Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[ClH:2].[ClH:1].[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][S:16][C:15](=[NH:14])[NH2:17]
Reactant: NC(N)=S
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A suspension, kept at 70° C., of 2-chloromethylquinoline hydrochloride (107 g) in ethanol (450 cc) is added dropwise and in the course of 15 minutes to a suspension of thiourea (45.5 g) in boiling ethanol (260 cc). The reaction mixture is stirred for 1 hour 30 minutes at the boil and then cooled to 20° C. The resulting crystals are filtered off, washed twice with ethanol (100 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Quinol-2-yl-methyl)-isothiourea dihydrochloride (141 g), melting at 250° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N[C@@H](CO)C(=O)O)c(O)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:24])[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.CO.[BH4-].[Na+]>C1COCC1>[NH:1]1[C:5]2=[N:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:24])[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: Cc1ncc(C=CC(=O)CCCCc2ccc3c(n2)NCC3)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncc(C=CC(O)CCCCc2ccc3c(n2)NCC3)cn1
Yield: 96.2 %

Procedure:
A solution of the enone 23-8 (0.400 g, 1.24 mmol) in THF:MeOH (5 mL each) was treated with NaBH4 (0.047 g, 1.24 mmol). The reaction was quenched with acetone (2 mL), concentrated in vacuo, partitioned between water (5 mL) and chloroform (5 mL), and extracted with chloroform (4×10 mL). The organics were combined, dried (Na2SO4), and concentrated in vacuo to afford 0.387 g (96% yield) of 23-9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1ccnc(-c2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-phenyl-pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=3)=[O:21])[CH:14]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:35][CH:34]=1)(=[NH:32])=[O:31]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]=[S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=2)([CH3:29])=[O:31])=[O:8])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=2)=[O:21])[CH:14]=1
Reactant: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)cc1
Yield: 41.9 %

Procedure:
In a manner similar to that described in Example 480 (step 6), 6-Amino-5-{3-[(2,5-dimethyl-2H-pyrazole-3-carbonyl)-amino]-phenylethynyl}-nicotinic acid (0.250 g, 0.666 mmol) and methyl 3-(4-(S-methylsulfonimidoyl)-phenyl)propanoate (0.160 g, 0.666 mmol) were reacted to give the title compound (0.167 g, 42%)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[NH2:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([C:37]#[N:38])[CH:30]=[CH:29][C:28]1=2>>[C:37]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]([NH:26][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]1[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=1)(=[O:13])=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:36][CH2:35][CH2:34]2)#[N:38]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: N#Cc1ccc2c(c1)CCCC2N
Product: N#Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid and 5-amino-5,6,7,8-tetrahydro-naphthalen-2-carbonitrile (Step E) by a method similar to that described in Example 1, Step F. MS (−APCI m/z): 508 (M−H)−.
Reaction SMILES: C1(P(=[N:20][C:21]2[C:22](/[CH:27]=[CH:28]/[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:23][CH:24]=[CH:25][CH:26]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:39]=[C:40]([N:44]=[C:45]=O)[CH:41]=[CH:42][CH:43]=1>>[F:36][C:37]([F:47])([F:48])[C:38]1[CH:39]=[C:40]([N:44]=[C:45]=[N:20][C:21]2[C:22](/[CH:27]=[CH:28]/[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ncccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)/C=C/c1ncccc1N=C=Nc1cccc(C(F)(F)F)c1

Procedure:
65 mg (0.14 mmol) of iminophosphorane from Example 11A are reacted by general procedure [B] with 27 mg (0.14 mmol) of 3-trifluoromethylphenyl isocyanate, and the crude product is reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.CCOCC.[Mg].Cl[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1Cl
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1CCCCC1c1ccc(F)cc1
Reaction time: 18 h

Procedure:
The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in 800 ml. of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of ether was added, with cooling to keep the temperature of the reaction less than 15° C., to a solution of 158.4 g of 2-chlorocyclohexanone in 800 ml. of anhydrous benzene. The reaction was stirred at 25° for 18 hrs. then the ether was distilled off and the resulting benzene solution refluxed for 24 hrs. It was then poured into a mixture of 1 liter water and 200 ml. hydrochloric acid and extracted with ether. After evaporation of the ether the residue was distilled to yield 117 g (51%), b.p. 115 (0.2 mm). The material solidified on standing and was recrystallized from hexane, m.p. 56°-59° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.[ClH:11].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[ClH:11].[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:19][NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ncc(C=NNc2ccccc2)c(N)n1
Yield: 99.8 %

Procedure:
In 333 ml of methanol was dissolved 8.6 g of 2-methyl-4-amino-5-formylpyrimidine. To the solution was added gradually 10.6 g of phenyl hydrazine hydrochloride. As the reaction proceeded, crystals precipitated out. Five hours later, the crystals were collected by filtration and dried under reduced pressure to obtain 16.5 g (93%) of 1-(2-methyl-4-aminopyrimidyl)methylidene-2-phenylhydrazine hydrochloride. Physical properties of 1-(2-methyl-4-aminopyrimidyl)methylidene-2-phenylhydrazine hydrochloride are as follows:
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1nn(C)c(=O)cc1Cl
Product: COC(=O)c1nn(C)c(=O)cc1Nc1ccccc1F
Yield: 61 %

