Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([F:43])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:43][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1cc(F)cc(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)cc(C(F)(F)F)c1

Procedure:
Compound 35 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.25 (s, 1H), 9.01 (d, J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.57 (s, 1H), 3.15 (dd, J=12.3, 8.3 Hz, 1H), 2.95 (dd, J=12.3, 5.5 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([O:10][CH3:11])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:14])C>C(OCC)(=O)C>[C:1]([N+:5](=[N:6][C:7]([O:10][CH3:11])([CH3:9])[CH3:8])[O-:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: COC(C)(C)N=NC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(C)(C)N=[N+]([O-])C(C)(C)C

Procedure:
2-t-Butylazoxy-2-methoxypropane was prepared by oxidizing 7.9 grams (0.05 moles) 2-t-butylazo-2-methoxypropane with 50 ml. of 25% peracetic acid in ethyl acetate at 30°-40° C. for 2 hours. The yield was 7.3 grams (84% yield) of a colorless liquid. The infrared spectrum of the product was in agreement with the structure of 2-t-butylazoxy-2-methoxypropane (2 strong bands at 1450-1510 cm-1).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]=[CH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2].CO.C(=O)([O-])[O-].[K+].[K+].CC(C)(O)[C:26]#[N:27]>O1CCCC1>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]([C:26]#[N:27])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(O)C#N
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Temperature: 90 °C

Procedure:
A mixture of 50 g of 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one, 1200 ml of methanol, 120 ml of tetrahydrofuran, 100 ml of a 10% aqueous potassium carbonate and 50 ml of acetone cyanhydrin under nitrogen was refluxed for an hour in a bath at 90° C. and the mixture was concentrated to about 200 ml under reduced pressure. The mixture was cooled to 20° C. and was extracted with methylene chloride. The organic phase was washed with water, dried and distilled to dryness under reduced pressure. The 58 g of brown oil residue were crystallized from 50 ml of methanol and the mixture was vacuum filtered to obtain 46 g of 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile with a melting point of 107° C. and then 120° C.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[F:37][C:38]1[CH:46]=[C:45]2[C:41]([C:42]([CH:47]=O)=[CH:43][NH:44]2)=[CH:40][CH:39]=1.N1CCCCC1>C1(C)C=CC=CC=1.O>[F:37][C:38]1[CH:46]=[C:45]2[C:41]([C:42]([CH:47]=[C:15]3[C:14]4[N:10]([C:11]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:12][N:13]=4)[C:9]4[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=4[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[O:28])[C:16]3=[O:17])=[CH:43][NH:44]2)=[CH:40][CH:39]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4cc(F)ccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (150 mg, 0.311 mmol) and 6-fluoro-1H-indole-3-carbaldehyde (61 mg, 0.373 mmol) in toluene (20 mL) was added piperidine (100 μL). The reaction vessel was equipped with a Dean-Stark trap that contained toluene and 4A molecular sieves and was heated at reflux for 24 hours. The solution was cooled to room temperature and was diluted with water. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) to yield 158 mg of 2-[4-(6-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. MS 628.3 (M+1), 626.2 (M−1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][C:17](=[O:18])[NH:16][C:14]1=[S:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]N1C(C)(C)CCCC1(C)C.[I:38]I.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl.C(O)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:19]([I:38])[C:17](=[O:18])[NH:16][C:14]1=[S:15])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCCOCn1c(-c2ccccc2)cc(=O)[nH]c1=S
Agent: O=C([O-])O
Agent: [Li]N1C(C)(C)CCCC1(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCOCn1c(-c2ccccc2)c(I)c(=O)[nH]c1=S
Temperature: -70 °C
Yield: 23.6 %

