Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.08 h
Yield: 63.1 %

Procedure:
In an atmosphere of argon, a mixture of 32 mg (4.0 mmol) of lithium hydride and 7 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 1.0 g (3.5 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 12 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 5 minutes. The mixture was further stirred for 20 minutes. To the mixture was then added a mixture of 605 mg of ethyl bromoacetate and 4 ml of DMF. The mixture was then stirred for 11 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 830 mg of ethyl 2-[2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetate was obtained as a low polarity substance, and 350 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate was obtained as a high polarity substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH3:27])=[CH:21][CH:20]=2)=[CH:12]\[C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH3:27])=[CH:21][CH:20]=2)[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O

Procedure:
An (R,S) mixture of the title compound was obtained by performing substantially the same reaction as in Examples 4-207 and 4-208(2) except for using 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridin-2(1H)-one obtained in Example 4-164. This was preparatively isolated by a chiral HPLC column (CHIRALCEL OD-H, hexane:ethanol=50:50 v/v, 40° C., 7.0 mL/min, 210 nm) to give one diastereomer (A) of the title compound as a colorless amorphous (9.5 mg) and the other diastereomer (B) of the title compound as a colorless powder (11.9 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.Cl>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([OH:13])([CH3:14])[CH3:12])=[N:4][C:5]([NH:16][C:17]2[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Reactant: CS(=N)(=O)c1cccc(N)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](Nc1nc(Nc2cccc(S(C)(=N)=O)c2)ncc1Br)C(C)(C)O

Procedure:
127 mg (0.43 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1 ml of acetonitrile is added to 74 mg (0.43 mmol) of (RS)-S-(3-aminophenyl)-S-methyl sulfoximide in 0.5 ml of acetonitrile. It is mixed with 0.1 ml of a 4N solution of HCl in dioxane, and the batch is refluxed overnight. The solvent is drawn off, and the remaining residue is purified by chromatography (DCM/EtOH 9: 1). 37 mg (0.09 mmol, corresponding to 20% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:24][C:25]1(OCC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:25]3([O:24][CH2:22][CH3:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC1(OCC)CCCCCC1
Product: CCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 44.1 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-diethoxycycloheptane (2.03 g, 10 mmol) in the same manner as the example 20 to give the compound 26 (214 mg, 39.8%). Mp 53-54° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[N:2]1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1>CC#N.CN(C1C=CN=CC=1)C>[C:15]([C:14]1[CH:13]=[CH:12][S:11][C:10]=1[NH:9][C:6]([C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:7])(=[O:16])[NH2:17]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)c1cc[nH]n1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: NC(=O)c1ccsc1NC(=O)c1cc[nH]n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 1H-Pyrazole-3-carbonyl chloride (5 mmol) in MeCN (5 mL) is added drop wise to a solution of 2-amino-thiophene-3-carboxylic acid amide (570 mg, 4 mmol), pyridine (0.5 mL, 6 mmol) and DMAP (25 mg, 0.20 mmol) in MeCN (5 mL). The resulting solution is than stirred at 60° C. over 2 days. Next, the mixture is quenched with aqueous NaHCO3. Evaporation of the MeCN gives a suspension that is filtered, the cake is dried, and used as such.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:37][C:38]1([F:43])[CH2:42][CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C>ClCCl>[F:37][C:38]1([F:43])[CH2:42][CH2:41][N:40]([C:19](=[O:20])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:22])([F:1])[F:23])=[N:4]3)=[CH:17][CH:16]=2)[CH2:39]1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (33 mg, 0.2 mmol). This mixture was allowed to stir at room temperature for 15 minutes. 3,3-difluoropyrrolidine hydrochloride (29 mg, 0.2 mmol) was then added followed by triethylamine (21 mg, 0.21 mmol) and the stirring continued for 1 hour at room temperature. The reaction mixture was reduced to minimum volume under reduced pressure then purified by mass directed auto-prep to give the title compound as a yellow oil (53 mg, 64%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:17]([N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1F)OCC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1F)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A mixture of diethyl trans-4-fluoropiperidin-3-ylphosphoramidate (0.35 g, 1.38 mmol), benzaldehyde (0.21 mL, 2.07 mmol) and acetic acid (0.16 mL, 2.75 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.13 g, 2.07 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-fluoropiperidin-3-ylphosphoramidate (0.47 g, 99%), which was used directly in the next step without purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M29) (216 mg, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (121 mg).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[C:34]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])=[C:33](Cl)[N:32]=[C:31]([N:45]3[CH2:50][CH2:49][N:48]([CH:51]=[O:52])[CH2:47][CH2:46]3)[N:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].Cl>CS(C)=O.O>[C:1]1([CH:7]([NH:9][C:10](=[O:13])[CH2:11][O:12][C:33]2[C:34]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])=[C:29]([NH:28][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[N:30]=[C:31]([N:45]3[CH2:50][CH2:49][N:48]([CH:51]=[O:52])[CH2:47][CH2:46]3)[N:32]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(C=O)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(NC(=O)CO)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCC(=O)NC(C)c1ccccc1
Yield: 33.9 %