Procedure:
The title compound was prepared in 61% yield by the procedure as previously described in Example 166 (step H) using methyl 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (109 mg, 0.54 mmol, prepared as previously described in Example 1 (steps A-G) and 2-fluoroaniline (0.053 mL, 0.54 mmol).
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1([C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:10][O:9][CH2:8][O:7][CH2:6]1.Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[CH:21]1([CH2:20][CH:12]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:11]([C:5]2([CH3:4])[CH2:10][O:9][CH2:8][O:7][CH2:6]2)=[O:18])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Reactant: BrCC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C(=O)C(CC2CCCCC2)n2cncn2)COCOC1
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
2.96 g (0.05 mol) of powdered potassium hydroxide and 3 ml of water are added to a solution of 11.0 g (0.05 mol) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 40 ml of dimethylsulphoxide, with stirring. After 10 minutes, 9.6 g (0.05 mol) of bromomethylcyclohexane (90% pure) are added and the mixture is stirred at 50° C. for 6 hours. For working up, the cooled reaction mixture is poured onto 500 ml of water and extracted twice with 200 ml of diethyl ether each time, the combined ether extracts are washed twice with 100 ml of water each time and dried over sodium sulphate and the solvent is removed in vacuo. The oily residue crystallizes from methylene chloride/diethyl ether. 8.0 g (52.1 g of theory) of 3-cyclohexyl-1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-propan-1-one of melting point 68°-71 ° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[CH:3]=[C:2]([NH:15][CH2:14][CH2:13][NH2:16])[N:7]2[N:8]=1
Reactant: NCCN
Reactant: Cc1cc(Cl)n2nc(C)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NCCN)n2nc(C)cc2n1
Yield: 94.5 %

Procedure:
To a stirred solution of 7-chloro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (3.0 g, 16.5 mmol) in ethanol (60 mL) was added ethylene diamine (4 mL, 60 mmol). After refluxing 18 hours the reaction was cooled, poured into saturated aqueous sodium bicarbonate, and then washed with ethyl acetate. The aqueous layer was then extracted with 3:7 isopropyl alcohol/chloroform, the combined extracts were dried (Na2SO4) and then concentrated under reduced pressure to give the title compound as an amorphous brown solid (3.2 g, 94%): +APcI MS (M+1)+ 206; 1H NMR (methanol-d4) δ: 6.05 (s, 1H), 6.00 (s, 1H), 3.45 (m, 2H), 2.91 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 268 mg (0.92 mmol) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (which can be prepared according to Example 6) in 5 mL of dichloromethane was added 160 μL (1.84 mmol) of oxalyl chloride and two drops of DMF in sequence at room temperature. The mixture was then stirred at the same temperature for about 1 hour. The crude mixture was then concentrated in vacuo. The title material is typically used without additional purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Na].[C:12]([NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=S)#[N:13]>>[NH2:13][C:12]1[N:1]=[C:2]2[N:6]([C:15](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=1)[C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[NH:3]2
Reactant: Nc1nc2ccccc2[nH]1
Reactant: N#CNC(=S)Nc1ccccc1
Agent: [Na]
Product: Nc1nc(=Nc2ccccc2)n2c(n1)[nH]c1ccccc12
Reaction time: 16 h
Yield: 27.8 %

