Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]([NH:13][C:14]2[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)[N:15]=2)[CH2:3]1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[Cl:20][C:19]1[C:14]([NH:13][CH:4]2[CH2:5][CH2:6][C:7]3([CH2:8][CH2:9][N:10]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:11][CH2:12]3)[CH2:2][CH2:3]2)=[N:15][C:16]([NH:21][C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)=[N:17][CH:18]=1
Reactant: N#CCC(=O)O
Reactant: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)CC#N)CC4)n2)c1
Reaction time: 2 h
Yield: 28.8 %

Procedure:
To a solution of N4-(9-azaspiro[5.5]undecan-3-yl)-5-chloro-N2-(1-methylimidazol-4-yl)pyrimidine-2,4-diamine hydrochloride (200 mg, 0.4850 mmol), 2-cyanoacetic acid (41.6 mg, 0.489 mmol) and TEA (98.4 mg, 0.972 mmol) in a mixture of DCM and DMF (8 mL/2 mL) were added HOAT (99.6 mg, 0.732 mmol) and EDCI (138.7 mg, 0.724 mmol). The reaction was stirred for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a light yellow solid (61.8 mg, 28.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]2[NH:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.C=O.[CH:15](O)=O.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O.CO>[CH3:1][C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:8][CH2:9][CH2:10][N:11]2[CH3:15])[O:4][N:3]=1
Reactant: Cc1cc([C@@H]2CCC(=O)N2)on1
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 67 °C
Reaction time: 2 h

Procedure:
The compound from step 4b above (3.047 kg, 18.3 mol) was dissolved in 14 L of THF and placed under N2. At room temperature, borane-THF complex (55 L, 55 mol) was introduced at a rate such that the internal temperature remained at 30° C. At the end of the exothermic and foaming addition, the reaction was heated at reflux (67° C.) for 1 hr. The reaction mixture was then cooled to 0° C., and 8.2 L of methanol was slowly added so that the internal temperature remained at 20° C. The mixture was then stirred for 2 hr. at room temperature, and the solvent was evaporated under vacuum to yield a yellow oil, which solidified upon standing. This residue was emulsified with water and cooled to 10° C. A solution of formaldehyde (35%, 2.1 L, 27.5 mol) and formic acid (97%, 990 mL, 18.3 mol) was added to the emulsion, and the exothermic and effervescent reaction was maintained at an internal temperature below 30° C. The mixture was the cooled to 10° C., 1 kg (9.5 mol) of Na2CO3 was added in portions, and the mixture was stirred for 1 hr. NaOH (10%, 2.29 L) was added, followed by 5.5 L of water. The product was isolated by extraction with ethyl acetate, which was dried over MgSO4, filtered and concentrated to dryness. The product was double distilled, dissolved in ethyl acetate, converted to the HCl salt with ethanolic HCl, recrystallized from ethyl acetate, suspended in ethyl acetate, re-converted to the base with treatment with 30% NaOH solution, the layers separated, the organic layer washed with brine, dried and evaporated, to yield the product, which was finally distilled to yield 490 g of the pure title product (e.e.=99.5%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][C:25]([CH:28]=[O:29])=[CH:24][C:23]=1[F:30].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:22]3[C:23]([F:30])=[CH:24][C:25]([CH:28]=[O:29])=[CH:26][N:27]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: O=Cc1cnc(Cl)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C=O)cc3F)CC2)CC1
Temperature: 60 °C

