Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>O.O1CCOCC1>[C:14]([O:18][C:19]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1CCc2ccccc2NC1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O

Procedure:
A solution of 3-amino-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one (4.0 g), 2-t-butyloxycarbonyloxyimino-2-phenylacetonitrile (6.1 g) and triethylamine (5 ml) in water (20 ml) and dioxane (25 ml) was stirred at room temperature for 18 hours. The resulting solid was filtered off and washed with water. Recrystallization from ethyl acetate gave 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 199°-201°.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([C@@H:10]1[C@@H:14]([CH2:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=2)[CH2:13][NH:12][C:11]1=[O:22])[CH3:9].C([C:25]([O:27][CH3:28])=[O:26])#N>O1CCCC1.CCCCCC>[C:25]([N:12]1[CH2:13][C@H:14]([CH2:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=2)[C@@H:10]([CH2:8][CH3:9])[C:11]1=[O:22])([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C#N
Reactant: CC[C@H]1C(=O)NC[C@@H]1Cc1cncn1C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC[C@H]1C(=O)N(C(=O)OC)C[C@@H]1Cc1cncn1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
To a solution of diisopropylamine (58 mg, 0.57 mmol) in tetrahydrofuran (THF) (2 mL) at 0° was added 251 μL of a 2.5 M solution of D-butyl lithium (0.63 mmol) in hexane. The solution was stirred at 0° for 15 min., then cooled to -78° and (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidinone (118.2 mg, 0.57 mmol) in THF (2.5 mL) was added via cannula, followed by a THF (0.5 mL) rinse. After 2 hours at -78 , methyl cyanoformate (50.9 mg, 0.60 mmol) was added and the reaction was maintained at -78° for 1.5 hours, then warmed to room temperature for 15 hours. The reaction was quenched with saturated aqueous NaHCO3, extracted three times with CHCl3, dried (Na2SO4), filtered, concentrated and the residue was chromatographed on silica gel (5% MeOH satured with NH3 /CHCl3) to give 44.3 mg of (3R, 4R)-1-carbomethoxy-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidinone as an oil (28%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1.N1C=CC=CC=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: c1ccncc1
Product: Cc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)cc2c1
Yield: 66 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 5-methylbenzothiophene-2-sulfonyl chloride (30.0 mg, 0.12 mmol), pyridine (49 μL, 0.61 mmol) and 3-aminobenzoic acid (16.7 mg, 0.10 mmol). The title compound was obtained in 66% yield (23 mg). MS (ESI+) calcd mass for C16H13NO4S2 347.028599, found 347.029559.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CN1CCNCC1=O
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 8.5 h

Procedure:
6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 3.0 g, 8.58 mmol), KF (2.52 g, 42.9 mmol), 1-methylpiperazine-2-one hydrochloride (3.88 g, 25.7 mmol), N-ethyldiisopropylamine (5.99 mL, 35 mmol) were suspended in NMP (60 mL). The RM was stirred at 180° C. for 8.5 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in EtOAc to afford the title compound as a white solid (tR 3.19 min (conditions 1), (tR 8.84 min (conditions 2), MH+=423.2, 1H-NMR in DMSO-d6: 8.94 (d, 1H); 8.45 (d, 1H); 7.84 (d, 1H); 7.63 (s, 1H); 7.59 (m, 2H); 7.08 (d, 1H); 4.98 (m, 1H); 4.02 (d, 1H); 3.73 (d, 1H); 3.60 (m, 2H); 3.31 (m, 1H); 3.25 (m, 1H); 2.80 (s, 3H); 1.88 (d, 3H)).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(F)cc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in dry DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added all in one portion. The mixture was stirred for 10 minutes at room temperature before 4-fluorobenzenesulfonyl chloride (12 mg, 0.062 mmol) was added. The reaction mixture was stirred for 10 minutes, and TFA (1 mL) was added dropwise. The reaction mixture was heated at 50° C. overnight and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.8 mg) in the form of the trifluoroacetate salt. MS m/z 381 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[O:18]=[C:19](Cl)[O:20][C:21](Cl)(Cl)Cl.[O:26]1[CH2:31][CH2:30]C(O)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:26]1[CH2:31][CH2:30][CH:21]([O:20][C:19]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)=[O:18])[CH2:28][CH2:27]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCOCC1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)OC1CCOCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Benzyl 4-aminopiperidine-1-carboxylate (100 mg) is dissolved in toluene (1 mL), treated dropwise with a solution of diphosgene (52 μL) in toluene (1 mL) and stirred for 12 hours at 80° C. Tetrahydro-2H-pyran-4-ol (41 μL) is added and the mixture is heated for 3 hours at 80° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=363 [M+H]+.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Na+].[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1)=[O:19]>[Mo](=O)(=O)=O.CC1CCCCC1>[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:5][C:1]2([CH3:4])[CH2:3][CH2:14][CH2:13][CH2:12][CH2:2]2)[C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:27])([CH3:28])[N:24]([O:5][C:1]2([CH3:4])[CH2:3][CH2:11][CH2:10][CH2:9][CH2:2]2)[C:23]([CH3:29])([CH3:30])[CH2:22]1)=[O:19]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCCC1
Product: CC1(ON2C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC3CC(C)(C)N(OC4(C)CCCCC4)C(C)(C)C3)CC2(C)C)CCCCC1
Temperature: 25 °C
Yield: 140.7 %

Procedure:
t-Butyl hydroperoxide (70%, 133.9 g, 1.04 mol), methylcyclohexane (250 ml), and sodium chloride (20 g) are agitated in a separatory funnel. The organic layer is dried over magnesium sulfate. The t-butyl hydroperoxidemethylcyclohexane solution is mixed with 50.0 g (104 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 3.0 g of molybdenum trioxide, and 100 ml of methylcyclohexane. The reaction mixture is heated at reflux for 4.5 hours and water is collected in a Dean-Stark trap. The reaction is cooled to room temperature and filtered. The filtrate is concentrated at reduced pressure to obtain an oil which is purified by flash chromatography (silica gel; 19:1 heptane:ethyl acetate) to obtain 51.6 g (72% yield) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:18]=2[N:19]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:26])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2cc(F)c(F)cc2s1
Reactant: CNc1ccc(C(=O)OC)cc1N
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 51.4 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester (579 mg) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (650 mg), 2-amino-5,6-difluorobenzothiazole (560 mg), 1,1′-thiocarbonyldiimidazole (715 mg), and EDC (865 mg). LC/MS: m/z 375.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.51 (bs, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 3.86 (s, 3H), 3.67 (bs, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH3:9][C:10]([CH3:12])=O>CC(O)=O>[CH3:9][C:10]1([CH3:12])[C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: CC(C)=O
Reactant: NCCc1c[nH]cn1
Solvent: CC(=O)O
Product: CC1(C)NCCc2[nH]cnc21
Yield: 79.8 %

Procedure:
A solution of histamine (500 mg, 4.5 mmol) and acetone (3.3 mL, 45 mmol) in AcOH (3 mL) was heated at 100° C. overnight. The crude reaction mixture was concentrated and purified on 16 g SiO2 column with 0-80% NH3/MeOH CH2Cl2 to give the desired compound (543 mg, 80%). MS (ESI): mass calcd. for C8H13N3, 151.1. m/z found, 152.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 3.16 (t, J=5.7 Hz, 2H), 2.61 (t, J=5.7 Hz, 2H), 1.43 (s, 6H).
Reaction SMILES: Cl.C([CH:4](CC)[C:5]([CH3:10])([CH3:9])[C:6](=[NH:8])[NH2:7])C.[CH2:13]([O:15][CH:16]=[C:17]([C:21]([O-])=O)[C:18]([O-])=[O:19])[CH3:14].[O-:24]CC.[Na+].C(O)C>C(O)C>[C:5]([C:6]1[NH:7][C:18](=[O:19])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:24])=[CH:21][N:8]=1)([CH3:4])([CH3:9])[CH3:10]
Reactant: CCOC=C(C(=O)[O-])C(=O)[O-]
Reactant: CC[O-]
Reactant: CCC(CC)C(C)(C)C(=N)N
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(C)(C)C)[nH]c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 104.3 %

Procedure:
To a solution of diethyl 2,2-dimethylpropanimidamide hydrochloride (1.36 g) and (ethoxymethylene)malonate (2.16 g) in ethanol (100 ml) was added 20% sodium ethoxide-ethanol solution (6.8 g) under ice-cooling, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (10 ml) was added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, hexane was added to the residue, and the precipitate was collected by filtration to give the object product (1.65 g) as a powder.
Reaction SMILES: B.[OH:2][C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].O>C1COCC1>[OH:2][C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: O=C(O)c1ccc(I)cc1O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1M solution of borane in THF was added dropwise at 0° C. to a solution of 2-hydroxy-4-iodobenzoic acid (13.2 g, 0.05 mol) in THF (100 ml). The mixture was stirred for 6 hours at room temperature and 20 ml of a solution of THF and water (1:1) were then added. After concentration on a rotary evaporator under vacuum at 40° C. The residue was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40° C. The product was purified by flash chromatography on a column of silica (60% EtOAc, 40% heptane). Its properties were as follows:
Reaction SMILES: [C:1]([N:4]1CC(C)(C)N[C:5]1=O)(=N)[NH2:2].[C:12]([OH:15])(=O)[CH3:13].[N:16]1C=CC=N[CH:17]=1>COCCOC>[C:17]([C:13]1[C:12](=[O:15])[NH:2][CH:1]=[N:4][CH:5]=1)#[N:16]
Reactant: c1cncnc1
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Reactant: CC(=O)O
Solvent: COCCOC
Product: N#Cc1cnc[nH]c1=O
Reaction time: 8 h

Procedure:
First, 22.5 g (0.187 mol) of 1-amidino-4,4-dimethylimidazolidin-2-one are introduced as a suspension in 300 ml of absolute DME with stirring and exclusion of moisture. Next, 56 g (0.119 mol) of ethoxymethylene-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-[(3-trifluoromethyl)phenyl]cyanoacetamide in 300 ml of absolute DME are slowly added dropwise at 0° C. After addition, the mixture is stirred at room temperature for 2 hours. After this time the reaction has ended (TLC checking). 125 ml of glacial acetic acid are added dropwise with stirring to this solution and it is stirred for 2 hours at a temperature of 50° C. After allowing to stand overnight at room temperature, the cyclization to the pyrimidine derivative has ended. For working-up, the precipitated 5-cyano-4-pyrimidone derivative formed as a by-product is filtered off. The filtrate is concentrated, the glacial acetic acid is evaporated with toluene, and the semisolid residue is taken up in ethyl acetate. Additionally precipitated amounts of the 5-cyano-4-pyrimidone derivative formed are removed again by filtration. The ethyl acetate phase is then washed 2× with 2N aqueous NaOH solution and 2× with saturated sodium chloride solution, dried using MgSO4, filtered and concentrated on a rotary evaporator, after which, as a residue, 51 g of crude product remain as a dark oil. Purification is carried out by means of column chromatography using silica gel and ethyl acetate as eluent. After evaporating the solvent, 12.56 g of 4-amino-2-(4,4-dimethylimidazolidin-2-on-1-yl)pyrimidine-5-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-[(3-trifluoro- methyl)phenyl]carboxamide remain as yellowish crystals (18% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:40][C:37]2[CH:38]=[CH:39][C:32]3[CH2:31][CH2:30][CH:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:35][CH2:34][C:33]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine, in a similar manner as Example 601b, to yield desired product 5-Chloro-N*4*-(4-methoxy-2-pyrazol-1-yl-phenyl)-N*2*-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-pyrimidine-2,4-diamine as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.64 (bs, 1H), 9.33 (s, 1H), 8.75 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=8.97 Hz, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.25 (m, 2H), 7.1-6.95 (m, 2H), 6.54 (s, 1H), 4.00 (m, 2H), 3.88 (s, 3H), 3.8-3.7 (m, 2H), 3.6-3.5 (m, 1H), 3.4-3.1 (m, 4H), 2.8-2.6 (m, 4H), 2.29 (m, 2H), 1.42 (m, 2H); MS (m/e) 546.37 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2nccnc2Cl)CC1

