Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=12>C(Cl)Cl>[N+:12]1([O-:9])[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=12
Reactant: c1cnc2c(c1)CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
mCPBA (10.0 g, 44.6 mmol) was added slowly to a mixture of 6,7-dihydro-5H-cyclopenta[b]pyridine (from Aldrich, 5.0 g, 42 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was then washed with aq. Na2S2O3 (50 mL) and 1 M NaOH (50 mL). The aqueous layer was extracted with DCM (5×70 mL). The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (4.5 g, 79%). LCMS calc. for C8H10NO (M+H)+: m/z=136.1. Found: 136.2.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH3:11])[CH2:8][CH2:9][CH3:10])(=O)=O.C(O)C.[SH:15][C:16]1[S:17][C:18]([NH2:21])=[N:19][N:20]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:11][CH:7]([CH2:8][CH2:9][CH3:10])[CH2:6][S:15][C:16]1[S:17][C:18]([NH2:21])=[N:19][N:20]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCC(C)COS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCC(C)CSc1nnc(N)s1
Temperature: 25 °C

Procedure:
A three-necked 3-L round bottom flask was charged with 2-methylpentyl methanesulphonate (90 g, 0.5 mol), ethanol (1.5 L) and 2-mercapto-1,3,4-thiadiazole-5-amine (66.5 g, 0.5 mol). Sodium hydroxide (20 g, 0.5 mol) was added to the stirred suspension. The mixture was heated to reflux and held at reflux over night. As the mixture warmed the cream suspension gradually dissolved. Just before refluxing began a cloudy precipitate formed. The reaction mixture was cooled to room temperature, filtered, and the residue was washed well with ethanol. The resulting filtrate was concentrated to dryness to give an off-white solid that was dissolved in ethyl acetate (1.2 L) and washed with 1) water (800 mL) and 2) brine (1 L). The filtrate was dried (MgSO4) and concentrated to dryness. An off-white solid was obtained that was recrystallised from boiling acetonitrile (150 mL). The filtered material was washed well with acetonitrile and dried (Vac/40° C.). The required product was obtained as a white solid wt 83 g; 76.5%.
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][C:17]([C:19]2[C:20]([F:32])=[C:21]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=2)=O)[CH:13]=[CH:12][N:11]=1.[NH2:33][C:34](=[S:46])[C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:37])[CH3:36]>ClCCl.CCOC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[S:46][C:34]([C:35]([NH:38][C:39]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:45])([CH3:37])[CH3:36])=[N:33][C:17]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
N-Bromosuccinimide (0.763 g, 4.29 mmol) was added to a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (1.5 g, 4.29 mmol) in dichloromethane (DCM) (50 mL). After 1 h of stirring, 1,1-dimethylethyl (2-amino-1,1-dimethyl-2-thioxoethyl)carbamate (0.936 g, 4.29 mmol) was added to the reaction mixture and heated to 80° C. for 2 h. The reaction mixture was diluted with 150 cc of EtOAc and washed with water (5×100 cc). The EtOAc layer was dried over MgSO4 and filtered and concentrated in vacuo. The residue was purified via chromatography on silica gel using Hex to 25% EtOAc in Hex to obtain the title compound (1.28 g, 54% yield). MS (ESI): 548.3 [M+H]+
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[CH2:14]([O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COc1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (5.26 g, 140 mmol) was washed with hexane and the hexane was removed. To the washed sodium hydride was added 75 mL of anhydrous DMF. The resultant slurry was well stirred and 21.38 g (140 mmol) of 2-hydroxy-3-methoxy benzaldehyde (commercially available from Aldrich Chemical Company) was added dropwise, over a period of 45 minutes. The mixture was stirred at 50° C. for 1 h and then 16.2 mL (140 mmol) of benzyl chloride was added in one portion. The reaction mixture was stirred at 50° C. for 3 days and then allowed to slowly (overnight) cool to ambient temperature and the reaction was quenched with 60 mL of 10% aqueous hydrochloric acid solution. The mixture was extracted with 3×250 mL of ethyl acetate and the combined ethyl acetate extracts were washed with 250 mL of aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with ethyl acetate:hexane (1:9 v/v) to give 26.39 g (77.5%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[N:29]#[C:30]Br.[OH-].[Na+]>ClCCl.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:30]([NH2:29])=[N:28][C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cn1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine (3.82 g, 7.77 mmol) in dichloromethane (40 mL) and methanol (20 mL) was added cyanogen bromide solution (5.0 M in acetonitrile, 7.8 mL, 38.87 mmol). The resulting brown reaction mixture was allowed to stir at room temperature. After 18 h, the mixture was treated with 1N sodium hydroxide solution (50 mL) and allowed to stir. After 30 min, the phases were separated, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 5.26 g of a brown semi solid. Chromatographic purification (Combi-Flash, 80 g SiO2 column, 5-10% methanol/dichloromethane elute) afforded 2.78 g (69%) of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine as a brown solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[S:5]1[CH:6]=[CH:2][C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2
Reactant: Brc1csc2ccccc12
Agent: Oc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: c1ccc2sccc2c1
Yield: 28 %

Procedure:
To a solution of 3-bromo-benzo[b]thiophene (69.62 g, 0.325 mol) in 55 mL of anhydrous collidine under N2 was added 4-benzyloxyphenol (97.6 g, 0.488 mol) and cuprous oxide (23.3 g, 0.163 mol). The mixture was heated to reflux for 24 hours. Upon cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and the crude mixture filtered through a pad of Celite® (Aldrich, Milwaukee, Wis.) to remove inorganic salts. The filtrate was washed with 1N hydrochloric acid (3×150 mL). The organic was dried (sodium sulfate) and concentrated in vacuo to a liquid. Thianaphthene was removed by distillation (10 mm Hg, 115-120° C.). The remainder of the material was chromatographed (silicon dioxide, hexanes:ethyl acetate 85:15) to provide 12.2 g of benzo[b]thiophene and 12.95 g (35% based on recovered starting material) of [3-(4-benzyloxy)phenoxy]benzo-[b]thiophene as an off-white solid. mp 84-86° C. 1H NMR (CDCl3) d 7.91-7.83 (m, 2H), 7.47-7.34 (m, 7H), 7.04 (q, JAB =9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H). Anal. Calcd. for C21H16O2S: C, 75.88; H, 4.85. Found: C, 75.75; H, 5.00.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:5][C:6]=1[CH3:7].Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:37]=[C:38]([Cl:40])[N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH2:26][CH2:25]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:31]=[C:32]([CH:37]=[C:38]([Cl:40])[N:39]=3)[C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:29]2)=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (intermediate 17, 1.81 g, 4.90 mmol) and TEA (682 μl, 4.9 mmol) were added to methyl 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinate hydrochloride salt (Intermediate 93; 1.5 g, 4.90 mmol) in anhydrous DMA (10 ml). The mixture was stirred at room temperature 18 h then partitioned between EtOAc and water. The organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The solid material was purified by flash chromatography eluting with EtOAc/n-hexanes mixture (7:3) to give the title compound as a brown solid (1.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:36])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53])=[N+](C)C)C>>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:36])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([O:34][N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)NCCCOCCOCCOCCCNC(=O)CCC(=O)O
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCC(=O)NCCCOCCOCCOCCCNC(=O)CCC(=O)ON1C(=O)CCC1=O

Procedure:
7-[3-(2-{2-[3-(3-Carboxypropionylamino)-propoxy]-ethoxy}-ethoxy)-propylcarbamoyl]-heptanoic acid tert-butyl ester (0.78 g, 1.46 mmol) was activated by means of TSTU as described in example 8 step 4. Crude yield 360 mg, LCMS Method 6: Rt 4.40 min; m/z (M+1) 630; Calcd.: 630. The compound was used without further purification.
Reaction SMILES: [N:1]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:2]=[N-:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:9][C@H:5]1[C@H:4]([N:1]=[N+:2]=[N-:3])[NH:7][C:6]1=[O:8]
Reactant: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1N

Procedure:
To a solution 1.3 g of (3S,4S)-4-azido-3-tritylamino-2-oxoazetidine in 15 ml of acetone is added 0.736 g of p-toluenesulfonic acid monohydrate. The mixture is treated in a same manner to Reference Example 45B to give 0.886 g of tosyl salt of (3S,4S)-3-amino-4-azido-2-oxoazetidine.
Reaction SMILES: [Br:1][C:2]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[C:14](OC)([O:18][CH3:19])([O:16][CH3:17])[CH3:15].C(O)(=O)C(C)C>>[Br:1][C:2]([Cl:13])([C:9]([F:10])([F:11])[F:12])[CH:3]([O:8][C:14]([O:18][CH3:19])([O:16][CH3:17])[CH3:15])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Reactant: COC(C)(OC)OC
Solvent: CC(C)C(=O)O
Product: COC(C)(OC)OC(C=C(C)C)C(Cl)(Br)C(F)(F)F
Temperature: 111 °C

Procedure:
5-Bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (10.0 g), trimethyl orthoacetate (48.0 g) and isobutyric acid (0.29 g) were charged to a round-bottomed flask fitted with: nitrogen inlet/bubbler, thermometer and Dean and Stark received packed with 5 A molecular seives. The mixture was heated with agitation to reflux and distillates collected until reaction mass temperature increased to 111° C. (ca. 1 hr). Once the reaction was complete, the residual trimethyl orthoacetate was removed by distillation under vacuum (ca. 50° C. @50 mmHg) to give the product, 5-bromo-5-chloro-4-(1,1-dimethoxyethoxy)-2-methyl-6,6,6-trifluorohex-2-ene, as an orange oil (10.9 g, 85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Reaction time: 0.58 h

Procedure:
To 3-bromo-4-methoxyphenylacetic acid (24 g, 97.9 mmol) in EtOH (240 mL) was added thionyl chloride (7.8 mL, 107.7 mmol), and the reaction was stirred for 35 minutes. Once no starting material was seen by analytical LCMS, the mixture was quenched with NaHCO3 until the solution was basic, and then extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Br:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:53]=2)[NH:48][C:47]=1[C:63](O)=[O:64].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:53]=2)[NH:48][C:47]=1[C:63]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:64]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Br)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
HATU (0.231 g, 0.608 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.126 g, 0.405 mmol), 3-bromo-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.144 g, 0.405 mmol) and diisopropylethylamine (0.106 mL, 0.608 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.086 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (br. s., 1H), 9.27 (br. s., 1H), 8.45 (br. s., 1H), 7.66-7.84 (m, 2H), 7.38-7.56 (m, 4H), 7.17-7.34 (m, 2H), 4.57 (d, 2H), 1.14-1.62 (m, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[I:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(N(CC)CC)C>CCOC(C)=O>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[I:21])[C:3]1=[O:20]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)c2ccccc2I)N=C(c2ccccc2)c2ccccc21
Reaction time: 1 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, o-iodobenzoylchloride and triethylamine were mixed at room temperature and stirred 1 hour. Flash chromatography of the reaction solution on silica gel (5% Et2O in CH2Cl2) provided the title compound as a crystalline solid from EtOAc: m.p. 115°-120° C. (physical change), 173°-175° C. (melt).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][CH:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])=[CH:23][CH:22]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-fluorobenzoyl chloride. LCMS: RT=1.54 minutes, MS: 382 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=2)[CH2:20][CH2:19]1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[N:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[N:29][CH:28]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCN(c2ncc(N)cn2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Yield: 68.6 %

Procedure:
A N,N-dimethylformamide solution (1.6 mL) of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (254 mg, 0.77 mmol), and 2-(4-methyl-piperazin-1-yl)-pyrimidin-5-ylamine (157 mg, 0.813 mmol) is heated at 90° C. for 40 min. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 259 mg (65%) of the title compound as a yellow solid. MS (ESI) m/z 491 (M+H)+1
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2ncccn2)C1
Yield: 66.5 %

Procedure:
A solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (120.7 mg), 2-chloropyrimidine (40.5 mg) and potassium carbonate (46.5 mg) in ethanol (3 mL) was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (97.8 mg).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:15][CH2:14][C:13]2=[O:29])[CH2:8][CH2:7]1)=O)C.S1CCCC1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[C:23]1([C:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:13](=[O:29])[CH2:14][N:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCSC1
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1C1CCNCC1
Temperature: 110 °C
Yield: 106.1 %

Procedure:
To a solution of 1 g (2.6 mmol) of 12 in 1.1 ml (2.6×5 mmol) of tetrahydrothiophene is added 2 ml of methanesulfonic acid, and the mixture is heated at 110° C. (bath temperature) for 50 minutes. The reaction mixture is poured into ice water and shaken with ether. The aqueous layer is besified with aqueous potassium carbonate and extracted with methylene chloride. The methylene chloride layer is concentrated, and the residue is dissolved in 1 ml of methanol and mixed with 0.27 ml of 48% hydrobromic acid. The resultant crystals are recrystallized from methylene chloride-methanol to give 881 mg of 13 as crystals melting at 281°-283° C. (dec.). The yield is 86%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH:23](O)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>ClCCl.O>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(=O)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
1-Acetyl-4-piperidinone (77 g) was dissolved in dichloromethane (300 ml), and trimethylsilyltrifluoromethanesulfonate (200 ml) and benzhydrol (92 g) were added thereto with stirring under ice-cooling. The mixture was allowed to stand at room temperature overnight, and then water (500 ml) and sodium acetate (50 g) were added thereto and the reaction mixture was vigorously stirred. The dichloromethane layer was preparatively separated, washed with an aqueous sodium bicarbonate solution, dried, and then the solvent was evaporated under reduced pressure. The residue was treated with ethyl ether to obtain 1-acetyl-3-benzhydryl-4-piperidinone as colorless crystals (132.6 g, 86%).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[NH:10][N:9]=1)([CH3:3])[CH3:2].[NH2:19][C:20]([CH:24]([F:26])[F:25])=[CH:21][C:22]#[N:23]>C(O)(=O)C.C1COCC1>[F:25][CH:24]([F:26])[C:20]1[NH:19][C:20]([CH:24]([F:26])[F:25])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:21]=1[C:22]#[N:23]
Reactant: CC(C)OCCOc1n[nH]c2ccc(C=O)cc12
Reactant: N#CC=C(N)C(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)OCCOc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Temperature: 25 °C

Procedure:
80 mg (0.32 mmol) 3-(2-isopropoxyethoxy)-1H-indazole-5-carbaldehyde (Example 32A), 84 mg (0.71 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] and a small amount of powdered 4 Å molecular sieve in acetic acid (310 μl) were heated to 115° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to give 85 mg (59% of th.) of the title compound.