Procedure:
N-(1-Phenylethyl)-hydroxyacetamide (50 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (0.56 ml). Sodium (11.5 mg; 0.5 mmol) was added to the solution, and the resultant mixture was stirred at room temperature for two hours. 4-t-Butyl-N-[6-chloro-2-(4-formylpiperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (56 mg; 0.1 mmol) was added thereto, and the resultant mixture was stirred for 1 hour at 120° C., then poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate. The extracted was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), to thereby obtain 23.8 mg (yield: 34%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH2:28][NH2:29]>CO>[CH3:1][O:2][C:3]([C:5]1[N:29]([CH2:28][C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (539 mg) in methanol (10 ml) was added 3,5-dimethoxybenzylamine (1.25 g), and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and 4N hydrogen chloride ethyl acetate solution (5 ml) was added to the obtained residue. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→4/1) to give the title compound (555 mg, 73%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[O:31]=[S:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 79.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (389 mg) described in Preparation Example 145 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 20262, the title compound (353 mg) was obtained.
Reaction SMILES: [ClH:1].Cl.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[O:15])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Cl.[N:27]([O-])=O.[Na+]>O>[ClH:1].[C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][NH2:27])=[CH:21][CH:20]=2)=[O:15])=[CH:11][CH:12]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(CC(=O)NCCc2ccc(N)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(CC(=O)NCCc2ccc(NN)cc2)cc1
Temperature: 0 °C
Yield: 158.6 %

Procedure:
The compound of Section (b) (6.25 g) was suspended in a mixture of water (17 ml) and concentrated hydrochloric acid (8.5 ml). The mixture was cooled in an ice bath and a solution of sodium nitrite (1.39 g) in water (8.5 ml) was added dropwise. The reaction mixture was stirred in the ice bath for 10 min to give a yellow solution with a fine suspension. The suspension was removed by filtration and the filtrate was collected in a cool receiver. The fltrate was poured into a solution of tin (II) chloride (20.6 g) in concentrated hydrochloric acid (8.5 ml) to give a yellow gum, which was removed and dissolved in ethanol (100 ml). The ethanol solution was evaporated in vacuo and re-evaporation with toluene gave a yellow gum. This gum was triturated with ER (250 ml) to give the title compound (9.36 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:13][C:14]1[CH:29]=[CH:28][C:17]3[O:18][CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22](O)[C:16]=3[CH:15]=1)[CH:6]=[CH:5]2.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(F)ccc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(F)ccc4n3)cc21

Procedure:
2-(6-Fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([OH:32])=[O:31])[C:17]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])=[O:14])[C:7](=[O:33])[C:6]=2[CH:34]=1.[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:43](=[O:44])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([OH:32])=[O:31])[C:17]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])=[O:14])[C:7](=[O:33])[C:6]=2[CH:34]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccccc1C(=O)O)CCO2
Reactant: O=C=NCc1ccccc1
Product: O=C(O)C[C@H](NC(=O)CN1CCOc2ccc(NC(=O)NCc3ccccc3)cc2C1=O)C(=O)Nc1ccccc1C(=O)O

