Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:17])=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[C:9]([CH:25]=[O:26])[NH:8][C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(CCCN(C)C)c[nH]c1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN(C)C
Yield: 96 %

Procedure:
4-(3-Dimethylamino-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (600 mg, 2.5 mmol) was formylated using phosphorus oxychloride and dimethylformamide to give 645 mg (96% yield) of 4-(3-dimethylamino-propyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 12.15 (br s, 1H, NH), 9.59 (s, 1H, CHO), 4.19 (q, 2H, OCH2), 2.93 (m, 2H, CH2), 2.41 (s, 3H, CH3), 2.18 (m, 2H, CH2), 2.09 (s, 6H, N(CH3)2), 1.63 (m, 2H, CH2), 1.27 (t, 3H, CH3). MS m/z 266 [M+].
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H][H]>[Pd].CO>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Yield: 96.2 %

Procedure:
20 mg of 10% w/w palladium on charcoal was added to a solution of 100 mg of benzyl 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylate, as obtained in Example 51, in 5 ml each of methanol and of tetrahydrofuran. The reaction mixture was stirred for 3 hours under a stream of hydrogen gas at room temperature, filtered to remove the catalyst, and concentrated by evaporation under reduced pressure. The resulting residue was recrystallized from ethyl acetate and hexane, to yield 75 mg of the title compound, melting at 189°-190° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[O:10]1[C:14]2[CH:15]=[C:16]([C:19]([NH:21][C@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23](O)=[O:24])=[O:20])[CH:17]=[CH:18][C:13]=2[O:12][CH2:11]1>>[CH3:28][CH:27]([CH3:29])[CH2:26][C@@H:22]([NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][O:10][C:14]=2[CH:15]=1)=[O:20])[C:23](=[O:24])[NH:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[C@@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)O
Reactant: NCCc1cccnc1
Product: CC(C)C[C@@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)NCCc1cccnc1

Procedure:
Prepared in a similar manner to example 13 using 2-(3-pyridyl)ethylamine and (R)-2-(benzo[d][1,3]dioxole-6-carboxamido)-4-methylpentanoic acid (example 13a). (MS M+384.2).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C

Procedure:
A solution of 3.0 g (0.017 mol) L-Leucine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.05 ml (0.029 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred ten minutes, filtered and concentrated at reduced pressure. The oil is dissolved in 17 ml of dichloromethane and the following is added in a single addition: 4.35 g (0.021 mol) of dicyclohexylcarbodiimide; 100 mg (0.0008 mol) of 4-dimethylaminopyridine; 2.66 g (0.017 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 20 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 93:7 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 50 ° C. yields crystalline analytically pure (as a 0.33 hydrate) N-[1-oxo-3-(5-oxo-2-pyrrolidinyl) propyl]-L-leucine, methyl ester with a melting point of 70°-74.5° C.
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl.CCOCC.Cl>CCOCC.CCO>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1)[CH2:13]2)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A mixture of 22 g (0.048 mole) of ethyl 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoate, 86 mL of 3N NaOH and 200 mL of EtOH was refluxed for 1 h. After cooling the mixture was made acidic with conc. HCl. The solvent was decanted away from the gum which formed. The gum was titurated with Et2O and Et2O/HCl and was placed into a drying oven overnight at 45° C. to yield 19.2 g of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoic acid; mp. 285-290° C. MS m/z (MH+) 425. 1H NMR δ 7.9 (d, 2H); 7.4-7.2 (ar, 12H); 3.7 (bs, 2H); 3.0 (bs, 4H); 2.8 (bd, 2H); 2.2 (t, 2H); 2.0 (m, 2H); 1.65 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)C=C.[CH2:15](OC1C=C(C=CC=1)CCl)[CH:16]=[CH2:17].OC1C=C(NC(=O)C)C=CC=1>O(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[CH2:17]([C:10]1[CH:9]=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[OH:4])[CH:16]=[CH2:15]
Reactant: C=CCOc1cccc(CCl)c1
Reactant: C=CCOc1cccc(NC(C)=O)c1
Agent: CC(=O)Nc1cccc(O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: C=CCc1ccc(NC(C)=O)cc1O

Procedure:
A mixture of N-(3-allyloxyphenyl)acetamide (13.2 g) prepared by a similar method to that of Example 2, Footnote c (A), from N-(3-hydroxyphenyl)acetamide, in Ph2O (100 ml) was heated at 250° C. for 10 minutes, cooled and diluted with hexane (100 ml) to give crystals. The crystals were re-crystallised from ethyl acetate. The liquors were evaporated and dissolved in 0.2M aqueous NaOH, filtered though Celite, and acidified with 1M aqueous HCl solution to give N-(4-allyl-3- hydroxyphenyl)acetamide (3.6 g) mpt. 164°-165° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(=O)(O)[O-].[Na+].[CH2:11]([C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1)[CH3:12].O>ClCCl>[Br:1][CH2:2][C:3]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][C:16]2[CH:24]=[CH:25][C:13]([CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH2:19][CH2:20]1)=[O:4]
Reactant: CCc1ccc(OC2CCNCC2)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(OC2CCN(C(=O)CBr)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.7 %

Procedure:
To a stirred suspension of 6.03 ml (69.3 mmol) of bromoacetyl bromide, 13.0 g (155 mmol) of sodium bicarbonate and 160 ml of dry dichloromethane in an ice bath was added dropwise a solution of 13.0 g (63.4 mmol) of 4-(4-ethylphenoxy)piperidine in 140 ml of dry dichloromethane. The mixture was stirred 1 hour at 0° and 45 minutes at room temperature. The mixture was subsequently poured into water, extracted twice with dichloromethane, washed with saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided 20.0 g (61.3 mmol) of 1-(2-bromoacetyl)-4-(4-ethylphenoxy)piperidine as an oil.
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1COCC1>[CH:1]1([C:7](=[S:19])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCCCC1
Solvent: C1CCOC1
Product: NC(=S)C1CCCCC1
Yield: 78.7 %

Procedure:
Cyclohexanecarboxamide (1 g, 7.86 mmol) and Lawesson's Reagent (2 g, 4.94 mmol) in THF (50 mL) was heated at 70° C. for 3 h. Silica was added and the volatiles were removed under reduced pressure. The residue was column chromatographed with EtOAc/DCM to afford cyclohexanecarbothioamide (0.557 g, 49% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (br. s., 1H), 6.91 (br. s., 1H), 2.56 (tt, J=11.8, 3.3 Hz, 1H), 1.90-2.02 (m, 2H), 1.78-1.90 (m, 2H), 1.71 (d, J=12.0 Hz, 1H), 1.51 (qd, J=12.3, 2.8 Hz, 2H), 1.16-1.40 (m, 3H), e/z (ES+): 144 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [I:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7](O)[C:6]=1[O:14][CH2:15][CH2:16][I:17].[C:18]([O:26]CC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1CCCCC1.C(O)C>[I:17][CH2:16][CH2:15][O:14][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][C:5]=1[O:4][CH2:3][CH2:2][I:1])[O:26][C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(OCCI)c(OCCI)c1O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCCI)c(OCCI)cc2oc1=O

Procedure:
To 1.73 g (10.8 mmol) of the bis-iodoethoxy-hydroxybenzaldehyde from Example 33 was added diethyl malonate, 2.1 g (4.6 mmol), and this mixture was heated on a steam bath. When the mixture had become homogeneous, two drops of piperidine were added. After the mixture had cooled, a precipitate formed. The solution was diluted with a few milliliters of ethanol and reheated to boiling on the steam bath. After the solution had cooled, it was filtered and the precipitate product retained. The product was a solid with a m.p. of 162°-165° C. Proton NMR confirmed the structure of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][N:15]=[C:16](Br)[C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2].[CH2:22]([N:24]([CH2:27][CH3:28])[C:25]#[N:26])[CH3:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:22]([N:24]([C:25]1[N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:15]=[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:26]=1)[CH2:27][CH3:28])[CH3:23]
Reactant: CC(C)(C)C(Br)=NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCN(C#N)CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
7.4 g (0.02 mol) of 2,2-dimethylpropionyl bromide 2-nitro-4-trifluoromethylphenylhydrazone and 2.0 g (0.02 mol) of N,N-diethylcyanamide were added to 100 ml of toluene. Then, 2.2 g (0.022 mol) of triethylamine was dropwise added under stirring at room temperature. After completion of the dropwise addition, stirring was continued at room temperature for further 1 hour. Then, 100 ml of toluene was added and washed with water. The organic layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 6.5 g (yield: 84.4%) of the desired compound as a pale yellow liquid. Refractive index nD20 : 1.4911.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11]C)=O)[CH3:3].[C-]#[N:14].[Na+]>N.CO>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([NH2:14])=[O:11])[CH3:3]
Reactant: CCN1CCC[C@H]1C(=O)OC
Reactant: [C-]#N
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CO
Product: CCN1CCC[C@H]1C(N)=O
Yield: 632.9 %

Procedure:
Crude methyl (S)- 1-ethyl-2-pyrrolidinecarboxylate hydrochloride (2.1 g, 0.01 mol; Example 6A) and NaCN (50 mg, 0.001 mol) in 30 ml 9M NH3 in MeOH was heated to 45° C. in a sealed glass flask for 2 days. GLC showed a conversion of 95% and usual work-up afforded 0.9 g (63%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:39][CH2:38]1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: NC1CC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNC3CC3)cc2)cc1
Yield: 62 %

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.30 g) as obtained in Example 16-(1) and cyclopropylamine (0.19 mL), there was obtained (2S)-2-{[4-({4-[(cyclopropylamino)methyl]phenyl}ethynyl)benzoyl](methyl)amino}-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (white solid) (0.20 g, 62%) in the same manner as in Example 16-(2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[NH2:18][C:19]1[N:20]=[C:21]([NH:25][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:22]=[CH:23][CH:24]=1
Reactant: COCCOCC(=O)O
Reactant: Nc1cccc(N)n1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.9 ml of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 3.96 g of 2,6-diaminopyridine is added, and it is stirred for another 4 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and after purification by chromatography on silica gel, 5.04 g of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25]([CH2:27]CO)[CH3:26].C1(C)C=CC=CC=1.[H-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH2:18][CH2:24][N:25]([CH3:27])[CH3:26])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C)CCOC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Temperature: 50 °C

Procedure:
A mixture of 4 g of the ester of Example 1, 2.45 ml of dimethylaminoethanol and 50 ml of anhydrous toluene was heated to reflux and then cooled to 50° C. and 95 mg of a 50% sodium hydride oil suspension was added thereto. The mixture was again heated to reflux and was then cooled to 40° C. and 0.2 ml of acetic acid were added thereto. The mixture was evaporated to dryness and the residue was dissolved in methylene chloride. The solution was filtered and the filtrate was washed with water, dried and filtered. The filtrate was evaporated to dryness to obtain 4.01 g of 2-dimethylaminoethyl 2-(7-chloro-4-quinolinylamino)-5-fluorobenzoate.
Reaction SMILES: C([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH2:5]1)(=O)C.[O-:19]CC.[Na+].Cl>C(O)C.O1CCOCC1>[CH2:17]([O:16][C:14]([C:12]1[N:13]=[C:9]([N:6]2[CH2:7][CH2:8][C@H:4]([OH:19])[CH2:5]2)[S:10][CH:11]=1)=[O:15])[CH3:18]
Reactant: CC[O-]
Reactant: CCOC(=O)c1csc(N2CC[C@H](C(C)=O)C2)n1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Reaction time: 8 h
Yield: 1953.3 %

Procedure:
To a solution of (3S)-3-acetyl-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (5.0 g, 17.6 mmol) (obtained as described in Reference Example 20(2)) in ethanol (150 ml) was added sodium ethoxide (60 mg, 0.879 mmol) at room temperature, and the mixture was stirred overnight under the same conditions. After checking the completion of the reaction, a solution of 4N hydrogen chloride in 1,4-dioxane (0.22 ml) was added thereto to neutralize the reaction mixture. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:1→1:2) as the eluant to afford (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.16 g, yield 98%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+].C(O)C.[C:18](=S)=[S:19]>O>[SH:19][C:18]1[N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1ccccc1NCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCn1c(S)nc2ccccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 93 parts of 3-(2-aminophenyl) amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of an ethanol solution 85% in water are added dropwise 60.8 parts of carbon disulfide. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in 1500 parts of water. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The oily product solidifies on scratching. It is filtered off, washed with water and dried, yielding 2-mercapto-1H-benzimidazole-1-propanol; mp. 110° C.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C(N(C(C)C)C(C)C)C.[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][CH2:49][NH2:50]>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:51])[CH3:45])=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.019 g (0.19 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.045 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-279) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:64][N:54]3[C:55](=[O:63])[NH:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=4[C:53]3=[N:52][CH2:51]2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:64][N:54]3[C:55](=[O:63])[NH:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=4[C:53]3=[N:52][CH2:51]2)=[CH:46][CH:45]=1)=[O:9]
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 3-methyl-furan-2-carboxylic acid (3.7 mg, 0.029 mmol), N,N-diisopropylethylamine (0.025 mL, 0.145 mmol), and HBTU (13.2 mg, 0.035 mmol) in 0.8 mL DMF was stirred at rt for 10 minutes, then 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (7.6 mg, 0.026 mmol) added and the reaction continued at rt. After 40 min, a spatula tip of 3-methyl-furan-2-carboxylic acid and HBTU was added, the reaction briefly warmed to approximately 60° C. several times, then allowed to cool to rt. At 1.25 hours the reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed on a prep plate eluting with 15% MeOH/CHCl3. The obtained solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as an off-white solid (7.6 mg, 86%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.03 (dd, J=7.9, 1.2 Hz, 1H), 7.65-7.71 (m, 2H), 7.43-7.52 (m, 2H), 7.26-7.32 (m, 2H), 7.14 (ddd, J=8.1, 7.2, 1.2 Hz, 1H), 7.00-7.05 (m, 1H), 6.45 (d, J=1.5 Hz, 1H), 4.45 (ddd, J=13.0, 4.4, 2.8 Hz, 1H), 3.83-3.91 (m, 1H), 3.59-3.70 (m, 2H), 3.04-3.16 (m, 1H), 2.42 (s, 3H)