Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:17])[CH2:15][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8])[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Cl)cc1C#N
Yield: 98.2 %

Procedure:
To a solution of 5-chloro-2-hydroxy-benzonitrile (10 g, 65.0 mmol) in acetone (100 mL) was added ethylbromoacetate (11 g, 71.4 mmol) followed by K2CO3 (19.7 g, 143 mmol). After heating at reflux for 10 h, the mixture was filtered and the filtrate was concentrated to afford the desired product (15.3 g), which was used in the next step without further purification. 1H NMR (CDCl3): 7.57 (d, J=2.5 Hz, 1H), 7.48 (dd, J=9.0, 2.5 Hz, 1H), 6.81 (d, J=9.0 Hz 1H), 4.78 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: CC1(C)[O:7][C:6](=O)[CH:5]=[C:4]([CH3:9])[O:3]1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14]>>[O:3]=[C:4]([CH3:9])[CH2:5][C:6]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:7]
Reactant: OCC(F)(F)F
Reactant: CC1=CC(=O)OC(C)(C)O1
Product: CC(=O)CC(=O)OCC(F)(F)F

Procedure:
The title compound is prepared in analogy to example 3 (stage 3a) starting from 2,2,6-trimethyl-1,3-dioxin-4-one and 2,2,2-trifluoroethanol.
Reaction SMILES: NC1(C[O:8]C2C=CC(C#N)=CC=2)CCCC1.[C:17]([O:21][C:22](=[O:39])[NH:23][C:24]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#N)=[CH:33][CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:39])[NH:23][C:24]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]=[O:8])=[CH:33][CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C#N)cc2)CCCC1
Reactant: N#Cc1ccc(OCC2(N)CCCC2)cc1
Product: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1

Procedure:
Synthesized from 4-(1-aminocyclopentylmethoxy)benzonitrile according to an analogous synthetic method to Preparation Example 19, tert-butyl[1-(4-cyanophenoxymethyl)cyclopentyl]carbamate (1.0 g) was used according to an analogous synthetic method to Preparation Example 20 to provide the title compound (688 mg).
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15](F)[N:14]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([NH:29][C:15]1[C:16]([F:20])=[CH:17][C:18]([F:19])=[C:13]([NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])[N:14]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Nc1nc(F)c(F)cc1F
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 160 °C
Reaction time: 24 h
Yield: 119.2 %

Procedure:
To 20 ml of N-methylpyrrolidone were added 9.7 g of 2-(t-butylamino)-3,5,6-trifluoropyridine together with 15.5 g of benzylamine, and the mixture was stirred at 160° C. for one day and allowed to cool. After adding 50 ml of chloroform, the mixture was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about 16.5 g of the title compound as a dark green oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:19][C:13]=2[N:12]=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][S:28]([CH:25]2[CH2:27][CH2:26]2)(=[O:30])=[O:29])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:19][C:13]=2[N:12]=1
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(N4CCCC4)ccc3[nH]2)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(NCc1ccc(Cl)c(Nc2nc3cc(N4CCCC4)ccc3[nH]2)c1)C1CC1
Reaction time: 8 h