Procedure:
A suspension of 2-aminobenzimidazole (10.0 g) and the sodium salt of N-cyano-N'-phenyl thiourea (7.5 g) was stirred at room temperature for 30 minutes. Mercuric chloride (10.2 g) was added and stirring continued for 16 h. The mixture was filtered and the filtrate evaporated to a gum. A solution of the gum in methanol soon yielded a solid (3.25 g). The solid was collected, suspended in tetrahydrofuran and hydrogen sulphide added until no further black precipitate formed. The mixture was filtered and the filtrate evaporated to give a yellow solid which showed several components on thin layer chromatography. The components were separated on a column of silica gel to give the sub-title compound as white crystals (1.22 g) mp, 271°-3°.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:28]>C(Cl)Cl>[NH2:28][CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: N
Reactant: COc1nc(Cl)ccc1CCO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(Cl)ccc1CCN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.20 g (0.8 mmol) of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine in 10 ml of dry CH2Cl2 cooled to -50° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for 30 min at this temperature and an additional 10 min at -78° C. before a rapid addition of 30 ml of cold (-78° C.) NH3 (l). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford 1.0 g of crude 3-(2-aminoethyl)-6-chloro-2-methoxypyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: C1COCCN1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CN(C(=O)c1cc2c(s1)-c1cc(N3CCOCC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and morpholine were reacted to give 129bp. 1H NMR (400 MHz, CDCl3) δ: 7.27 (m, 1 H), 7.11-7.14 (m, 2 H), 6.90-6.98 (m, 3 H), 6.75 (s, 1 H), 5.09 (s, 2 H), 4.04 (m, 2 H), 3.38 (s, 3 H), 3.32 (m, 2 H). LCMS (ESI) m/z: 442.9
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:17])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:17])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)Cc2ccc(Cl)s2)ccc1N
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccc(N(C)Cc2ccc(Cl)s2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of N(4)-(5-Chloro-thiophen-2-ylmethyl)-2,N(4)-dimethyl-benzene-1,4-diamine (54 mg, 0.20 mmol) and triethylamine (84 μL, 0.60 mmol) in dry tetrahydrofuran (1 mL) was added pentanoyl chloride (36 μL, 0.30 mmol), and the mixture was stirred for 1 hour at room temperature after which it was partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The organic layer was dried over sodium sulfate, volatiles were evaporated, and the residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a white solid (61 mg, 86%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
Heat 101.6 g (0.65 mol) of methyl 4-fluorobenzoate, 66.65 g (0.98 mol) of imidazole, and 182.0 g (1.31 mol) of potassium carbonate in dimethylsulfoxide at ca. 120° C. for about 3 hr. Cool the solution to room temperature and pour into 500 mL of cold water. Filter to obtain crystals of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:30])=[N:21][N:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24][C:23]=23)=[CH:15][C:14]=1[CH3:31]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:30][C:9](=[O:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:21][N:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24][C:23]=23)=[CH:15][C:14]=1[CH3:31]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Cc1cc(C)n2nc(N)c(-c3ccc(Cl)c(C)c3)c2n1
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NC(=O)CCc3ccccc3)c(-c3ccc(Cl)c(C)c3)c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Phenylpropionyl chloride (0.078 mL, 0.53 mmol) was added to a stirring solution of the product from Example 47C (85 mg, 0.296 mmol) in pyridine (5 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under vacuum, and the residue diluted with MeOH (5 mL) and stirred for 30 minutes at room temperature. The mixture was concentrated under vacuum and the residue was crystallized from 80% aqueous ethanol (15 mL) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 2.53 (s, 3H) 2.60-2.69 (m, 2H) 2.66 (s, 3H) 2.87 (t, J=7.6 Hz, 2H) 6.98 (d, J=0.7 Hz, 1H) 7.14-7.32 (m, 5H) 7.38 (d, J=8.5 Hz, 1H) 7.56 (dd, J=8.5, 2.0 Hz, 1H) 7.72 (d, J=1.7 Hz, 1H) 10.21 (s, 1H); MS (ESI) m/z 419/421 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:31])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)Nc4ccccc4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 63.2 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and phenylisocyanate (0.36 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-phenyl-urea as a white solid (0.77 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.38 min (99.57%); mp: 288-290° C.; 1H NMR (DMSO-d6) δ 1.99-2.07 (m, 1H, CHH), 2.44-2.62 (m, 2H, CHH, CHH), 2.82-2.96 (m, 3H, CHH, CH2), 4.47 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.5 Hz, 1H, CH), 6.82-6.93 (m, 2H, Ar), 7.22 (t, J=7.6 Hz, 2H, Ar), 7.40 (d, J=8.0 Hz, 2H, Ar), 7.78-7.91 (m, 3H, Ar, NH), 8.72 (s, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.01, 30.93, 42.62, 48.99, 117.83, 121.26, 121.69, 123.48, 128.64, 129.67, 131.60, 133.21, 140.27, 148.79, 155.28, 167.03, 167.20, 169.83, 172.74; LCMS: MH=407; Anal Calcd for C21H18N4O5+0.2H2O: C, 61.52; H, 4.52; N, 13.66. Found: C, 61.33; H, 4.36; N, 13.46.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>C1COCC1>[Br:12][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:15](=[O:16])[C:14]([F:21])([F:20])[F:13])[CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(O)c1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-amino-1-(3-bromophenyl)propan-1-ol (24) (2.30 g, 10 mmol) in anhydrous THF (20 mL) was added ethyl trifluoroacetate (4.0 mL, 33.5 mmol). The reaction mixture was stirred at room temperature for 3 h, then concentrated under reduced pressure. Purification by column chromatography (10 to 70% EtOAc-hexanes gradient) gave N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (25) as an oil containing ˜15% of 2,2,2-trifluoro-N-(3-hydroxy-3-phenylpropyl)acetamide. Yield (1.96 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.51 (t, J=2.0 Hz, 1H), 7.41 (dt, J=7.6, 2.0 Hz, 1H), 7.25-7.32 (m, 2H), 5.46 (d, J=6.4 Hz, 1H), 4.55-4.60 (m, 1H), 3.20-3.23 (m, 2H), 1.75-1.82 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2N=[N:11][CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].[CH2:16](OC(=O)C1C=CN=C(C)C=1Cl)[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[C:16]([CH3:17])[N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Product: CCOC(=O)c1oc2c(C)nccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 3-chloro-2-methylisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester. Purification by CC (KP-SIL™ from Biotage) using EtOAc/MeOH (8/2) gives the desired product as brown solid;