Procedure:
After cooling 35 ml of tetradydrofuran to -70° C., 2.1 g (15 mmol) of 2,2,6,6-tetramethylpiperidine and 15 mmol of n-butyl lithium were successively added thereto to obtain a lithium tetramethylpiperidide solution. Separately, 2.04 g (15 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil was dissolved in 20 ml of tetrahydrofuran and added dropwise to the said lithium tetramethylpiperidide solution to react for an hour at -70° C. Then, a solution of 3.81 g (15 mmol) of iodine in 20 ml of tetrahydrofuran was further added to the reaction solution while maintaining the reaction temperature at -70° C. to react for an hour. After the completion of the reaction, the reaction solution was added to 0.8 ml of acetic acid, allowed to warm to room temperature and distributed between a chloroform layer and a saturated aqueous solution of sodium bicarbonate. The chloroform layer was concentrated to dryness. The residue was crystallized from petroleum ether to obtain 1.835 g of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil (Yield: 62.8%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)=[O:4].[H-].[Na+].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[C:11]([CH3:13])[N:12]=2)[C:3](=[O:4])[C:2]([F:14])([F:1])[F:15])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1csc(CCNC(=O)C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of 224 mg of 2,2,2-trifluoro-N-[2-(4-methyl-thiazol-2-yl)-ethyl]-acetamide (0.94 mmol) in 4 ml DMF was added to a suspension of 45 mg of sodium hydride (60% in mineral oil) in 4 ml DMF at 0° C. After 30 min 0.173 ml 4-tert-butyl-benzylbromide were added and the reaction mixture was allowed to warm to rt. Stirring was continued for 3 h at ambient temperature, then water was added and the mixture was extracted with EtOAc. The organic layers were dried over magnesium sulfate, filtrated and the solvent was evaporated. Chromatography (silica gel; cyclohexane/EtOAc 4:1) yielded 265 mg (73%) of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-[2-(4-methyl-thiazol-2-yl)-ethyl]-acetamide as a light yellow liquid. 1H NMR (CDCl3, 300 MHz): δ 1.30 (s) and 1.31 (s, 9H), 2.42 (s, 3H), 3.23 (q, J=7 Hz, 2H), 3.70 (t, J=7 Hz) and 3.79 (t, J=7 Hz, 2H), 4.48(s) and 4.62 (s, 2H), 6.77 (m, 1H), 7.10 (d, J=8 Hz) and 7.17 (d, J=8 Hz, 2H), 7.36 (d, J=8 Hz) and 7.38 (d, J=8 Hz, 2H); MS (ISP) 385.4 (M+H)+.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:35])(=[O:34])[NH:30][CH:31]([CH3:33])[CH3:32])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:31]([NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:35])=[O:34])([CH3:33])[CH3:32]
Reactant: CC(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CC(C)NS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-isopropylsulfamoyl-benzoic acid and morpholine and obtained in 38% yield. MS (m/e): 327.2 (MH−, 100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(O)[CH3:7])C.O.[NH2:24][NH2:25]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:25][NH:24]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: NN
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A mixture of 30.2 g of 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and 25 g of 100% strength hydrazine hydrate is heated at 100° for 4 hours. The mixture is worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196 °.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:4]1=[O:15])[CH3:2]
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC(C)(O)CCCCCBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCn1cnc2c1c(=O)n(CCCCCC(C)(C)O)c(=O)n2CC

Procedure:
6.2 g of 3,7-diethylxanthine, 4.1 g of ptassium carbonate, and 6.6 g of 1-bromo-6-hydroxy-6-methylheptane are stirred in 100 ml of dimethylformamide at 120° C. for 18 hours. The mixture is filtered hot with suction, the filtrate is concentrated under recuced pressure final recrystallization from diisopropylether with addition of petroleum ether.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=1)=[O:4]>Cl>[CH2:14]([CH:13]([C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1cc(OC)cc(C(=O)OC)n1
Agent: Cl
Product: CCC(CC)c1cc(OC)cc(C(=O)O)n1
Yield: 139.6 %