Procedure:
2d (0.45 g, 1.6 mmol), 6-chloro-5-fluoro-pyridine-3-carbaldehyde 53a (0.6 g, 3.76 mmol) and diisopropylethylamine (0.75 mL, 4.5 mmol) were combined in 5 mL of DMSO and heated at 60° C. for 18 h. The mixture was poured into ethyl acetate (30 mL), washed with water (2×20 mL) and brine (2×20 mL) and concentrated to give the crude 53b.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[C:31]1[O:32][C:33]2[C:38]([N:39]=1)=[CH:37][CH:36]=[CH:35][N:34]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:59]1([CH2:64][CH2:65][CH2:66]O)[CH2:63][CH2:62][CH2:61][CH2:60]1>ClCCl.CN(C=O)C>[N:39]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[O:32][C:31]=1[C:19]1[C:18]([NH2:17])=[N:23][CH:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:66][CH2:65][CH2:64][N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)=[CH:26][CH:25]=2)[CH:20]=1
Reactant: Nc1ncc(-c2ccc(O)cc2)cc1-c1nc2cccnc2o1
Reactant: OCCCN1CCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(OCCCN3CCCC3)cc2)cc1-c1nc2cccnc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (DTAD) (227 mg) in dichloromethane (1 ml) was added to a stirred solution of 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)phenol (100 mg), polystyrene bound triphenylphosphine (330 mg, 3 mmol/g) and 3-pyrrolidin-1-ylpropan-1-ol (64 mg) in DMF (2 ml) at room temperature under argon. The resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered and the resulting solid was washed with methanol. The filtrates were combined, concentrated to dryness and diluted with DCM/TFA (1 ml: 1 ml). The mixture was stirred for 30 min and concentrated. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 micron silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 1% acetic acid) and Methanol as eluent. The fractions containing the desired compound were evaporated to dryness to afford 3-oxazolo[5,4-b]pyridin-2-yl-5-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]pyridin-2-amine (36 mg) as a solid. NMR Spectrum: (DMSOd6) 1.86 (bs, 4H), 2.03-2.15 (m, 2H), 3.02-3.33 (m partially hidden by H2O, 6H), 4.11 (t, 2H), 7.06 (d, 2H), 7.53 (dd, 1H), 7.68 (d, 2H), 7.77 (bs, 2H), 8.30 (dd, 1H), 8.40 (dd, 1H), 8.46 (d, 1H), 8.58 (d, 1H); Mass spectrum: M+H+ 416. The 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)phenol used as starting material was made as follows:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH:9]=[C:8]2[C:22]([OH:24])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([N:7]2[C:15]3[C:10](=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH:9]=[C:8]2[C:22]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:22]([C:8]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:15]4[C:10]([CH:9]=3)=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=4)=[O:24])[CH2:27][CH2:26]2)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2c(cc(C(=O)O)n2-c2ccccc2)c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2c(cc(C(=O)N3CCCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5n4-c4ccccc4)CC3)n2-c2ccccc2)c(OC)c1OC

