Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[CH3:2][C:3]([O-:6])(C)C.C[C:8]([O-:11])(C)C.CC([O-])(C)C.[Al+3].[O:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>S(=O)(=O)(O)[O-].[Na+]>[OH:18][CH2:22][C:21]1([C:8]([O:6][CH2:3][CH3:2])=[O:11])[CH2:19][CH2:20]1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [Li]
Product: CCOC(=O)C1(CO)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
A 1M solution of lithium aluminum tri-tert-butoxyhydride in tetrahydrofuran (70.90 mL, 70.90 mmol) was added to a stirred solution of diethyl cyclopropane-1,1′-dicarboxylate (6 g, 32.20 mmol) in tetrahydrofuran (129 mL) at 23° C. The resulting solution was heated to 65° C. and stirred for 24 h. The cooled reaction mixture was diluted with a 10% solution of sodium bisulfate (275 mL) and extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, and concentrated to dryness to give the desired product as a pale yellow oil (4.60, 91%): 1H NMR (300 MHz, CDCl3) δ 4.16 (q, J=7 Hz, 2H), 3.62 (s, 2H), 2.60 (br s, 1H), 1.22-1.30 (m, 5H), 0.87 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[OH2:7]>>[CH3:1][C:2]1([CH3:6])[NH:4][CH2:3][C:2]([CH3:6])([CH3:1])[NH:4][C:3]1=[O:7]
Reactant: CC(C)(O)C#N
Reactant: O
Product: CC1(C)CNC(C)(C)C(=O)N1

Procedure:
In a manner analogous to that described in example 3A above, 2,methyl-1,2-diaminopropane, water and acetone cyanohydrin are reacted, and the reaction product recovered. When dissolved in acetone and recrystallized it is identified as 3,3,6,6-tetramethyl-2-piperazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)(=[O:21])=[O:20])=[O:6]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Br)cc1Cl
Reaction time: 72 h

Procedure:
An 8 mL reaction vial is charged with 2-chloro-4-bromobenzoic acid (0.39 mmol, 1.5 eq) and 2.0 mL of dichloromethane. A stock solution (4.0 mL) containing 4-chlorophenylsulfonamide (0.26 mmol, 1 eq) and N,N-[dimethyl]-4-aminopyridine (48 mg, 0.39 mmol, 1.5 eq) in dichloromethane is added, followed by 0.261 g carbodiimide polystyrene resin (2.0 mmol/g, 0.52 mmol, 2.0 eq, Novabiochem) and the vial is capped and rotated. After 72 hr, 0.77 g sulphonated polystyrene resin (NP-TsOH) is added (1.53 mmol/g, 1.17 mmol, Argonaut). After about 18 hr the reaction mixture is filtered and concentrated under a stream of nitrogen. The residue is subjected to reverse phase HPLC; CombiPrep column, YMC ODS-A 20×50 mm column with 5 micron, C18, 120 Angstrom pore size, gradient: 5% to 95% CH3CN/0.01 HCl aqueous solution. Fractions containing product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[C:30](O)=[O:31])=[CH:24][CH:23]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:30](=[O:31])[C:29]([CH2:28][C:25]3[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=3)=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c(Cc2ccc(O)cc2)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 61.2 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (196 mg) and 3-(4-hydroxyphenyl)pyruvic acid (162 mg) in ethanol (5 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(4-hydroxybenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (186 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[OH:9]O>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9])[CH3:2]
Reactant: OO
Reactant: CCc1ccccn1
Solvent: CC(=O)O
Product: CCc1cccc[n+]1[O-]
Temperature: 80 °C

Procedure:
To the solution 500 g (4.7 mol) 2-ethylpyridine in 2.0 L acetic acid is added H2O2 (1586.0 g, 13.900 mol). Then the mixture is heated to 80° C. overnight. After cooling to room RT, the mixture is poured into the crushed ice, and extracted with DCM (8×1.0 L). The DCM layers are combined, washed with saturated Na2SO3 solution, dried over anhydrous Na2SO4. The solvent is removed in vaccuo to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11]([C:18]([OH:20])=O)=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:44][C:45]([NH2:47])=[NH:46]>O1CCCC1>[CH3:21][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11]([C:18]([NH:46][C:45]([NH2:47])=[NH:44])=[O:20])=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)N
Reactant: CN(C)c1cccc(-n2cc(C(=O)O)c3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)c1cccc(-n2cc(C(=O)NC(=N)N)c3cccnc32)c1
Temperature: 20 °C
Reaction time: 384 h