Procedure:
Treatment of (S)-2-[2-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-3-carboxy-propionylamino]-benzoic acid with benzylisocyanate as described in Example 1 d), gave (S)-2-[2-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5-H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-carboxy-propionylamino]-benzoic acid as acetate salt: mp. 166° C. (dec.); MS (ISP): 604 (M+1)+.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OCC2C=CC=CC=2)[C@H:7]([CH2:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:6]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)C(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)OC1CC[C@H](N)[C@H](CS(=O)(=O)C(C)C)C1

Procedure:
A sample of benzyl (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylcarbamate (7.73 g, 18.8 mMol) and Pd/C (2 g) were taken in MeOH (250 mL) and stirred at rt under 50 psi hydrogen. After 2.5 h the reaction was filtered through Celite with EtOAc. The resulting solution was concentrated and dried in vacuo to yield (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexanamine as a clear oil which-was used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27](Br)=[CH:26][N:25]=[C:24]([N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH3:30])[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][CH:8]=1)[CH3:2].[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[F:38])=[CH:26][N:25]=[C:24]([N:29]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH3:30])[N:23]=1)[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A suspension of (R)-3-(5-bromo-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester (1.0 eq), 2-fluorophenylboronic acid (3.0 eq), K3PO4 (3.0 eq) and Pd(PPh3)4 (0.03 eq) in DMF under nitrogen was stirred at 90° C. for 5 h. The DMF was evaporated, the residue was dissolved in EtOAc, and the resulting solution was washed successively with 0.5 M citric acid, sat. NaHCO3 and sat. NaCl. The EtOAc extracts were treated with MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel using 6:4 hexanes/EtOAc to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]3=[N:9][C:8]=2[OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:25][C:26]1[N:27]([CH3:31])[N:28]=[CH:29][N:30]=1.[H-].[Na+].C(Cl)Cl>CN(C)C=O>[C:1]1([C:7]2[N:11]3[CH:12]=[N:13][N:14]=[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:10]3=[N:9][C:8]=2[O:22][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1CCl
Reactant: Oc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol (500 mg, 1.74 mmol) and 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (320 mg, 1.91 mmol) in anhydrous N,N-dimethylformamide under an atmosphere of nitrogen was added sodium hydride (153 mg of a 60% dispersion in oil, 3.8 mmol). The reaction mixture was stirred at room temperature for 72 h. The mixture was partitioned between EtOAc (80 ml) and water (150 ml), the organic layer was separated, and the aqueous layer extracted with a further two portions of EtOAc (80 ml). The combined EtOAc layers were washed with saturated NaCl solution (100 ml), separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 2% MeOH in CH2Cl2+0.5% NH3), and the product recrystallised from CH2Cl2 to afford 235 mg (0.6 mmol, 35%) as a white solid. (Found: C, 63.66; H, 4.23; N, 24.54; C21H17N7O.0.5H2O.0.07CH2Cl2 requires C, 63.47; H, 4.59; N, 24.59%); m.p. 179° C. (from CH2Cl2); δH (400 MHz; CDCl3) 3.95 (3H, s, NCH3), 5.75 (2H, s, OCH2), 7.46 (1H, t, J 7.3, aromatic), 7.52-7.60 (5H, m, aromatics), 7.63 (2H, d, J 7.6, aromatics), 7.88 (1H, s, triazole H5), 8.57-8.65 (2H, br m, aromatics), 9.43 (1H, s, imidazotriazine H5); m/z (ES+) 384 (M++H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:27]=[CH:26][C:21]5[N:22]=[C:23]([NH2:25])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:27]=[CH:26][C:21]5[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2ccc(Sc3nnc4ccc(-c5cccc(F)c5)nn34)cc2s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5cccc(F)c5)nn34)cc2s1

Procedure:
The N-(6-{[6-(3-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1, benzothiazol-2-yl)acetamide can be prepared according to the method described in Example 18b, but using 100 mg of 6-{[6-(3-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine in 5 cm3 of pyridine and 0.318 cm3 of acetic anhydride at 50° C. for 4 h. 54 mg of N-(6-{[6-(3-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows: