooling, the resulting mixture was concentrated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D7 (0.380 g, 89%) as a white solid.
Reaction SMILES: [NH:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH2:2].[CH:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[CH:10][CH:9]=1>C(O)C>[C:11]1(/[CH:14]=[CH:15]/[CH:16]=[N:2]/[NH:1][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)NN
Reactant: O=C/C=C/c1ccccc1
Solvent: CCO
Product: CCOC(=O)N/N=C/C=C/c1ccccc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 5a (4.00 g, 38.4 mmol) and trans cinnamic aldehyde (7.60 g, 57.5 mmol) in ethanol (100 ml) was heated under reflux for 3 h. After cooling to room temperature, the mixture was filtered, and the residue dried under vacuum to give 6.77 g of a white solid. Refiltration of the filtrate gave another 0.73 g of the residue and an overall yield of 91%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)C[N:20]1C3.C(O)C.Cl>C(Cl)(Cl)Cl>[NH2:20][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18]
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
78 g of 1-(4-benzyloxyphenyl)-2-chloroethanone and 63 g of hexamine are dissolved in 2.2 liters of chloroform, and the mixture is stirred at room temperature overnight. The mixture is condensed to a volume of 1.1 liters, and refluxed for 3 hours. After cooling, the precipitated crystals are collected by filtration, washed and then dried. The colorless crystals thus obtained are added to a mixture of 750 ml of ethanol and 120 ml of conc. hydrochloric acid, and the mixture is refluxed for 50 minutes. After cooling, the precipitated crystals are collected by filteration, washed and then dried. 55.6 g of 2-amino-1-(4-benzyloxyphenyl)ethanone are obtained as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3[C:34]4([C:42]5[C:37](=[CH:38]C=CC=5)[NH:36][C:35]4=[O:43])COC3=CC=2ON=1.CC1C=CC(S(OC[C@@H]2CCC(=O)N2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:43]=[C:35]1[NH:36][C@H:37]([CH2:38][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[CH2:42][CH2:34]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1CC[C@@H](CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)N1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 133-136° C.; 1H NMR (300 MHz, CDCl3) δ7.35-7.27 (m, 1H), 7.24-7.14 (m, 1H), 7.14-7.03 (m, 1H), 7.00-6.85 (m, 1H), 6.54-6.42 (m, 1H), 6.42-6.37 (m, 1H), 4.93 (t, J=9.3 Hz, 1H), 4.67 (dd, J=9.3, 3.0 Hz, 1H), 4.53 (t, J=8.5 Hz, 2H), 4.18-4.04 (m, 1H), 3.93 (dt, J=13.9, 4.6 Hz, 1H), 3.72 (dt, J=13.9, 4.6 Hz, 1H), 3.07-2.80 (m, 3H), 2.42-2.15 (m, 3H), 2.06-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.6, 178.5, 161.8 (2C), 161.3, 161.2, 142.2, 142.1, 132.6, 132.5, 129.0 (2C), 128.9, 128.8, 124.1, 123.6, 119.9 (3C), 119.7, 118.8, 108.3, 93.2, 93.1, 80.6, 80.5, 72.3, 57.5, 53.2, 53.1, 45.2 (2C), 29.6, 29.6, 28.9, 24.7 (2C); MS (ES+) m/z 377.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=1>>[CH2:33]([O:32][C:30]([C:27]1[O:26][C:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([NH:10][C:11]3[C:20]4[C:15](=[C:16]([C:21](=[O:22])[NH2:23])[CH:17]=[CH:18][CH:19]=4)[N:14]=[CH:13][N:12]=3)[CH3:9])[CH:3]=2)=[N:29][CH:28]=1)=[O:31])[CH3:34]
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reactant: CCOC(=O)c1cnc(Cl)o1
Product: CCOC(=O)c1cnc(Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)o1

Procedure:
2-{3-[1-(8-Carbamoyl-quinazolin-4-ylamino)-ethyl]-phenylamino}-oxazole-5-carboxylic acid ethyl ester was prepared according to Example 549 starting 4-{[1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide and ethyl 2-chloro-1,3-oxazole-5-carboxylate. LCMS (M+1) 447.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH:3]=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:15])=[O:10])([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(C=O)c1cccc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cccc(C(C)(C)C=O)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(l,l-dimethyl-2-oxoethyl)benzoic acid in acetone (60 mL) were added potassium carbonate (3.78 g, 27.3 mmol) and methyl iodide (3.40 mL, 54.6 mmol), and the mixture was stirred at 60° C. for 5 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(1,1-dimethyl-2-oxoethyl)benzoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([O:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cn1
Yield: 25.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 1.5 g (5.1 m mol) of 2-(5-chloropyridine-2-yl)-4,5-dichloropyridazinone and 0.73 g (5.1 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.34 g of powdery potassium hydroxide. Then, the procedures in Synthesis Example 2 were repeated to give 500 mg of the intended compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:18])[CH2:2][CH3:3].C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([O:30][C:31](=O)C)(=[O:29])[CH3:28]>O1CCCC1.N1C=CC=CC=1>[C:27]([O:30][CH2:31][N:6]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:18])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1C(=O)NC1Sc1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCC1C(=O)N(COC(C)=O)C1Sc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 273 mg (0.94 mmol) azetidinone from Step A, 26.3 mg paraformaldehyd and 178 mg (0.56 mmole) cesium carbonate was stirred in 20 ml dry tetrahydrofuran at ambient temperature 16.5 hours under nitrogen. A mixture of 430 μl pyridine and 2.56 ml acetic anhydride was added to the reaction mixture and the stirring continued 5 more hours. The solvents were evaporated in vacuo to give 604 mg crude product which was chromatographed on a silica gel flash column in hexane-ethyl acetate 3/1. This gave 102 mg (30%) of 1-acetoxymethyl-4-p-nitrophenylthio-3-n-propylazetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=CC(OCC)=O)=[CH:5]2.CC(C[AlH]CC(C)C)C.C1C[O:31]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[O:31])=[CH:5]2
