Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([NH2:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:25](OC)(OC)(OC)[CH3:26].C(O)(C(F)(F)F)=O>C1COCC1>[CH2:22]([C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:24]=[C:25]2[CH3:26])=[CH:21][CH:20]=1)[CH3:23]
Reactant: COC(C)(OC)OC
Reactant: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2N)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-n2c(C)nc3ccc(O)nc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(Benzyloxy)-N2-(4-ethylphenyl)pyridine-2,3-diamine (358 mg, 1.12 mmol) was dissolved in THF (1.0 mL). Trimethyl orthoacetate (1.0 mL) was added followed by TFA (10 μL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The benzyl group was then removed as described in Example 1.98, Step B to give the title compound as a white solid (55.3 mg). LCMS m/z=254.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:21])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][NH:19][CH:20]=2)[CH:15]=1.[Br:22]N1C(=O)CCC1=O>C(COC)OC>[Br:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:21])[NH:12][N:13]=[C:14]([C:16]2[CH:20]=[N:19][NH:18][CH:17]=2)[CH:15]=1
Reactant: O=c1[nH]nc(-c2cn[nH]c2)cc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: COCCOC
Product: O=c1[nH]nc(-c2cn[nH]c2)cc1-c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
39 mg of 4-(1H-indol-2-yl)-6-(1H-pyrazol-4-yl)-2H-pyridazin-3-one is dissolved in dimethoxyethane and 28 mg of N-bromosuccinimide is added. The solution is stirred for 3 h at RT. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 11 mg. LC-MS (ES+) 355/357 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C(OC([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[C:37]3[C:32](=[CH:33][C:34](F)=[CH:35][CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)=O)(C)(C)C>CS(C)=O.O>[NH:22]1[CH2:23][CH2:24][CH:25]([C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:35][CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1nc(C2CCNCC2)c2ccc(OCC3CCOCC3)cc2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of (tetrahydro-pyran-4-yl)-methanol (0.2 mmol), KOtBu (0.2 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 12b, in DMSO (1 mL), was stirred at 80° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo.
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[CH2:1]([CH:8]([CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)Cn1cccn1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(Cc1ccccc1)Cn1cccn1
Reaction time: 1 h
Yield: 101.9 %

Procedure:
The resultant compound from Example 46 (100.0 mg, 0.409 mmol) in dioxane (2 ml) at 0° C. was treated with LiOH.H2O (22.0 mg, 0.524 mmol) in water (1 ml). After 1 h at 0° C. and 30 min at room temperature the solvent was evaporated and the residue was taken up in water, the pH was adjusted to pH 3-4, and the mixture was extracted with CHCl3 which was dried over Na2SO4 and evaporated to afford 96 mg (100%) of a solid. 1H NMR (CDCl3) δ7.56 (d,1H), 7.10-7.35 (m,6H), 6.26 (dd,1H), 4.30 (m,2H), 3.34 (m,1H), 3.12 (dd,1H), 2.72 (dd,1H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(OC([NH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:16]1[CH2:17][CH2:18][CH:14]([NH2:13])[CH2:15]1)=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(N)C1
Reaction time: 0.5 h

