Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([N:19]([CH3:41])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(C(F)(F)F)cc1)C(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
To a solution of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide (Example 34) (22 mg, 0.041 mmol) in anhydrous DMF at room temperature was added sodium hydride (6.5 mg, 0.164 mmol). The resulting suspension was stirred at room temperature for 5 min, then iodomethane (25 μL, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (30 mL), washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluting with a gradient of EtOAc (0-60%) in hexanes to afford 15 mg (66%) of the title compound as a white powder. HPLC/MS (method A): retention time=3.85 min, (M+H)+=556.3
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:6][C:5]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1.[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[O:12]=[S:2]1(=[O:1])[CH2:6][C:5]2[C:7]([Cl:11])=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:4]=2[NH:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=S1(=O)Cc2c(Cl)cccc2N1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)c2c1NS(=O)(=O)C2
Reaction time: 24 h
Yield: 21.9 %

Procedure:
1 ,3-dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazole (1.5 mg, 0.92 mmol) was dissolved in methylene chloride (30 ml) followed by the addition of sodium nitrate (86 mg, 1.01 mmol). The addition of sulfuric acid (0.18 ml/3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture is allowed to stir. After about 24 hours, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (50% Ethyl acetate/Hexane) gave the desired product(50 mg, 21%). EI-MS m/z 263.5 (M+).
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:10])[C:7]([OH:9])=[O:8])(=[O:4])[CH:2]=[CH2:3].[CH3:11]OC(OC)OC.COC.C1(C=CC(O)=CC=1)O>CO>[CH3:11][O:10][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([OH:9])=[O:8]
Reactant: C=CC(=O)NC(O)C(=O)O
Reactant: COC(OC)OC
Agent: COC
Agent: Oc1ccc(O)cc1
Solvent: CO
Product: C=CC(=O)NC(OC)C(=O)O
Reaction time: 72 h

Procedure:
45 parts of acrylamidoglycolic acid, 90 parts trimethylorthoformate, 0.045 parts of the mono methyl ether of hydroquinone and 35 parts of methanol are mixed in a flask equipped with a stirrer, condensor and thermometer. The mixture was heated at a bath temperature of 60°-65° C. for 24 hours. A small amount of insoluble material was filtered off and discarded. The filtrate was stripped of solvent under vacuum and a rubbery substance was obtained. This material was extracted with ether with stirring for 3 days. The solid which was insoluble in the ether was filtered off and was further extracted with acetone. The acetone was removed to yield 24 g of crude AGME (Mp. 100-102.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:16]#[C:17][CH2:18][OH:19])[C:6]=2[CH:20]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl>N1C=CC=CC=1>[S:22]([O:19][CH2:18][C:17]#[C:16][C:7]1[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)(=[O:24])(=[O:23])[CH3:21]
Reactant: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
A solution of 6 g. of 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol in 50 ml. of pyridine is treated dropwise at -10° C. to 0° C. with 1.7 ml. of methanesulfonyl chloride in 10 ml. of pyridine and stirred at this temperature for 2 hours. After pouring onto ice, acidification with hydrochloric acid and extraction with eher, there is obtained 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol mesylate which melts at 100°-102° C. after recrystallization from ether.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15](OC)=[O:16])=[CH:11][C:9]=2[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[N:10]=1
Reactant: COC(=O)c1ccc2oc(-c3cccs3)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2oc(-c3cccs3)nc2c1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of methyl 2-(2-thienyl)-5-benzoxazolecarboxylate (1.50 g) in tetrahydrofuran (30 ml) was slowly added lithium aluminum hydride (220 mg) at 0° C., stirred for 30 minutes. To the reaction mixture was added water, which was made acidic with 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (4:1, v/v), 2-(2-thienyl)-5-benzoxazolyl methanol (1.03 g, 77%) was obtained. The recrystalization from ethyl acetate-hexane gave colorless needles, mp 158-159° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Yield: 82.8 %