Procedure:
2,3-Dichloropyrazine (1.0 g, 0.0067 mol), tert-butyl-4-(aminomethyl)piperidine-1-carboxylate (1.6 g, 0.0075 mol) (Astatech) and cesium carbonate (2.4 g, 0.0075 mol) in acetonitrile (10 mL) were heated to 90° C. under nitrogen for 18 h. The reaction was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and chromatographed on silica using a gradient of 10 to 30% ethyl acetate/hexane to give the title compound as a foam. M.S.(M+1): 327.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COCCNCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of N,N-bis(2-methoxyethyl)amine (2.40 g) and triethylamine (2.27 g) in dichloromethane (30 ml) was added 3-nitrobenzoyl chloride (2.78 g) in an ice-water bath. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified with column chromatography eluting with dichloromethane-methanol to give N,N-bis(2-methoxyethyl)-3-nitrobenzamide (4.12 g) as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)C1C=CC=CC=1>C(O)C.C1COCC1.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[O:18]1[C:17]2([CH2:22][CH2:23][CH:14]([CH2:13][O:12][C:11]3[CH:10]=[C:9]([OH:8])[CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: c1ccc(COc2cccc(OCC3CCC4(CC3)OCCO4)c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1cccc(OCC2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
8-{[3-(Benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (817 mg) was dissolved in a mixed solvent of ethanol (15 mL) and THF (15 mL), and cyclohexene (4.67 mL) and 20% palladium hydroxide-activated carbon (218 mg) were added thereto, followed by heating under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(1,4-dioxaspiro[4.5]dec-8-ylmethoxy)phenol (567 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:25][C:26]#[N:27])[CH:21]=[CH:22][C:23]=2[F:24])=[C:12]([CH3:28])[N:11]=1>C(O)CCC>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5])[C:13]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:25][C:26]#[N:27])[CH:21]=[CH:22][C:23]=2[F:24])=[C:12]([CH3:28])[N:11]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1cc(CC#N)ccc1F
Reactant: CCC[C@H](N)CCO
Solvent: CCCCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1cc(CC#N)ccc1F
Reaction time: 2 h

Procedure:
(S)-3-Aminohexan-1-ol (101 mg) was added to a stirred solution of the product from step (iv) (100 mg) in butan-1-ol (2 mL). The reaction was performed in a microwave, at 18° C. for 2 h. The solvent was removed and the crude product was purified using chromatography, to give the subtitle compound, 70 mg.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH:24]2[CH2:26][CH2:25]2)[CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:6][CH:5]=1>P([O-])([O-])([O-])=O>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH:24]2[CH2:26][CH2:25]2)[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(NC(=O)CCC(=O)Nc1ccc(C=NN)cc1)C1CC1
Agent: O=P([O-])([O-])[O-]
Product: NN=Cc1ccc(NC(=O)CCC(=O)NC(CC(=O)O)C2CC2)cc1
Reaction time: 20 h
Yield: 83 %

Procedure:
Porcine liver esterase (200 μL, Sigma, 11 mg/mL in 3.2M (NH4)2SO4 at pH=8) was added to the final product of Example 28 in 20 mL of 0.1M phosphate buffer (pH=7.4). After 20 h at 23° C., the reaction mixture was concentrated in vacuo. The residue was dissolved in 1N HCl (3 mL) and subsequently diluted with acetonitrile (5 mL) followed by immediate purification by reverse phase HPLC using the conditions of Example 1 to afford 23.0 mg (83%) of the title compound. The product was verified by 13C NMR (CD3OD) δ 1.8, 2.6, 15.0, 30.3, 31.8, 39.1, 50.6, 119.2, 122.1, 128.6, 144.3, 166.8, 172.0, 172.4, 173.4; Fast Atom Bombardment Mass Spectrometry (MH+)=347.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:40]([O-:44])([O-])(=[O:42])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:40]([C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:44])=[O:42])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccnc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.84 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.50 g of 3-ethylsulfanyl-N-(4-trifluoromethoxyphenyl)picolinamide (Compound of Present Invention 18) and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.50 g of 3-ethylsulfonyl-N-(4-trifluoromethoxyphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 21).