Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)=[CH:24][C:22]=2[N:23]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)=[CH:24][C:22]=2[N:23]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1ccc2oc(NCCCN)nc2c1
Reactant: N#Cc1ccccc1OCC1CO1
Product: CC1CC(=O)NN=C1c1ccc2oc(NCCCNCC(O)COc3ccccc3C#N)nc2c1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(3-aminopropylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:14][C:15]([NH:17][C:18]1[C:19]([I:33])=[C:20]([CH2:26][CH:27]([CH2:31][CH3:32])[C:28]([OH:30])=[O:29])[C:21]([I:25])=[CH:22][C:23]=1[I:24])=[O:16]>CC#N>[C:28]([CH:27]([CH2:31][CH3:32])[CH2:26][C:20]1[C:19]([I:33])=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:23]([I:24])=[CH:22][C:21]=1[I:25])([OH:30])=[O:29]
Reactant: C1CNCCNCCNCCN1
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCl)c1I)C(=O)O
Solvent: CC#N
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Yield: 7.4 %

Procedure:
According to the procedure described in Example 3, 105.8 g of 1,4,7,10-tetraazacyclododecane (0.62 mol) in 600 ml of CH3CN are added to a suspension of 40 g of 3-[(2-chloro-1-oxoethyl)amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid (prepared as described in Example 1) (0.62 mol) in 500 ml of CH3CN. 35.8 g of N-[3-(2-carboxybutyl)-2,4,6-triiodophenyl]-1,4,7,10-tetraazacyclododecane-1-acetamide (0.046 mol) are obtained.
Reaction SMILES: C(O[C:14]1[CH:40]=[CH:39][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](OCCCCCCCCCCCC)=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1)CCCCCCCCCCC.O.[NH2:42][NH2:43]>C(O)CCCC>[C:17]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N+:42]=[N-:43])[CH:39]=[CH:40][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCC)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCCCCO
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4,4′-dihydroxybenzophenone (21.4 g, 100 mmol), 1-bromododecane (49.8 g, 200 mmol), K2CO3 (50 g) in 500 mL of DMF were heated with stirring at 120° C. for 60 hours. After the mixture was cooled to room temperature, 1 L of water was added. The solution was extracted with CH2Cl2 (4×500 mL). The combined organic layers were dried with MgSO4 and the most of the solvent removed under reduced pressure as a white solid formed. The solids were collected by filtration, washed with cold hexanes, and air dried to give 4,4′-didodecyloxybenzophenone (41.2 g, 75%). A mixture of 4,4′didodecyloxybenzophenone (20.6 g) and hydrazine monohydrate (20 mL) in 150 mL of pentanol were heated at reflux for 24 hours. After cooling to room temperature, a white solid precipitated which is collected by vacuum filtration, washed with 20 mL cold ethanol and air dried (19.4 g, 92%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]=[C:15]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1cncc(OC2CCNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(Oc4cccnc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
A 16 mL vial was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL), 3-(pyrrolidin-3-yloxy)pyridine hydrochloride (64 mg, 0.32 mmol; which may be prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) and HATU (72 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on chromatography column (eluent: dichloromethane/MeOH, 95/5) to give a beige solid. This solid was triturated in acetone and diethyl ether, filtered, washed with acetone and diethyl ether then dried to give the title compound (7.3 mg, 13%) as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([N:13]([CH2:28][C:29]([OH:31])=O)[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:6]([C@@H:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH2:28][N:13]1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCCC[C@@H](Cc1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(S(=O)(=O)c2ccccc2OC(F)(F)F)[C@H](Cc2ccccc2)CCCN1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
To a solution of compound 31l (2.3 g, 5.0 mmol) in DCM (50 mL) was added DIPEA (2.6 g, 20 mmol) and BOP-Cl (1.5 g, 6.0 mmol). The reaction mixture was stirred at rt for 5 h under nitrogen, then 50 mL DCM and 10% citric acid were added to the mixture. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=3:1) to give compound 31m (1.9 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)cc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of 5-chloro-2-hydroxy-3-nitropyridine (15.0 g, 86 mmol) in DMF (200 ml) was cooled down to 0° C. under argon. Then NaH (4.13 g, 103 mmol) was added by portions in 25 min and the reaction mixture was stirred at 0° C. for 1 hour. After that CH3I (8.06 ml, 129 mmol) was added dropwise and the ice-bath was removed. The reaction mixture was stirred at RT for 4 hours. The solution was concentrated and then the slurry mixture was taken in 250 ml water and extracted twice with 300 ml ethyl acetate. The combined organic phases were washed twice with 200 ml brine, dried (Na2SO4) and evaporated to dryness to afford 14.63 g (78 mmol, 90% yield) of the title compound as dark yellow solid. LCMS: (M+H)=189; tR=0.55 min (LC-MS 4). HPLC: tR=1.77 min (HPLC 5). 1H-NMR (d6-DMSO, 400 MHz) δ ppm 8.53 (s, 2H) 3.52 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CN(C)C=O.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32].C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl>[Br:1][C:2]1[C:3]([O:16][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=2[F:32])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc([N+](=O)[O-])cc3F)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (350 mg, 1.23 mmol), N,N-dimethylformamide (10 mL), 1,2-difluoro-4-nitrobenzene (415 mg, 2.61 mmol) and cesium carbonate (1.3 g, 3.99 mmol). The resulting mixture stirred for 3 h at 110° C. After cooling to room temperature, the reaction mixture was poured into dichloromethane (50 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (450 mg, 86%) of as yellow oil. MS (ESI, neg. ion) m/z 421, 423[M−H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:13])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1CO
Solvent: ClCCl
Product: COc1ccccc1CCl

Procedure:
In a nitrogen atmosphere, 2.00 g (14.5 mmol.) of 2-methoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 1.06 ml (14.6 mmol.) of thionyl chloride in 2 ml of dichloromethane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35]>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:30]5[CH2:34][CH2:33][CH2:32][C:31]5=[O:35])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CCCN1
Product: N#Cc1cc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (440 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[C:41]([O:49][C:50]([F:53])([F:52])[F:51])[CH:40]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:45]([C:42]1[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][C:41]=1[O:49][C:50]([F:51])([F:52])[F:53])(=[O:47])=[O:46])[C:6](=[O:11])[C:5]2([N:21]1[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)OCc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)OCc3ccccc3)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 71.7 %

Procedure:
With 2.6 g of the compound obtained in Step 157-3 (Isomer B) and 1.79 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 2.8 g of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:1][CH2:2][CH2:3][NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCCC1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](NCCNC2CCCC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and cyclopentanone following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 458 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[F:47])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[C:27]1([CH2:26][NH:25][C:22](=[O:24])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(F)cc2F)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(F)cc5F)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate (amine intermediate “Q”) were reacted to give the title compound. LC/MS (M+H)+: 671. Ret. time: 2.07 min. (Condition L).
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12].[C:15](=O)([O:21]C(C)(C)C)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(=O)(O)[O-].[Na+].O.O1CCOCC1>[C:17]([O:16][C:15]([NH:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
7-Amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (371 g) is dissolved in a solution of sodium bicarbonate (307 g) in a mixture of distilled water (2 liters) and dioxane (2 liters). A solution of di-tert.-butyl carbonate (421 g) in dioxane (2 liters) is added in the course of 10 minutes. The reaction mixture is stirred for 48 hours at 25° C. The suspension obtained is concentrated under reduced pressure (20 mm Hg) at 50° C. to a residual volume of about 2 liters, and is then diluted with ethyl acetate (1 liter) and distilled water (2 liters). The aqueous phase is decanted, washed with ethyl acetate (500 cc) and acidified to pH 2 with 6 N hydrochloric acid in the presence of ethyl acetate (1500 cc). The aqueous phase is extracted with ethyl acetate (2×1 liter). The combined organic phases are washed with a saturated sodium chloride solution (2×250 cc) and dried over sodium sulphate. After filtration, the solvent is evaporated under reduced pressure (20 mm Hg) at 50° C. 7-tert.-Butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (486 g) is obtained in the form of yellow crystals (m.p.=190° C., with decomposition).
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=[O:14])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[Br:15]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5](=[O:14])[CH:4]3[CH2:3][CH2:2][CH2:1][CH:13]3[C:12]=2[CH:11]=1
Reactant: O=C1Nc2ccccc2C2CCCC12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccc(Br)cc2C2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (374 mg, 2.0 mmol) in DMF (10 ml) is mixed with N-bromosuccinimide (356 mg, 2.0 mmol). After 15 minutes of stirring at room temperature, the batch is heated for 15 minutes to 100° C., diluted with water and extracted with methyl-tert-butyl ether. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is purified on silica gel with ethyl acetate-hexane: 470 mg (88%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(C(=NO)N)[CH2:27][CH2:26]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH:25]4[CH2:27][CH2:26]4)[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)C1CC1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
15 g (43.8 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 6.60 g (65.8 mmol) of cyclopropanecarboxamidoxime and 100 ml of N,N-dimethylformamide are stirred at 70° for 1.5 hours, whereupon the mixture is evaporated to dryness, 100 ml of glacial acetic acid are added to the residue and the solution is heated to 120° for 1.5 hours. The solution is then evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained 7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 183°-184°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:17]=[C:16]([NH2:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>O1CCCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[N:17]=[C:16]([NH2:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: Nc1nc(Cl)nc2ccccc12
Solvent: C1CCOC1
Product: Nc1nc(N2CCOCC2)nc2ccccc12
Yield: 54.2 %

Procedure:
A solution of 7 g of morpholine in 25 ml of tetrahydrofuran was added dropwise to a solution of 7.2 g of 2-chloro-4-aminoquinazoline in 75 ml of tetrahydrofuran. After the addition was completed, the mixture was heated at reflux overnight. The reaction mixture was evaporated to dryness and the residue was recrystallized twice from ethanol to give 5 g of 2-morpholino-4-aminoquinazoline; m.p. 216°-219°. The following analytical data were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.[O:27]1[C@@H:29]([CH2:30][CH3:31])[CH2:28]1>>[OH:27][C@@H:29]([CH2:30][CH3:31])[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[CH:15][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]3)=[CH:17][CH:18]=1)[CH2:6][CH2:5]2
Reactant: CN1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2)CC1
Reactant: CC[C@H]1CO1
Product: CC[C@H](O)COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C)CC3)cc1)C2=O

Procedure:
6-Hydroxy-2-[4-(4-methyl-[1,4]diazepan-1-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one and (S)-(−)-1,2-epoxybutane were reacted according to Method T1. In this way the product was obtained with molecular weight 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:36]([OH:40])(=[O:39])[CH:37]=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)[CH:37]3[C:36]([OH:40])=[O:39])(=[O:15])=[O:14])=[CH:11][CH:12]=2)=[CH:34][CH:35]=1
Reactant: O=CC(=O)O
Reactant: O=S(=O)(NCCc1ccccc1OCCN1CCCCC1)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 52 %

Procedure:
110 mg (0.221 mmol) of 4-(4-fluorophenoxy)-N-{2-[2-(2-piperidin-1-ylethoxy)phenyl]-ethyl}benzenesulfonamide are stirred together with 49.1 μl (0.441 mmol) of glyoxylic acid (50% strength in H2O) in 5 ml of trifluoroacetic acid at room temperature. After standing overnight, the mixture is concentrated in vacuo and the residue is chromatographed on silica gel, resulting in the desired carboxylic acid in a yield of 52%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.8 %

Procedure:
A solution of 3.6 g (0.016 mole) of 3-cyclopentylamino-2,2-difluoro-propanoic acid ethyl ester in 3 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 3.2 g (0.016 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.47 g (0.064 mole) of sodium bicarbonate and 36 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 6.29 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-difluoro-propanoic acid ethyl ester (IV-100) as a yellow thick oil, which contained a small portion of a regioisomer. This material was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 35.0 g, 106 mmol, 1.00 equiv) in methanol (200 mL) at 0-5° C. was added dropwise aqueous sodium hydroxide (12.7 g, 318 mmol, 3.00 equiv in 100 mL water). The resulting mixture was stirred for 3 h at 60° C. After cooling to ambient temperature, the organic solvent was then removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to ˜4 with hydrogen chloride (aqueous, 2 M). The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield 31.0 g (93%) of the title compound as a white solid.