Procedure:
The title compound (30 mg, 83%) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using indolin-2-one (13.3 mg, 0.1 mmol) and 3-(pyridin-3-ylethynyl)-1H-indazole-6-carbaldehyde (24.7 mg, 0.1 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 10.64 (s, 1H), 8.90 (s, 1H), 9.64 (d, J=4.4 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.60-7.50 (m, 3H), 7.24 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H) 6.84 (t, J=7.8 Hz, 1H); MS ESI 363.1 [M+H]+, calcd for [C23H14N4O+H]+ 363.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:16][C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[N:14][C:13]=1[C:28]([NH2:30])=[O:29]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[S:16][C:15]([NH:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:14][C:13]=2[C:28]([NH2:30])=[O:29])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Yield: 42.1 %

Procedure:
To solution of 4-fluorobenzoyl chloride (0.16 g, 1.2 mmol) in pyridine (5 mL) was added dropwise a solution of 5-amino-2-(quinolin-6-ylamino)thiazole-4-carboxamide (0.30 g, 1.05 mmol) and a catalytic amount of DMAP in pyridine (5 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed successively with water, MeOH and ether to give 0.18 g (42% yield) of the titled compound.
Reaction SMILES: C1(=O)OC(=O)CCCC1.[CH2:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O=O.[CH2:20]([CH:28]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[O:31][C:29]1=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[CH2:20]([CH:28]1[CH2:35][CH2:34][CH:33]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:32](=[O:36])[O:31][C:29]1=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=CCCCCCC
Reactant: CCCCCCCCC1CCCC(=O)OC1=O
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=C1CCCCC(=O)O1
Solvent: CC(=O)O
Product: CCCCCCCCC1CCC(CCCCCCCC)C(=O)OC1=O

Procedure:
A mixture of 20 mmol of adipic anhydride, 2 mmol of 1-octene, 0.04 mmol of manganese (II) acetate, 0.002 mmol of cobalt (II) 0 acetate and 2 ml of acetic acid was stirred at 90° C. in an atmosphere of a gaseous mixture of nitrogen and oxygen (9:1) (1 atm=0.101 MPa) for 3 hours. The resulting reaction mixture was analyzed to find that 2-octyladipic anhydride and 2,5-dioctyladipic anhydride were produced in yields of 29% and 2%, respectively, with a conversion from 1-octene of 63%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:27]=[CH:26][C:25]([N:28]2C=NC=N2)=[N:24][C:23]1=[O:33])[C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.CO>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24][C:23]1=[O:33])[C@H:11]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:15])[CH3:16])[CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1ccc(-n2cncn2)nc1=O
Agent: N
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1ccc(N)nc1=O
Yield: 95 %

Procedure:
A solution of 18 (1.5 g, 3.2 mmol) in 100 ml of 6 M NH3/MeOH was heated at 100° C. in a Parr bomb for 2 days. The reaction was cooled, concentrated and chromatographed on silica eluting with 10% MeOH in ethyl acetate. Concentration of the product-containing fractions afforded 1.27 g (95%) of 19 as an off-white amorphous solid. 1H NMR (DMSO-d6): δ 7.43 (d, J=7.2 Hz, 1H), 7.29 (m, 5H), 6.97 (br s, 2H), 5.58 (d, J=7.2 Hz), 4.39 (d, J=1.8 Hz, 2H), 3.98 (m, 1H), 3.83 (m, 1H), 3.51 (m, 1H), 3.35 (m, 2H), 2.06 (m, 1H), 1.14 (d, J=6.3 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [BrH:1].[CH:2]1([N:5]([C:13]2[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=[C:15]([C:24]3[S:25][C:26]([CH2:29]O)=[CH:27][CH:28]=3)[CH:14]=2)C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>ClCCl>[Br:1][CH2:29][C:26]1[S:25][C:24]([C:15]2[CH:14]=[C:13]([NH:5][CH:2]3[CH2:4][CH2:3]3)[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2ccc(CO)s2)nc2c(C=O)cnn12)C1CC1
Reactant: Br
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Temperature: 40 °C
Yield: 34 %