Procedure:
A TEA solution (0.35 M in DMF, 0.1 mL) was added to a 4-Chloro-3-[5-(pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine solution (0.12 M in MeCN, 0.1 mL, prepared in analogy to example 4d) followed by a cyclopropylsulfonyl chloride solution (0.12 M in MeCN, 0.1 mL). The mixture was stirred overnight and filtered through basic alumina. The solids were washed with DMF/MeOH 9:1 and the combined filtrates were concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[O:15]=[C:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[O:22][C:23](ON1C(=O)CCC1=O)=[O:24]>C(#N)C>[O:15]=[C:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[O:22][C:23]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12])=[O:24]
Reactant: COC(=O)n1ncc2c(N)cccc21
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 4-amino-1H-indazole-1-carboxylate (1.9 g, 10 mmol) and 1-({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (2.8 g, 11 mmol) were combined in acetonitrile (100 mL), stirred for 48 hours at ambient temperature, and filtered. The filter cake was washed with acetonitrile (10 mL) and dried under reduced pressure at ambient temperature to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].O.[C:26]([O:30][C:31]([NH:33][C@@H:34]([C:39](O)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])([CH3:29])([CH3:28])[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:37][CH:36]([CH3:38])[CH2:35][C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[C:39](=[O:40])[NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24]
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(−)-3-Amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg) was dissolved in N,N-dimethylformaldehyde (5 mL), and to the solution were sequentially added N-tert-butoxycarbonyl-D-leucine monohydrate (382 mg), 1-hydroxybenzotriazole (207 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (294 mg) under cooling on ice, followed by stirring at room temperature for one hour. The resultant mixture was extracted with ethyl acetate and water, and the organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (chloroform:methanol=50:1), whereby the title compound (832 mg) was yielded.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(OC(C)C)O[CH:10]([CH3:12])[CH3:11].C(O)(C)C.O.S([O-])(O)(=O)=O.[Na+]>>[CH:10]([O:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)([CH3:12])[CH3:11]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC1=CCCCC1
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a mixture at room temperature containing 196.32 grams (2 mol) of cyclohexanone, 390.4 grams (2.06 mol) of triisopropyl orthoformate and 12.00 grams of isopropanol (0.2 mol), was added 7.6 grams (0.055 mol) of sodium hydrogensulfate monohydrate. The reaction was exothermic and upon addition of the catalyst, the temperature of the reaction mixture rose to 35° C., and was heated and maintained at 60° C. for 1 hour. The progress of the reaction was monitored by GC until the cyclohexanone content dropped to less than 2%. The isopropanol and isopropyl formate were distilled off under reduced pressure until the reaction mixture's temperature reached a maximum of 100° C. The reaction mixture was cooled to room temperature and filtered to remove sodium hydrogensulfate monohydrate (recovered). The pH value of the filtrate was adjusted to about 7˜8 by adding 0.8 gram of potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cyclohexanone. The product, 1-isopropoxy-1-cyclohexene was isolated by distillation as a clear liquid; the yield was 81.7% with a purity exceeding 98%.
Reaction SMILES: [CH2:1]([N:3]([CH3:7])[C:4]([NH2:6])=[O:5])[CH3:2].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1>[CH2:1]([N:3]([CH3:7])[C:4]([NH:6][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])=[O:5])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCN(C)C(N)=O
Solvent: C1COCCO1
Product: CCN(C)C(=O)NC(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 65.1 %

Procedure:
In 50 ml of anhydrous dioxane, 7.7 g (0.075 mole) of 1-ethyl-1-methyl-urea was dissolved, into this solution 8.9 g (0.075 mole) of phenylisocyanate was added dropwise under stirring condition. The reaction was continued at a room temperature for 15 hours, then the precipitate thus formed was obtained by filtration and recrystallized from ethanol to obtain 10.8 g (yield 65%) of 1-ethyl-1-methyl-5-phenylbiuret having a melting point of 157°-159° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, heptanoyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide (0.49 g, 66%) as a white solid: mp 130-132° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.44 (t, J=5.7 Hz, 1H), 7.86-7.78 (m, 2H), 7.71-7.65 (m, 1H), 5.19-5.12 (dd, J=5.2 and 12.4 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 2.98-2.83 (m, 1H), 2.64-2.50 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08-2.04 (m, 1H), 1.53 (t, J=6.0 Hz, 2H), 1.25 (s, 6H), 0.85 (t, J=5.9 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 172.66, 169.79, 167.47, 166.93, 139.54, 134.66, 133.13, 131.50, 127.06, 121.80, 54.86, 48.85, 37.57, 35.23, 30.96, 28.31, 25.16, 21.97, 13.87; Anal. Calcd. For C21H25N3O5+0.3H2O: C, 62.30; H, 6.37; N, 10.38. Found: C, 62.07; H, 6.29; N, 10.23.
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:40]([C:36]1[S:35][C:34]([N:31]2[CH2:32][CH2:33][N:29]([CH2:28][C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=3)[C:30]2=[O:43])=[N:38][C:37]=1[CH3:39])=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 16 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 16% yield: mp 192-193° C.; 1H NMR (300 MHz, CDCl3) δ 7.37-7.21 (m, 7H), 7.04-6.98 (m, 2H), 5.95 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.3, 157.2, 155.3, 152.9, 137.9, 133.8, 131.3, 129.9, 128.7, 127.7, 117.3, 115.9, 47.2, 44.0, 42.0, 41.6, 17.2; MS (ES+) m/z 425.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:5][N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])[CH2:4][O:3]1.Cl[C:13]1[NH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[N:17]=1.C([O-])(=O)C.[Na+].[H-].[Na+]>C(O)C>[CH3:1][C:2]1([CH2:5][N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])[O:3][C:13]2=[N:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][N:14]2[CH2:4]1
Reactant: CC1(CN2CCOC2=O)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC1(CN2CCOC2=O)Cn2cc([N+](=O)[O-])nc2O1
Yield: 31.5 %

Procedure:
A mixture of 3-(2-methyloxiran-2-ylmethyl)-oxazolidin-2-one (2.87 g, 18.23 mmol), 2-chloro-4-nitro-1H-imidazole (2.7 g, 18.23 mmol), sodium acetate (1.64 g, 20.05 mmol) and ethanol (30 ml) was stirred under reflux for 10 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, methylene chloride was added, and the resulting solution was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (50 ml). To the solution, sodium hydride (610 mg, 15.25 mmol) was added followed by stirring under reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)oxazolidin-2-one (1.54 g, yield 40%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[C:12](=[O:21])[N:13]([CH3:20])[N:14]=[C:15]([CH3:19])[C:16]=2[O:17][CH3:18])[CH:3]=1.C([O-])(O)=O.[Na+].C(Cl)[Cl:28]>>[CH3:18][O:17][C:16]1[C:15]([CH3:19])=[N:14][N:13]([CH3:20])[C:12](=[O:21])[C:11]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[C:3]1[Cl:28]
Reactant: ClCCl
Reactant: COc1c(C)nn(C)c(=O)c1-n1cc(Br)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1c(C)nn(C)c(=O)c1-n1c(Cl)c(Br)c2ccccc21
Reaction time: 0.08 h
Yield: 87 %

Procedure:
A solution of SO2Cl2 (47 μl, 0.583 mmol) in DCM (2 mL) is added dropwise to a solution of 4-(3-bromoindol-1-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (203 mg, 0.583 mmol) in DCM (6 mL) at 0° C. The solution went pale yellow. After stirring for 5 min the cooling bath is removed and the resulting reaction mixture stirred at ambient temperature for 2 h. The reaction mixture is shaken well with a solution of NaHCO3. The layers are separated and the aqueous layer extracted with DCM (3×20 mL). The combined DCM layers were filtered through MgSO4 and concentrated in vacuo. The resulting solid was purified by flash chromatography (combiflash, 0 to 10% DCM/EtOAc) to yield the desired product 5-methoxy-2,6-dimethyl-4-(2-chloro-3-bromoindol-1-yl)pyridazin-3-one (194 mg, 0.507 mmol, 87% Yield).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:80])[CH2:77][CH2:78][NH2:79]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:79][CH2:78][CH2:77][N:76]([CH3:80])[CH3:75])=[O:28])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(F)c1
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.243 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0605 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-fluoro-benzamide (I-226) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]Cl)=[CH:16][CH:15]=1>CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmole) was dissolved in 35 ml. of methylene chloride. p-Chlorobenzenesulfenyl chloride (4.0 g., 22 mmoles) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred at room temperature for 1 hour. Two volumes of ether were added, the mixture extracted twice with 20 ml. portions of water and the organic layer evaporated in vacuo. The resulting oil was chromatographed on 100 g. of silica gel with approximately 25 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 19 to 36 were combined and concentrated to yield methyl 5-(4-chlorophenylthio)pyrrole-3-carboxylate (1.4 g., m.p. 122°-124° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH2:15][CH2:16][OH:17]
Reactant: N#Cc1cccc(CBr)c1
Reactant: OCCNCCO
Product: N#Cc1cccc(CN(CCO)CCO)c1

Procedure:
The title compound was prepared following the general procedure 10, starting from 3-(bromomethyl)benzonitrile and diethanolamine. It was obtained as a colorless oil (820 mg, 73%). LC/MS (Method B): 219.1 (M−H)−, 221.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].COCOC.C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCOC
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 94.7 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 1.75 g (6.01 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2.5 mL (47.5 mmol) of acetonitrile, 13.5 mL of methylal (dielectric constant at 20° C.: 2.7), and 0.56 g (10.3 mmol) of sodium methoxide. The content was reacted at 41° C. for 9 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with two portions of saturated aqueous sodium chloride solution (10 mL), the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.79 g (yield: 96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH:21]1([CH2:26][CH2:27]Br)[CH2:25][CH2:24][CH:23]=[CH:22]1>>[CH:21]1([CH2:26][CH2:27][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24][CH:23]=[CH:22]1
Reactant: BrCCC1C=CCC1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CCC2C=CCC2)c1
Yield: 35.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-(cyclopent-2-en-1-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound (132 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12][CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])([OH:3])=O.N#N>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[CH2:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:12][C:13]3([C:1](=[O:3])[C:4]=2[CH:9]=1)[CH2:18][CH2:17][O:16][C:14]3=[O:15])[CH3:11]
Reactant: CCc1ccc(SC2CCOC2=O)c(C(=O)O)c1
Agent: N#N
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCc1ccc2c(c1)C(=O)C1(CCOC1=O)S2

Procedure:
A mixture of α-[(2-carboxy-4-ethylphenyl)thio]-γ-butyrolactone (1.0 g) in acetic anhydride (30 ml) and triethylamine (6 ml) was heated at 130° C. for 30 minutes under a stream of N2 gas with stirring. The mixture was evaporated in vacuo. The resulting residue was submitted to column chromatography on silica gel (20 g) and charcoal (5 g) eluting with CHCl3 to give 5-ethyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as colorless oil. Anal. Calcd. for C13H12O3S: C, 62.88; H, 4.87. Found: C, 62.83; H, 4.83.