Procedure:
1-Phenyl-4,5,6-trimethoxyindole-2-carboxylic acid (91 mg) and homopiperazine (14 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=O)=[N:7][O:8][C:4]=2[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[NH2:27])=[CH:22][CH:21]=1.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3/[CH:11]=[N:27]/[CH:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1-c1noc2cc(Br)ccc12
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Fc1ccc(C(/N=C/c2ccccc2-c2noc3cc(Br)ccc23)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred solution of 2-(6-bromobenzo[d]isoxazol-3-yl)benzaldehyde (compound 7) (2 g) in dichloromethane (33 mL) was added bis(4-fluorophenyl)methanamine (1.74 g) and anhydrous magnesium sulfate and stirred under nitrogen at room temperature for 18 h. Filtration and evaporation of the filtrate and crystallisation from dichloromethane-methanol gave the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:33][CH2:34]C=CCCC)[CH2:10][N:11]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH2:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C[O:43]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:33][CH:34]=[O:43])[CH2:10][N:11]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH2:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCOC1
Reactant: CCCC=CCCC(CN(CCC(=O)O)C(=O)c1c(CC)c(C#N)cc2ccccc12)c1ccc(Cl)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CCc1c(C#N)cc2ccccc2c1C(=O)N(CCC(=O)O)CC(CC=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
To a stirred slurry of N-[2-(3,4-dichlorophenyl)-4-pentenylbutyl]-N-[(carboxymethyl)methyl]-3-cyano-2-ethyl-1-naphthamide (0.51 g) and NaIO4 (0.47 g) in 100 mL 1:1 THF:H2O was slowly added 0.32 mL OsO4 solution (4% w/w in H2O). Mixture was stirred for 18 h, 10 mL sat'd Na2S2O3(aq) was added, THF was evaporated, and aqueous residue was extracted with DCM. Extracts were dried over Na2SO4, filtered, and concentrated. This gave 0.64 g of N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-[(carboxymethyl)methyl]-3-cyano-1-naphthamide after purification by chromatography (100:1, DCM:MeOH); MS: m/z 511 (M+); 1H NMR (CDCl3) δ 9.53 (s), 8.25 (s), 7.79 (d), 7.70-7.20 (m), 6.89 (d), 6.73 (d), 6.48 (dd), 4.58-4.20 (m), 3.88 (s), 3.84 (s), 3.60-3.21 (m), 3.18-2.82 (m), 2.65-2.32 (m), 1.33 (t).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][C@@H:14]([OH:31])[CH2:15][O:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([O:29]C)=[O:28])[CH3:18].O1CCCC1>CO>[F:3][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][C@@H:14]([OH:31])[CH2:15][O:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH3:18]
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C[C@@H]2CCCN2C[C@@H](O)CO[C@H](C)c2ccccc2/C=C/C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
2 N aqueous sodium hydroxide solution (0.36 mL, 0.72 mmol) was added to a solution of methyl (2E)-3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}prop-2-enoate (111 mg, 0.24 mmol), which had been obtained in Example 1 (1f), in mixture of tetrahydrofuran (0.72 mL) and methanol (0.72 mL), and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was added with water (10 mL), subsequently with 1N aqueous hydrogen chloride solution (0.72 mL), and extracted with ethyl acetate (10 mL×2). After that, the organic layers were combined, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a white amorphous substance (71 mg, yield 67%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([CH3:31])=[C:5]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:46])[CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][CH:40]=[C:41]([CH:43]=O)[CH3:42])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:46])[CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][CH:40]=[C:41]([CH3:43])[CH:42]=[CH:6][C:5]1[C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:3]([Cl:2])[C:4]=1[CH3:31])[CH3:33]
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(Cl)c1C

Procedure:
3-chloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce 9-(3-chloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, m.p.: 84°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[CH3:12].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl>O.C(O)C.O1CCCC1>[CH2:15]([O:14][C:13](=[O:17])[CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1)=[O:11])[CH3:16]
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1C
Agent: Cl
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(OC)c(C)c1

Procedure:
At room temperature, to a mixture of 1-(4-methoxy-3-methylphenyl)-ethanone (described in Reference Preparation example 48) and tetrahydrofuran 200 ml was added diethyl carbonate 16.1 g, 55% sodium hydride 6.2 g, dibenzo-18-crown-6 0.05 g and ethanol 3 mL, and the resulting mixture was stirred with heating under reflux for eight hours. To the reaction mixture was added water, and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester 14.8 g.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>CS(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 169 %

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.50 g, 3.0 mmol) in DMSO (5.0 mL) was added with 1-(tert-butoxycarbonyl)piperazine (1.7 g, 8.9 mmol), followed by stirring at 80° C. for 5 hours. The reaction mixture was added with water and the precipitated solid was collected by filtration to obtain 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2cc(F)ccc2F)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2-(2,5-difluorobenzyl)piperidine-4-carboxylate (6.65 g, 24.69 mmol) in DCM (100 mL) and DIPEA (5.16 mL, 29.63 mmol) was added methyl carbonochloridate (2.53 mL, 32.10 mmol) dropwise at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 0.15 M HCl (250 mL). The organic phase was separated, washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(2,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.1 g, 100%). MS m/z 328 (M+H)+
Reaction SMILES: [CH:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.CC(=O)OCC>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][C:15]=1[F:22]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(N)c(F)c1)C1CCCCC1