Procedure:
Hydrogen bromide (48% in water, 5 mL) was added dropwise to tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (980 mg, 2.4 mmol) suspended in dichloromethane (5 mL). The solution immediately became dark brown and homogeneous upon addition. The reaction was heated to 40° C. for 4 hours, then diluted with dichloromethane (10 mL). The liquid was decanted and the gummy residue was washed with dichloromethane (3×10 mL). The combined liquids were washed successively with sat. NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexanes and then purified via flash column chromatography (10-20% EtOAc/hexanes) to provide 5-(5-(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (300 mg, 34%) as a yellow solid. LCMS (ES): >95% pure, m/z 378 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[C:28]=2[CH:33]=[O:34])=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:33]([C:28]2[C:29]([CH3:32])=[N:30][O:31][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)[OH:34])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: Brc1cccc(Cc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1-Benzyl-3-bromo-benzene (0.811 g, 3.3 mmol) was dissolved in THF (2 mL), cooled to −78° C. and then n-butyllithium (2.0 M in THF, 1.65 mL, 3.3 mmol) was added dropwise. The reaction was stirred for 15 minutes then warmed to 0° C. and 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.05 g, 3.96 mmol) was added. The reaction was allowed to warm to room temperature while stirring for 1 hour. The reaction was quenched with aqueous ammonium chloride then submitted to standard aqueous workup and silica gel chromatography to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[Si:15]([CH2:22][CH2:23][CH:24]([OH:30])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.CCOCC>[Si:15]([CH2:22][CH2:23][CH:24]([O:30][C:8](=[O:10])[CH3:9])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C#N)C(O)CC[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(CC[Si](C)(C)C(C)(C)C)C(C)(C)C#N
Temperature: 0 °C

Procedure:
14.43 g (142.64 mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and, at 0° C., 14.56 g (142.64 mmol) of acetic acid anhydride are added to 28.24 g (109.7 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile, the title compound of Example 6a, and it is stirred for 5 hours at room temperature. It is poured onto 21 of ice water and extracted twice with 300 ml each of MTB-ether. The combined MTB-phases are washed once with 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on silica gel (hexane/MTB-ether).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](Cl)=[O:31]>C(Cl)Cl>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]([N:2]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20])[CH3:1])=[O:31]
Reactant: CNC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: ClCCl
Product: CN(C(=O)c1cc2ccccc2[nH]1)C1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,3-Dihydro-3-(RS)-methylamino-5-phenyl-2H-1,4-benzodiazepin-2-one (130 mg, 0.49 mmol) and indole-2-carbonyl chloride (88 mg, 0.49 mmol) were combined in CH2Cl2 (5 ml) and stirred 2 hours at 25° C. The reaction was concentrated and chromatographed on silica gel (3% MeOH in CH2Cl2) to give the title compound as a white solid from CH2Cl2 : (m.p. 287°-288.5°).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].ClC1C=CC2OC3C=CC=CC=3CN(C(O)=O)C=2C=1.[Cl:33][C:34]1[CH:52]=[CH:51][C:37]2[O:38][C:39]3[CH:50]=[CH:49][CH:48]=[CH:47][C:40]=3[CH2:41][N:42]([C:43]([NH:45][NH2:46])=[O:44])[C:36]=2[CH:35]=1.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[K+]>CN(C=O)C.CCOC(C)=O>[CH3:13][C:2]([CH3:1])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]([NH:46][NH:45][C:43]([N:42]1[CH2:41][C:40]2[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=2[O:38][C:37]2[CH:51]=[CH:52][C:34]([Cl:33])=[CH:35][C:36]1=2)=[O:44])=[O:12])=[O:6])[CH3:3]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 52 %

Procedure:
To a stirring solution of 3.78 g (20 mmol) of N-[(1,1-dimethylethoxy)carbonyl]-β-alanine (6), prepared as described above in Example 6, and 5.79 (20 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, hydrazine (1), prepared as described above in Example 1, in 50 mL of DMF cooled in an icebath was added 3.5 mL (20 mmol) of DIEA followed by 4.22 g (22 mmol) of N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The reaction was allowed to warm to ambient temperature over a period of 16 hours. To the reaction mixture was added 100 mL of EtOAc and 200 mL of M KHSO4. The layers were separated and then the organic layer was washed with 2×100 mL of M KHSO4, 2×100 mL of a saturated KHCO3 solution, and 100 mL of brine. The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The resulting product was purified by column chromatography to yield 4.75 g (52%) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]hydrazide (7).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][C@H:18]1[CH2:26][C:25]2[C:20](=[CH:21][C:22](C)=[CH:23][CH:24]=2)[C@@H:19]1[NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([NH:28][C@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26][CH2:18][CH2:17]2)[N:7]=1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1c(N[C@@H]2CCCc3ccccc32)nc(N)nc1-c1ccccc1
Yield: 70.4 %

Procedure:
A mixture of 0.40 g (1.21 mmol) of 2-amino-4-chloro-6-phenylpyrimidine-5-carbonitrile (crude mixture as precursor, ca. 70% purity), 0.27 g (1.82 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and 0.34 g (2.42 mmol) of potassium carbonate is heated in 1 ml of N-methylpyrrolidone as solvent at 150° C. for 60 minutes in a microwave appliance (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture is absorbed on silica gel and, following column chromatographic separation, 0.291 g of 2-amino-4-phenyl-6-[(1R)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidine-5-carbonitrile is obtained (solid, 67% yield, 95% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:25][C:22]1[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=1
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Reactant: CCOC(=O)c1csc(CBr)n1
Product: O=C(O)c1csc(COc2ccc(-c3ccccc3)cc2Cl)n1

Procedure:
2-(3-Chloro-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 2-chloro-4-phenylphenol (available from TCI America, Portland, Oreg.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 82 mg. Mass spectrum (ES) MH+=346.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[CH:7]=1
Reactant: CN(C)CCCN
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN(C)CCCNC1=C2N=c3cc(Cl)ccc3=C2Oc2ccccc2N1C

Procedure:
In the same way as described in example 1, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and 3-dimethylaminopropylamine were reacted and the crude product recrystallized from acetonitrile for analysis, mp. 156°-7°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.Br.O.[OH-].[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:11]([C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)ccn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)cc[nH]1
Yield: 31 %

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48% hydrobromic acid. The reaction mixture was heated at reflux for 3 hour. The cooled mixture was then treated with water, basified with ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (MeOH/CH2Cl2/NH4OH, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone, as a yellow solid (32% yield), mp: 250–251° C.; 1H NMR (DMSO-d6): δ 11.74 (s, 1H), 8.45 (d, J=5.0 Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 (d, J=5.0 Hz, 2H), 6.37 (s, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.0 (m, 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C21H17FN4O2.0.2H2O: C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:17])[CH3:2].Br[CH2:27][C:28]1[C:32]2[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[S:30][N:29]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:27][C:28]2[C:32]3[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=3[S:30][N:29]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 66.9 %

Procedure:
To a solution of (S)-(4-Chloro-phenyl)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid ethyl ester (50 mg, 0.14 mmol) (prepared according to example 1, steps 1-3) in DMF (10 mL) are added 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (54 mg, 0.21 mmol) (prepares according to example 5, steps 1-6) and K2CO3 (58 mg, 0.42 mmol) at room temperature under nitrogen atmosphere. The solution is heated to 100° C. for 2 hours. The solution is cooled down and water is added. The solution is extracted with EtOAc and the combined organic layer is dried with MgSO4. The solution is filtered and the filtrate is concentrated. The residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford (S)-(4-Chloro-phenyl)-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid ethyl ester (50 mg, 67%) as a colorless foam.