Procedure:
A solution of 6-(1-ethyl-propyl)-4-methoxy-pyridine-2-carboxylic acid methyl ester (450 mg, 1.90 mmol) in 25% aq. HCl is stirred at 65° C. for 18 h. The mixture is concentrated and dried to give the title compound (592 mg) as hydrochloride salt; LC-MS**: tR=0.38 min; [M+1]+=224.32.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[CH:28][S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:29][OH:30].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:30][NH:29][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25](=[O:27])[CH3:26])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(C)=O)cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ncc(C(=O)NO)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of compound (12h) (125 mg, 0.305 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (211 mg, 3.05 mmol) and a freshly prepared solution of sodium methoxide in methanol (105 mg, 4.57 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13 h (15 mg, yield 12.0%). HPLC: 92.26% (Rt=12.51 min).
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[K+]>CC(C)=O.O>[C:1]1([Si:7]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:16][Si:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:16][Si:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16][Si:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc([Si]2(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O2)cc1
Yield: 94.1 %

Procedure:
A mixture of 510 g of diphenyldichlorosilane in 500 ml of acetone was added dropwise in the course of 3 hours to a hot solution, at 60° C, of 340 g of KOH in 1 l of water, while stirring vigorously. The acetone and a little water were then distilled off and, after cooling the residue, the crystalline octaphenylcyclotetrasiloxane was filtered off and washed with water. After drying, 376 g (94% yield) of octaphenylcyclotetrasiloxane of melting point 187° C (metastable crystal modification) were obtained. After recrystallization from toluene, the product had a melting point of 201° C.
Reaction SMILES: BrC1C=C(C=CC=1)/C=C/C(Cl)=O.C(N)(C)C.[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)/[CH:21]=[CH:22]/[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C1(C)C=CC=CC=1.CCOCC>[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[CH:21]=[CH:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)NC(=O)/C=C/c1cccc(Br)c1
Agent: O=C(Cl)/C=C/c1cccc(Br)c1
Solvent: CC(C)N
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)NC(=O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans m-bromocinnamic acid (11.4 g) in dry benzene (75 ml) was heated to reflux and then a mixture of thionyl chloride (12 g) in dry benzene (50 ml) was added at such a rate as to maintain constant reflux. The reaction mixture was heated at reflux for an additional 2 hr after the addition of thionyl chloride. The solvent and excess thionyl chloride were then removed under reduced pressure to give trans 3-bromocinnamoyl chloride (ca. 12.3 g). A solution of the 3-bromocinnamoyl chloride in toluene (150 ml) was added dropwise with stirring to a solution of isopropylamine (10 g) in ether (200 ml). The reaction mixture was stirred at room temperature for one hour and then heated at reflux for one hour. The solvent and excess amine were removed under reduced pressure. The crude residue was triturated with water, filtered, and recrystallized from ethanol-water to give white, crystalline trans 3-bromo-N-isopropylcinnamamide, m.p. 85°-86° C. Elemental analysis, NMR and IR spectra all confirmed the identity of the product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25].Cl.Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:6]1[CH:5]=[CH:4][C:3]([NH:23][C:24]([NH:26][CH:27]2[CH2:28][CH2:29]2)=[O:25])=[C:2]([CH3:1])[C:7]=1[CH3:8])#[N:21]
Reactant: ClCCCN1CCCC1
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCCCN4CCCC4)c(C#N)cc23)c1C
Temperature: 60 °C
Yield: 38.1 %

Procedure:
After adding the N-[2,3-dimethyl-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-cyclopropylurea (100 mg) synthesized in Example 721, 1-(3-chloropropyl)pyrrolidine hydrochloride (95 mg) and potassium carbonate (150 mg) to dimethylformamide (2 ml), the mixture was heated at 60° C. for 7 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (49 mg) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:10][NH:11][C:12]=1C=O.[F:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([NH:31][NH2:32])=[O:30]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12](=[N:32][NH:31][C:29]([C:28]2[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=2[F:26])=[O:30])[N:11]=[N:10][C:9]=1[O:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Oc2n[nH]c(C=O)c2-c2ccccc2F)cc1
Reactant: NNC(=O)c1ccccc1F
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)OC2=C(c3ccccc3F)C(=NNC(=O)c3ccccc3F)N=N2)cc1

Procedure:
The product from step c) (10 g, 0.028 mol) was suspended in xylene (250 ml) with 2-fluorobenzoic hydrazide (4.7 g, 0.0231 mol) and heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solid produced was washed in the sinter funnel several times with dichloromethane then concentrated under vacuum to leave a solid (10.53 g). The product existed as a 1:1 mixture of 2 tautomers. 1H NMR (400 MHz, CDCl3) δ 2.37 (3H, s), 7.18-7.66 (12H, m), 8.06 (1H, s), 11.90 (0.5H, s), 13.78 (0.5H, s); MS (ES+) m/e 497 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8](=[O:17])[N:7]([CH2:18][C:19]([O:21]C)=[O:20])[C:6]2=[O:23].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8](=[O:17])[N:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]2=[O:23]
Reactant: COC(=O)CN1C(=O)c2cc(NS(C)(=O)=O)c(OC)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of methyl 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.584 mmol) in dioxane (10 ml), aqueous 37% HCl (3.5 ml) was added, and the mixture was stirred at room temperature overnight. Additional aqueous 37% HCl (4 ml) was added over 30 hours with stirring the reaction at room temperature. The volatiles were removed under vacuum affording 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (0.183 g, 0.557 mmol, 95% yield). MS/ESI+ 328.9 [MH]+. This product was used without purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O>[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1F)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.7 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (3.0 g, 15.2 mmol) in dimethylformamide (35 mL) under nitrogen was added potassium carbonate (6.3 g, 45.6 mmol) followed by a solution of the crude 2,4-difluorobenzoylchloride of Step A (22.8 mmol) in dimethylformamide (15 mL). After stirring at room temperature for 20 minutes, the reaction mixture was washed with water and stirred to give a solid which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title compound (2.6 g) as a white foam which crystallized by sonication from hexane-ethanol, m.p. 161-163° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8](N(C(C)C)C2C=C(C(C)C)C3OCC(C)(C)C=3C=2)=[CH:7][CH:6]=1)C.[CH3:30][C:31]1([CH3:47])[C:35]2[CH:36]=[C:37]([NH:43][CH:44]([CH3:46])[CH3:45])[CH:38]=[C:39]([CH:40]([CH3:42])[CH3:41])[C:34]=2[O:33][CH2:32]1.[OH-].[Na+]>C(O)C>[CH:44]([N:43]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:29])=[O:3])[C:37]1[CH:38]=[C:39]([CH:40]([CH3:42])[CH3:41])[C:34]2[O:33][CH2:32][C:31]([CH3:30])([CH3:47])[C:35]=2[CH:36]=1)([CH3:46])[CH3:45]
Reactant: CCOC(=O)c1ccc(N(c2cc(C(C)C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Reactant: CC(C)Nc1cc(C(C)C)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(N(c2ccccc2C(=O)O)C(C)C)cc2c1OCC2(C)C
Yield: 13.4 %

Procedure:
Following general procedure I and using 4-[isopropyl-(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester [(Compound 39, 0.15 g, contaminated with 3,3-dimethyl-7-isopropyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 35)] and 2 mL of 5M sodium hydroxide in 10 mL of ethanol, the title compound (0.043 g, 13.4% for 2 steps) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H, J=9.0 Hz), 6.71 (d, 1H, J=2.0 Hz), 6.64 (d, 1H, J=2.0 Hz), 6.51 (d, 2H, J=9.0 Hz), 4.36 (heptet, 1H, J=6.4 Hz), 4.30 (s, 2H), 3.09 (heptet, 1H, J=6.9 Hz), 1.33 (s, 6H), 1.23 (d, 6H, J=6.9 Hz), 1.15 (d, 6H, J=6.4 Hz).