Procedure:
Add methyl chloroformate (460 μL, 560 mg, 6.0 mmol, 3.0 equiv) to a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (TCI; 373 mg, 2.00 mmol, 1 equiv) and triethylamine (1.1 mL, 800 mg, 7.9 mmol, 3.9 equiv) in anhydr CH2Cl2 (4 mL). Vigorous gas evolution, a slight exotherm, and precipitation can occur. After stirring 30 min, rotary evaporate the reaction mixture (60° C.). Dissolve the resultant material in MeOH to quench any residual chloroformate and rotary evaporate the solution (60° C.). Add trifluoroacetic acid (5 mL) to this material causing gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 2× with MeOH). Resultanting in a yellow oil then dissolve in MeOH (30 mL) and add hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 9.3 g) to free-base the amine. Filter the mixture and evaporate the filtrate by rotary (40° C.; azeotroped 2× with CH2Cl2) to yield 914 mg (300%) of crude product as a light-brown oil. Mass spec indicates desired product is present. Absorb this oil to an SCX column (20 g) activated with 10% AcOH/MeOH. Push MeOH through the column to elute any non-amine material. Elute the product with 2.0 M NH3 in MeOH to yield 269 mg (93.2%) of 3-amino-pyrrolidine-1-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([SH:11])=[N:8][C:9]=1[CH3:10].[CH3:13][O-].[Na+].IC>CO>[OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([S:11][CH3:13])=[N:8][C:9]=1[CH3:10]
Reactant: Cc1nc(S)[nH]c(=O)c1CCO
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(C)c(CCO)c(=O)[nH]1
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a stirred suspension of 90 parts of 5-(2-hydroxyethyl)-2-mercapto-6-methyl-4(3H)-pyrimidinone in 320 parts of methanol were added 90 parts of a sodium methoxide solution 30%. After stirring for 20 minutes, 72 parts of iodomethane were added and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated in vacuo and water was added to the residue. The precipitated product was filtered off and crystallized from ethanol, yielding 78 parts (78%) of 5-(2-hydroxyethyl)-6-methyl-2-(methylthio)-4(3H)-pyrimidinone (interm. 1).
Reaction SMILES: [CH2:1]([C:37]([O:39]CC)=[O:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].CC([O-])(C)C.[K+].[O-][Mn](=O)(=O)=O.[K+]>CC(O)(C)C>[C:33]([O:32][C:30]([C:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:37]([OH:39])=[O:38])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of compound from step 3 (0.037 mmol) in tBuOH (1 mL) is added a solution of KOtBu (114 mg, 1.012 mmol) in tBuOH (2 mL) at 30° C. under N2. The mixture is stirred at r.t. and monitored by TLC (1:1 EtOAc/hexanes, KMnO4, reflux). After the reaction is completed, the reaction mixture is quenched with 1 M HCl (20 mL) and extracted twice with EtOAc (25 mL). The organic layers are combined, dried over Na2SO4, filtered and concentrated. The material was carried on to the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][O:27][CH3:28].Cl.N1C=CC=CC=1>CCO>[CH3:28][O:27][N:26]=[C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)[CH3:14]
Reactant: CON
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-ethanone (Compound 77, 15 mg, 0.04 mmol), NH2OMe—HCl (15 mg, 0.18 mmol) and pyridine (14 mg, 0.18 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid. (12 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CCNCC
Product: CCOC(=O)c1cnc(N(CC)CC)c(Cl)c1
Temperature: 80 °C
Reaction time: 72 h
Yield: 86.1 %

Procedure:
A mixture of 5,6-dichloronicotinic acid ethyl ester (2.91 g, 15.2 mmol) and diethyl-amine (11.1 g, 152 mmol) is stirred in a sealed vessel at 80° C. for 72 h. The mixture is cooled to rt and concentrated. The residue is dissolved in DCM (15 mL) and washed with 1 N aq. KHSO4 solution (2×50 mL). The washings are extracted back with DCM (50 mL). The combined org. extracts are dried over Na2SO4, filtered, concentrated and dried to give 5-chloro-6-diethylamino-nicotinic acid ethyl ester (3.36 g) as a yellow oil; LC-MS: tR=1.08 min, [M+1]+=257.12; 1H NMR (CDCl3): δ 1.26 (t, J=7.0 Hz, 6H), 1.39 (t, J=7.3 Hz, 3H), 3.62 (q, J=7.0 Hz, 4H), 4.36 (q, J=7.3 Hz, 2H), 8.07 (s, 1H), 8.70 (s, 1H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Br[CH:13]([OH:15])[CH3:14].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:1]([NH:4][N:5]([CH2:14][CH2:13][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(O)Br
Reactant: CC(=O)NNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NN(CCO)c1ccccc1
Yield: 34.8 %

Procedure:
To a solution of 1-acetyl-2-phenylhydrazine (2 g, 13.3 mmol) in anhydrous toluene 20 ml was added bromoethanol (1.04 ml, 14.6 mmol), diisopropylethylamine (2.54 ml, 14.6 ml) at room temperature. The reaction mixture was refluxed under nitrogen for 40 hours. After cooling, the reaction was then quenched with 100 ml water, extracted with dichloromethane 2×100 ml. The organic was dried (MgSO4) and removed in vacuo. The residue was purified by flash column chromatography over silica using a gradient 50% mixture of ethyl acetate and hexane to 100% ethyl acetate as eluant. Appropriate fractions were combined and the solvent was removed in vacuo to give the product as a yellow oil 0.9 g (Yield 35%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccn(C)c(=O)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccn(C)c(=O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 4-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI+): m/z=425.1 ([M+H]+, 1Br).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[OH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[OH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=1[C:24](=[O:25])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1ccc(C(=O)Cl)c(O)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1

Procedure:
Prepared according to above procedure using diisopropylamine (3.8 mL, 28 mmol), nBuLi (21 mL, 1.2 M), tert-butyl acetate (2.1 mL, 16 mmol), 2-hydroxy-4-methylbenzoyl chloride (5 mmol, prepared from 760 mg 4-methyl-salicylic acid and SOCl2, 1.2 mL, heated to 47° C. in 12 mL toluene for 4 h) yielding 327 mg (26%) as white needles. mp=88-90° C.; IR (film) 1733.8; 1652.6; 1145.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.95 (s, 1H); 7.54 (d, J=8.2 Hz, 1H); 6.81 (s, 1H); 6.72 (d, J=8.2, 1H); 3.88 (s, 2H); 2.36 (s, 3H); 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 198.5, 166.5, 163.0, 148.9, 130.5, 120.7, 118.8, 117.2, 82.6, 47.4, 28.1, 22.2; LRMS (electrospray): Mass calculated for C14H18O4, [M]+, 250.12. Found [M+23]+, 272.9.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1cccs1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cccs2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.5 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.400 g, 1.56 mmol) was reacted with 2-thiophene carboxaldehyde (0.264 g, 2.35 mmol) in 5.0 mL of 4% KOH in EtOH for 4.5 hours at room temperature to afford 0.369 g (67%) of the title compound as dark yellow crystals, mp 137-138° C.: CI-MS m/e 350 (M+), 351 M++1);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:22][CH:21]=3)=[N:16][C:17]#[N:18])[N:8]=[C:7]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:6]=2[CH:43]=1.O.FC(F)(F)C(O)=[O:48]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14]/[C:15](/[NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:22][CH:21]=3)=[N:16]/[C:17]([NH2:18])=[O:48])[N:8]=[C:7]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:6]=2[CH:43]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C(=O)C(NC(=NC#N)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C(N/C(=N/C(N)=O)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 40.8 %

Procedure:
A mixture of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N″-cyano-N′-[4-(4-morpholinyl)-1-naphthalenyl]guanidine (EXAMPLE 10) (21.9 mg, 35.8 μmol), water (4.6 μL, 260 μmol) and trifluoroacetic acid (19.8 μL, 257 μmol) in THF (3 mL) was heated to reflux for 43 h. The reaction was concentrated in vacuo, and the residue was purified by reverse phase HPLC (gradient 20-70% CH3CN in H2O) to provide the title compound (0.0092 g, 35%) as its TFA salt. 1H-NMR (CD3OD): δ 8.37 (br s, 1H), 8.06 (br s, 1H), 7.75-7.41 (br m, 9H), 7.26 (br s, 1H), 7.04 (br s, 1H), 5.66 (br s, 1H), 4.00 (br s, 4H), 3.58 (br s, 3H), 3.17 (br s, 4H). HRMS calculated for (C32H29Cl2N7O3+H) (M+H)+: 630.1787. Found (ESI): 630.1800.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:26][C:25]([C:45]([CH3:48])([CH3:47])[CH3:46])=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:45]([C:25]1[CH:26]=[C:27]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[CH:36][CH:37]=2)=[O:30])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:18][CH:19]=2)[N:24]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3ccc(Oc4cccnc4)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3cccnc3)cc2)n(-c2ccc(OCCC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
4-{2-[4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester was coupled with 4-(pyridin-3-yloxy)phenylamine by reaction with CDI in a similar manner to that described above, to provide the urea 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (LC-MS [M+H]+=655, RT=3.51 min). Step 2. To a solution of 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.32 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred at room temperature for 16 h, concentrated at reduced pressure, re-dissolved in methanol and purified by preparative HPLC. The HPLC fraction containing the desired product was basified by addition of saturated aq Na2CO3 and then extracted with EtOAc. Evaporation of the solvent at reduced pressure gave the desired product 1-{5-tert-butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea (46.6 mg, 26%). 1H-NMR (DMSO-d6) δ 9.20 (s, 1H), 8.30 (m, 3H), 7.45-7.35 (m, 5H), 7.00 (m, 3H), 6.30 (s, 1H), 4.0 (m, 4H), 2.40 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=555.3, RT=2.73 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:19]1[CH:20]=[CH:21][C:22](C)=[C:23](O)[CH:24]=1.COCCOC>CCOC(C)=O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(I)cc1O
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2)cc1
Yield: 50.8 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (4.55 g, 21.38 mmol), Na2CO3 (32.1 ml 2 N aqueous, 64.2 mmol), Pd(PPh3)4 (1.24 g, 1.07 mmol), 5-iodo-2-methylphenol (Hodgson, Moore J. Chem. Soc. 1926, 2038) (5.0 g, 21.38 mmol), and ethylene glycol dimethyl ether (225 ml) was heated to reflux overnight. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Chromatography (30% EtOAc/hexanes) afforded 1.64 g (36%) product as a white solid and 2 g 4-methoxy biphenyl as an undesired by-product: mp 146–147° C.; 1H NMR (300 MHz, DMSO-d6): δ 2.13 (3H, s), 3.78 (3H, s), 6.94 (1H, dd, J=8.1 Hz, 2.7 Hz), 7.00 (3H, m), 7.09 (1H, d, J=8.1 Hz), 7.48 (1H, d, J=9.5 Hz), 9.36 (1H, s).
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].O>C1COCC1>[CH3:26][CH:25]([CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)CCCCBr
Reactant: COC(=O)C1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CCCCC(C)C)CCCC1
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
To a solution of methyl cyclopentanecarboxylate (300 mg, 2.3 mmol) in THF (20 ml) at −78° C. was added LHMDS (4.6 mL, 4.6 mmol) and stirred for 30 min, and followed by 1-bromo-5-methylhexane (626 mg, 3.5 mmol). The mixture was stirred from −78° C. to rt over 16 hr, before 30 ml of H2O was added and then was extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated, then purified using flash chromatography to give an oil (110 mg, 21%). MS [M+H]+333.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15](=[O:21])[NH:14][C:13]=2[N:12]=1)(=O)=O.[Na+].[I-].CCN(CC)CC.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]1[CH2:45][CH2:44][CH2:43][N:42](CCCCOC2C=C3C(CCC(=O)N3)=CC=2)[CH2:41][CH2:40]1>CC#N>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]3[C:18]([CH2:17][CH2:16][C:15](=[O:21])[NH:14]3)=[CH:19][CH:20]=2)[CH2:41][CH2:40]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Intermediate 12 (85 mg, 0.27 mmol) was dissolved in CH3CN then NaI (55 mg, 0.37 mmol), Et3N (91 mg, 0.9 mmol), and intermediate 2 (102 mg, 0.36 mmol) were added. The resulting mixture was stirred at 70° C. overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (compound 3) (78 mg, 63%). 1H NMR (300 MHz, CDCl3): δ 7.64 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H), 4.36 (t, J=6.0 Hz, 2H), 3.61-3.49 (m, 7H), 3.32-3.20 (m, 5H), 2.90-2.85 (m, 2H), 2.67-2.62 (m, 2H), 2.21-2.16 (m, 2H), 1.90-1.85 (m, 2H). HPLC: 99%, RT 2.682 min. MS (ESI) m/z 463.1 [M+H]+. mp: 110-111° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[Cl:28][C:26]1[CH:25]=[C:17]([CH:16]=[C:15]([Cl:14])[CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Nc1ncn(Cc2cc(Cl)cc(Cl)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cc(Cl)cc(Cl)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3,5-dichloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (yield=27%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].C([O-])(O)=O.[Na+].[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>CO>[CH2:12]([S:14]([NH:1][NH:2][C:3]([NH:5][NH:6][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[O:4])(=[O:16])=[O:15])[CH3:13]
Reactant: CCS(=O)(=O)Cl
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)NNC(=O)NNS(=O)(=O)CC
Reaction time: 1 h

Procedure:
A mixture of 45 g (0.5 mole) carbohydrazide, 85 g NaHCO3 (1.0 mole) and 250 ml methanol was stirred and 128.5 g (1.0 mole) ethane sulfonyl chloride was dropped in. The temperature rose from 25° to 45° C during the reaction which took 1 hour. Stirring was continued for two hours. The product was filtered, washed and dried. Yield: 145.9 g m.p. 195° C.