Procedure:
1-(3-(Dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 0.46 g (2.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.027 g (0.2 mmol) of 1-hydroxybenzotriazole were added to 0.59 g (10 mmol) of guanidine in 15 cm3 of tetrahydrofuran under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 days, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was triturated in 20 cm3 of methanol and then filtered. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was purified by flash chromatography on silica gel, elution being carried out with a 100% of dichloromethane to dichloromethane/methanol/triethylamine (50/48/2 by volume) gradient over 90 minutes. After concentrating the fractions comprising the expected product to dryness under reduced pressure (2.7 kPa), the solid obtained was triturated in 20 cm3 of ethanol and filtered off, resulting in 0.004 g of N-[1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine in the form of a powder melting at 269–271° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO with addition of a few drops of CD3COOD, δ in ppm): 3.00 (s, 6H), 6.84 (dd, J=8.5 and 2 Hz, 1H), 7.09 (dd, J=8.5 and 2 Hz, 1H), 7.15 (t, J=2 Hz, 1H), 7.39 (t, J=8.5 Hz, 1H), 7.42 (dd, J=8 and 5 Hz, 1H), 8.46 (dd, J=5 and 2 Hz, 1H), 8.55 (dd, J=8 and 2 Hz, 1H), 8.84 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:17](=O)([O:20]C)[O:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:17]([O:18][CH3:19])=[O:20])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Br)ccn1
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-2-methylpyridine (1 g, 5.8 mmol) in 15 mL of anhydrous THF was added LDA (9.2 mL, 2M) dropwise at −70, stirred for 30 min dimethyl carbonate (630 mg, 7.0 mmol) was added dropwise to the above solution. After stirring for another 1 h, LC-MS found the reaction finished. It was quenched by Sat. NH4Cl solution and extracted with EtOAc. The organic layer was separated and evaporated under reduced pressure. The crude product was purified by a standard method to give desired product. LC-MS: m/z (M+H) 231.1.
Reaction SMILES: [CH:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.Cl.[CH3:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3](=[CH:1][N:19]([CH3:20])[CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C=O)c1ccc(OC)cc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Yield: 98.7 %

Procedure:
21 g (0.0945 mol) of ethyl α-formyl-p-methoxyphenylacetate, 80 ml of ethanol and 31,1 g (0.38 mol) of dimethylamine hydrochloride were mixed in a 250 ml balloon flask provided with magnetic stirring and thermometer under a gentle nitrogen flow. Subsequently 7.4 g (0.054 mol) of potassium carbonate were added. The thus obtained solution was stirred at room temperature for 3 days. The solvent was evaporated to dryness in the rotary evaporator and 120 ml of water were added over the thus obtained solid residue. The pH was adjusted to 5-6 with 5N hydrochloric acid and the product of the aqueous phase was extracted with 2×80 ml of dichloromethane. The organic extracts were dried with sodium sulfate and the solvent was removed under vacuum, to give a residue weighing 23.26 g and solidifying at room temperature (Yield: 98.7%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14](CC[Si](C)(C)C)[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25]CC2C=CC=CC=2)[CH:6]=1.C([O:35][C:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]=[C:44]=[O:45])C.N1C2C(=CC=CC=2)C=NC=1>>[OH:25][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:1]2[C:36](=[O:35])[C:37]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:43][C:44]2=[O:45])[CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[NH:14][S:15]1(=[O:16])=[O:17]
Reactant: CCOC(=O)c1ccccc1N=C=O
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCN)cc2OCc2ccccc2)S1(=O)=O
Agent: c1ccc2ncncc2c1
Product: O=C1CN(c2ccc(CCCn3c(=O)[nH]c4ccccc4c3=O)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-[4-(3-aminopropyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 2-isocyanatobenzoic acid ethyl ester analogous to Example 214. Cyclization to the quinazoline occurs during the TMS-ethyl deprotection step. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (dq, J=7.71, 7.54 Hz, 2 H) 2.51-2.56 (m, 2 H) 3.92 (d, J=7.33 Hz, 2 H) 4.00 (s, 2 H) 6.63 (dd, J=8.08, 2.02 Hz, 1 H) 6.70 (d, J=2.02 Hz, 1 H) 7.17 (d, J=7.83 Hz, 2 H) 7.26 (d, J=8.08 Hz, 1 H) 7.61 (dd, J=15.41, 1.26 Hz, 1 H) 7.91 (dd, J=8.34, 1.52 Hz, 1 H) 8.93 (br. s., 1 H) 11.36 (br. s., 1 H)
Reaction SMILES: [OH:1][NH:2][CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:38](O)(=[O:40])[CH3:39].C(OC(=O)C)(=O)C>C1COCC1>[C:38]([N:2]([OH:1])[CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7])(=[O:40])[CH3:39]
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(O)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.100 g, 0.192 mmol) and acetic acid (2 mL) in THF (20 mL) was added acetic anhydride (0.018 mL, 0.192 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from EtOH-ethyl acetate-diethyl ether-hexane to give the title compound as a white powder (0.085 g, 79%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][CH:4]=[CH:5][C:6]([CH3:11])=[C:7]2[N:8]=1
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccccc1
Product: Cc1ccnc2c1nc(C)n2-c1ccccc1
Yield: 62.7 %

Procedure:
Method A applied to 2-chloro-4-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as pale yellow solid (70 mg, 63%). mp 117-119° C. 1H NMR (DMSO) δ 2.59 (s, 3H), 2.73 (s, 3H), 7.26 (d, J=4.8Hz, 1H), 7.58-7.72 (m, 5H), 8.22 (d, J=4.8Hz, 1H); 13C NMR δ 13.8, 16.0, 120.8, 127.3, 129.3, 129.4, 129.5, 130.1, 136.0, 144.2, 146.4, 152.1. HRMS (FAB): cal. for C14H14N3 [M+H+]: 224.1188; found: 224.1180.
Reaction SMILES: Cl[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: COc1ccccc1S
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1SC(CCc1ccc(Cl)cc1)Cn1ccnc1

Procedure:
1-[2-Chloro-4-(4-chlorophenyl)-n-butyl]imidazole (prepared from 2.0 g of alcohol as in Preparation D) was treated with 2-methoxythiophenol (1.68 g) and anhydrous potassium carbonate (1.60 g) in acetone using the procedure of Example 1 to afford 1-[2-(2-methoxyphenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole which was converted to its nitrate salt and recrystallized from ethyl acetate to give 3.10 g of microcrystals, mp 105°-106.5° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][C:49]=1[S:50][CH2:51][C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1)[NH2:46]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:46][C:45]4[CH:47]=[CH:48][C:49]([S:50][CH2:51][C:52]5[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=5)=[C:43]([CH3:42])[CH:44]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: Cc1cc(N)ccc1SCc1nccn1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]aniline (448 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred overnight at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (335 mg) (Compound 355) as yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[C:15]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:15][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: N#Cc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1OC(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-3-trifluoromethoxybenzonitrile (10.0 g, 37.6 mmol), K2CO3 (15.6 g, 113 mmol), trimethylboroxine (5.5 mL, 39.5 mmol) and DMF (150 mL) is degassed for 10 min with nitrogen before Pd(PPh3)4 (4.34 g, 3.76 mmol) is added. The mixture is then sealed and heated to 120° C. for 14 h. The mixture is then concentrated and then partitioned between Et2O and 50% brine solution. The aqueous phase is further extracted with Et2O and the combined organic layers are dried (Na2SO4) and concentrated. The residue is purified via flash chromatography (10% EtOAc/hexanes) to give 4-methyl-3-trifluoromethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 2.40 (s, 3H), 7.40 (d, J=7.7 Hz, 1H), 7.50 (s, 1H), 7.51 (dd, J=7.7, 1.5 Hz, 1H). MS (ESI) m/z 202.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([O:27][CH3:26])=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-[(3-Chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (2.72 g, 7.54 mmol) and 0.5 M sodium methoxide in methanol (40 mL) were heated under nitrogen at 60° C. for 2 days, cooled, evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with brine, dried and solvent evaporated to afford crude material, purified by flash chromatography on silica (gradient 25 to 100% EtOAc hexane) to give the desired compound as a solid. The solid was stirred with approx. (10 mL) 2:1 isopropyl acetate:hexane and filtered to give the title compound as white solid. M.S.(M+1): 357.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:12]3[NH:13][C:14](=O)[N:4]([C:5]=23)[CH2:3]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:14]1[N:4]2[C:5]3[C:12](=[CH:11][CH:10]=[CH:9][C:6]=3[CH2:7][NH:8][C@@H:2]([CH3:1])[CH2:3]2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@H]1Cn2c(=O)[nH]c3cccc(c32)CN1
Product: C[C@H]1Cn2c(Cl)nc3cccc(c32)CN1
Reaction time: 0.25 h