Reactant: CCOC(=O)C=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: O=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
ethyl 3-(5,6-dichloro-2indolyl)-2-propenoate (16.23 g, 57.1 mmol) was dissolved under nitrogen in dry THF (300 ml) cooled at -20° and 1M DIBAL in hexanes (115 ml, 115 ml) was added dropwise at -20° C. The reaction mixture was maintained at this temperature for 1 hour and then quenched with H2O. The mixture was warmed to RT, diluted with Et2O (200 ml) and filtered on a Celite pad, washing with 300 ml of Et2O. The dark-red solution was dried over MgSO4 and evaporated under vacuum to give pure title compound (13.8 g, 57.0 mmol, yield 99.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])[CH:37]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (70 mg, 0.19 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (64.9 uL, 0.48 mmol) (Aldrich), followed by the addition of 3-isocyanato-benzoic acid methyl ester (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 70 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:4]=2[O:3]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:12][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)CCc2ccc(O)cc2O1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)CCc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 110 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
2,3-Dihydro-2,2-dimethyl-7-hydroxy-4H-1-benzopyran (2.0 g) synthesized as in Referential Example 19, 1.8 g of p-chloronitrobenzene, 0.9 g of potassium hydroxide, 20 ml of N,N-dimethylformamide and 10 ml of toluene were put into a flask equipped with the DeanStark condenser, and were heated to 110° C. While removing evaporated water as an azeotrope with toluene, the reaction was carried out for 1 hour. After cooling, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvents were evaporated. The residue was purified by column chromatography to give 2.8 g (yield 84%) of the desired product as a brown liquid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][Si](C)(C)C)=[N:29][CH:30]=1)=[O:24])[CH3:21].C([O-])(=O)C.[K+].O>O1CCOCC1>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:32]=2)=[N:29][CH:30]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cc3cc(SC)cnc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a solution of 2-benzenesulfonylamino-5-methylthio-3-iodo-pyridine (100 mg) in 1,4-dioxane (2.5 ml), 5-ethoxycarbonyl-2-trimethylsilylethynylpyridine (185 mg), bistriphenylphosphine palladium dichloride (9 mg), cuprous iodide (5 mg) and potassium acetate (37 mg) were added successively and the mixture was stirred in a sealed tube at 100° C. for 15 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=2:1) to obtain 110 mg of the desired product as an orange oil.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CO>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:2])=[O:28]
Reactant: O=C(O)CCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.28 g, 1.45 mmol) was added to a solution of the above 14-hydroxy-tetradecanoic acid (7.10 g, 29.1 mmol) in methanol (150 mL) and the resulting solution was stirred at room temperature for 3 days. Methanol was removed under reduced pressure; the residue was dissolved in ethyl acetate (170 mL); washed with 5% aqueous solution of sodium carbonate (3×50 mL) and brine (25 mL); dried over anhydrous magnesium sulfate and evaporated in vacuo to give methyl 14-hydroxy-tetradecanoate as white solid.
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](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:44]=[CH:45][CH:46]=[N:47]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>>[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:47][CH:46]5[CH2:44][CH2:45]5)=[O:27])=[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: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-propylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.66, 2.40 Hz, 2H) 0.70 (dd, J=6.95, 2.15 Hz, 2H) 1.50-1.77 (m, 6H) 1.88-1.97 (m, 2H) 2.82 (td, J=7.33, 3.54 Hz, 1H) 3.17 (s, 3H) 3.92 (s, 3H) 3.99-4.08 (m, 3H) 4.75 (d, J=8.84 Hz, 1H) 7.40-7.51 (m, 2H) 7.96 (s, 1H) 8.26 (d, J=8.34 Hz, 1H) 8.35 (d, J=4.04 Hz, 1H). [M+H] C24H28F2N6O3 calc'd for, 487. found 487.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][C:1]([CH3:4])([O:5][Si:7]([CH3:10])([CH3:9])[CH3:6])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C)O[Si](C)(C)C

Procedure:
1 mole of tert. butanol, 1.5 moles of trimethylchlorosilane and 0.001 moles of tetra-n-butyl ammonium bromide were reacted at the reflux temperature (54°-67° C.) as in Example 1 and then worked up by distillation.