Procedure:
Ethyl 2-cyclohexyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mixture of EtOH and EA (420 mL) and hydrogenation was carried out in an H-cube (1 bar, 25° C., 1 mL/min and 0.25 mol/L). Following removal of the solvent and drying, 5 g of the desired product were obtained (quantitative conversion).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9])=[O:5]>[OH-].[K+]>[NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1c(N)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Nc1cccc([N+](=O)[O-])c1C(=O)NC(Cc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
1.04 g (3.03 mmol) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate are dissolved in 3 ml 20% ethanolic KOH and stirred for 1.5 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:19])[CH:9]([NH2:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl.[CH2:21]([O:23][C:24]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:25]=1[C:26](=N)OCC)[CH3:22].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:19][C:26]([C:25]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:24]=3[O:23][CH2:21][CH3:22])=[N:18][CH:9]2[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Reactant: NC(CCC1CCCCC1)C(N)c1ccc(Cl)cc1
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CCC2CCCCC2)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-4-(2-cyclohexyl-ethyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-4-cyclohexyl-butane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 441.2309, calculated for C26H34N2O2Cl [(M+H)+]441.2304.
Reaction SMILES: C1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]([OH:19])=[O:18])=[CH:12][CH:13]=3)[N:8]=2)C=CC=CC=1.COC(=O)[C:23]1[CH:28]=[CH:27][C:26](C=O)=[C:25](N)[CH:24]=1.C1(CC=O)C=CC=CC=1>>[C:23]1([C:16]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Reactant: O=C(O)c1ccc2ccc(-c3ccccc3)nc2c1
Agent: O=CCc1ccccc1
Product: O=C(O)c1ccc2cc(-c3ccccc3)cnc2c1
Yield: 87 %

Procedure:
Following the same reaction procedure and workup for Compound 405f, 500 mg (2.8 mmol) of Compound 53 was reacted with 340 mg (2.8 mmol) phenylacetaldehyde to produce 603 mg (87% yield) of the title intermediate.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[NH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[NH2:14][C:9]1[N:8]=[C:7]([NH2:15])[C:6]2[C:11](=[N:12][CH:13]=[C:4]([CH2:3][C:17]([CH2:3][C:4]3[N:5]=[C:6]4[C:11](=[N:12][CH:13]=3)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]4[NH2:15])([NH2:16])[C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[N:5]=2)[N:10]=1
Reactant: NCc1cccc2ccccc12
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CC(N)(Cc3cnc4nc(N)nc(N)c4n3)c3cccc4ccccc34)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N,N dimethylacetamide was added 1-aminomethyl-naphthalene (31.67 ul, 0.22 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 9 mg product was obtained. Yield: 15%; 1H NMR(500 MHz, DMSO-d6): δ 4.0970 (s, 4H), 4.2526 (s, 2H), 7.3530–7.3692 (dd, J1=7.25 Hz, J2=7.25 Hz, 2H), 7.439–7.5202 (m, 2H), 7.5414–7.5553 (d, J=6.94 Hz, 1H), 7.67408–7.69065 (d, J=8.285 Hz, 1H), 7.78789–7.7713 (d, J=8.285 Hz, 1H), 8.14819–8.1313 (d, J=8.44 Hz, 1H), 8.7144 (s, 2H), 8.93305 (s, 2H), 9.23424(s, 2H); ESI-MS: m/z 506 (M++1)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[OH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:39]3[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: OCCN1CCNCC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(CCO)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 1-(2-hydroxyethyl)piperazine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C26H39N7O5SF [(M+H)+] 580.2712, observed 580.2716.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][CH:2]([NH:1][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH3:22])(=[O:32])=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: NC(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: COc1ccccc1S(=O)(=O)NC(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of compound 2b (800 mg, 2.8 mmol) in pyridine (20 mL) was added 2-methoxybenzene-1-sulfonyl chloride (942 mg, 4.5 mmol) at 10° C. The mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in DCM (20 mL), washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=2:1) to give compound 2c as a white solid (1.13 g, 83% yield).