Procedure:
4.55 g (0.022 mol) of (S)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one in 90 ml of phosphoryl chloride are heated at 130° C. in an oil bath for 4 hours. The solvent is evaporated under vacuum and the oily residue taken up while hot in water. The mixture is left stirring for 15 minutes, is cooled and a concentrated aqueous ammonia solution is added. Extraction is carried out with dichloromethane, washing is carried out with water, drying is carried out over sodium sulphate and the solvent is evaporated to dryness. There are obtained 4.3 g of product in the form of an oil which is used as is in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([C:25]([CH3:32])([CH3:31])[C:26]([O:28]CC)=[O:27])[N:9]=2)[CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([C:25]([CH3:31])([CH3:32])[C:26]([OH:28])=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(C)(C)n1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC)n1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)cc1-c1nn(C(C)(C)C(=O)O)cc1NC(=O)c1cnn2cccnc12
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-methylpropanoate (0.918 g, 1.90 mmol, 1 equiv) was added 2 N aqueous sodium hydroxide solution (4 mL). After 18 h, additional 2 N aqueous sodium hydroxide solution (4 mL) was added. After 5 h, the reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in water (15 mL). The aqueous solution was acidified with 6 N aqueous hydrochloric acid until pH=2. The resulting aqueous solution was extracted with ethyl acetate (3×30 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated to provide crude acid (quantitative). LCMS (ESI): M+H=455.1.
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[O:26]1C(CNCCCNC2N=CC=CN=2)CCC2C=CC3C(OCCC=3)C1=2.O1C(CNCCCNC2N=CC=CN=2)CCC2C=CC3CCCCC=3C1=2.N1CCN=C1NCCCNCC1CCC2C=CC3CCCC=3C=2O1.O1C(CNCCCNC2NCCCN=2)CCC2C=CC3CCCOC=3C1=2.O1C2C3CCCC=3C=CC=2CCC1CNCCCNC1NCCCN=1.O1C2C3OC(CNCCCNC4NCCCN=4)CCC=3C=CC=2OCC1.O1C(CNCCCNC2NCCCN=2)CCC2C=CC3CCCCC=3C1=2.FC1C=C(C=CC(OC)=O)C2OC(CNCCCNC3N=CC=CN=3)CCC=2C=1.FC1C=C(C2OC=CC=2)C2OC(CNCCCNC3N=CC=CN=3)CCC=2C=1.FC1C=C(C2SC=CC=2)C2OC(CNCCCNC3NCCCN=3)CCC=2C=1.O1C2C=CC=CC=2CCC1CNCCCNC1CCCCN=1.O1C2C=CC=CC=2CCC1CNCCCNC1C=CN=C(NC)N=1>>[O:1]1[CH:2]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH2:13][O:26][C:7]=3[C:6]1=2
Reactant: C1=CC2=C(OC(CNCCCNc3ncccn3)CC2)C2OCCC=C12
Reactant: c1cnc(NCCCNCC2CCc3ccc4c(c3O2)CCC4)nc1
Agent: CNc1nccc(NCCCNCC2CCc3ccccc3O2)n1
Agent: COC(=O)C=Cc1cc(F)cc2c1OC(CNCCCNc1ncccn1)CC2
Agent: Fc1cc2c(c(-c3ccco3)c1)OC(CNCCCNc1ncccn1)CC2
Product: c1cnc(NCCCNCC2CCc3ccc4c(c3O2)OCCC4)nc1

Procedure:
N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine; (±)-N-[(2,3,4,8,9,10-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propane diamine; N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine; N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediamine; N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[(2,3,7,8-tetrahydro-9H-pyrano[2,3-f]-1,4-benzodioxin-9-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; methyl 3-[6-fluoro-3,4-dihydro-2-[[[3-(2-pyrimidinylamino)propyl]amino]methyl]-2H-1-benzopyran-8-yl]-2-propenoate; N-[[6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-yl]methyl]-N'-2-pyrimidinyl-1,3-propanediamine; N-[[6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-yl]methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(3,4,5,6-tetrahydro-2-pyridinyl)-1,3-propanediamine; N4 -[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N2-methyl-2,4-pyrimidinediamine, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof.