Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[NH:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>C(Cl)(Cl)Cl>[C:9]([NH:3][CH2:4][CH2:5][NH2:6])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: CNCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.2 %

Procedure:
The intermediate N-t-BOC, N-methyl-ethylenediamine monohydrochloride prepared in example 5 (10 mmol, 2.1 g) was stirred with 2M NaOH (11 cm3) at room temperature for 10 min. The solution was then cooled to 0° C., and to this, was added a solution of methacryloyl chloride (11 mmol, 1.1 cm3) in chloroform (30 cm3), dropwise. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 1 h. The organic and aqueous phases were then separated, and the aqueous phase extracted with chloroform. The organic extracts were combined, dried (MgSO4), filtered and conc. in vacuo, to give the crude product. The crude product was stirred at room temperature over a slurry of basic alumina in chloroform for 18 hr. Removal of the alumina and concentration of the filtrate then gave a pale yellow oil. Purification by flash chromatography (silica gel, diethyl ether: hexane : methanol elution) afforded N-t-BOC, N-methyl, N′-methacryloyl-ethylenediamine (Rf0.51) as a yellow oil (1.63 g, 67%). δH (400 MHz; CDCl3) 6.94 (1H, br s), HNOC(H3C)C═CHaHb; 5.74 (1H, br m), (H3C)C═CHaHb; 5.30 (1H, br m), (H3C)C═CHaHb; 3.43 (4H, br m), 2×CH2; 2.87 (3H, s), N(CH3); 1.93 (3H, br m), CH3; 1.44 (9H, s), C(CH3)3. δC (75.4 MHz; CDCl3) 168.52, NHOC(H3C)C═CH2; 157.33, NHCO2C(CH3)3; 139.36, (H3C)C═CH2; 119.81, (H3C)C═CH2; 80.85 C(CH3)3; 47.32, CH2N(CH3)OC(H3C)C═CH2; 39.32, CH2NHCO2C(CH3)3; 34.68, N(CH3); 28.33, C(CH3)3; 18.47, CH3. Found: (HM+.) 243.17178.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[CH:29](=O)[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C=C(C=C(OC)C=1C)C(NCC1C=CC(C2N=C(C)ON=2)=CC=1NCCC1C=CC=CC=1)=O>>[CH3:17][O:16][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[CH3:15])[C:6]([NH:5][CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[CH:22][C:2]=1[NH:1][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:18]
Reactant: O=CCCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCCc2ccccc2)cc(OC)c1C

Procedure:
Compound 1g (50 mg, 0.13 mmol) was reductively aminated with hydrocinnamaldehyde (0.020 mL, 0.15 mmol) following a procedure analogous to the preparation of compound 9a to afford compound 10a. ESI-MS m/e 501.4 (M+1).
Reaction SMILES: [N:1]1[NH:2]N=N[C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:24](Cl)(=[O:34])[C:25]1[CH:33]=[CH:32][CH:31]=[C:27]([C:28](Cl)=[O:29])[CH:26]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:34][C:24]([C:25]3[CH:33]=[CH:32][CH:31]=[C:27]([C:28]4[O:29][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[C:14]([C:18]7[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=7)[N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:1][N:2]=4)[CH:26]=3)=[N:2][N:1]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:13]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2cccc(-c3cccc(-c4nn[nH]n4)n3)n2)nc1
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3cccc(-c4nnc(-c5cccc(-c6nnc(-c7cccc(-c8cccc(-c9ccccn9)n8)n7)o6)c5)o4)n3)n2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
2.0 g of 6-(2H-tetrazol-5-yl)-2,2′:6′2″-terpyridine was dissolved in 50 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 30 ml was dehydrated by azeotropy. After cooling to 50° C., 0.68 g of isophthaloyl dichloride was added. Temperature was elevated to 110° C., and stirring was conducted for 3 hours under flux. After cooling to room temperature, the reaction solution was poured into 200 ml water, and a precipitated yellowish-brown solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 80° C. for 20 hours, and purified with adsorption purification (carrier: NH silica gel, eluting solution: chloroform) to obtain 1.53 g (yield 67%) of TpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.12 ppm (1H), 8.85 ppm (2H), 8.62-8.73 ppm (6H), 8.37-8.51 ppm (6H), 7.79-8.12 ppm (7H), 7.35 ppm (2H).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][O:9][C:10](=[O:13])[CH2:11][NH2:12].[CH:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])=[O:15]>O1CCCC1>[CH3:8][O:9][C:10]([CH2:11][NH:12][C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH:19]=[O:20])=[O:15])=[O:13]
Reactant: O=Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 20.1 %

Procedure:
To a mixture of 200 ml of tetrahydrofuran, 26.00 g of pyridine and 20.70 g of glycine methyl ester hydrochloride was added a solution of 16.00 g of 3-formylbenzoic acid chloride in 20 ml of tetrahydrofuran at 10° C. After stirred at room temperature for 60 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4.23 g of oily 3-[[(methyoxycarbonylmethyl)amino]carbonyl]benzaldehyde [Compound No. (b)].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3o2)cc1
Reactant: C1CCNCC1
Agent: Cl
Product: C(=C/c1nc2ccccc2o1)\c1ccc(OCCCN2CCCCC2)cc1
Yield: 41 %

Procedure:
The procedure of Example 1 was followed starting with (C) of Example 1 (2.0 g, 6.4 mmol) and using piperidine in place of dibutylamine to produce 1.1 g, (41% yield) of the named compound as the HCl salt, mp 127°-128° C. IR(KBr): 3400,1600 cm−1. MS: 363(MH+). 1H NMR (CD3 OD): δ 7.89-6.81 (m, 10H), 4.24 (t, J=5.5 Hz, 2H), 2.65 (m, 6H), 1.75 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1.B.O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][CH2:8][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc(Cl)cc2)CC1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNCc2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To a solution of 4-(N-(4-chlorobenzyl)aminocarbonyl)-1-t-butoxycarbonylpiperidine (1.76 g, 5.0 mmol) in dry tetrahydrofuran (20 mL) stirring under argon at room temperature, was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 20 mL, 20 mmol). The resulting solution was heated to 80° C. for 16 h before cooling to 0° C. Saturated aqueous ammonium chloride (20 mL) was added, and the resulting mixture was stirred for 30 min before extraction with ethyl acetate (25 mL three times). The combined extracts were dried (anhydrous sodium sulfate) and evaporated under vacuum to obtain a gum, which was purified by column chromatography (silica gel, 100% ethyl acetate) to provide 4-(N-(4-chlorobenzyl)aminomethyl)-1-t-butoxycarbonylpiperidine (1.37 g, 81% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.O=[C:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].CO>[CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C4CCOCC4)CC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (44.0 mg, 0.105 mmol), 4-oxotetrahydropyran (37.7 mg, 0.366 mmol) and sodium triacetoxyborohydride (100 mg, 0.471 mmol) in 1,2-dichloroethane (1.0 mL) was stirred at room temperature over the weekend. The reaction was diluted with saturated NaHCO3 (aq) and methanol. The mixture was concentrated to dryness and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((3-methyl-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.34 (26 mg) as its trifluoroacetic acid salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:7]([CH3:8])[C:6]=1[CH3:14])=[O:4].CN(C)C=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O>[N:20]1([CH2:2][C:3]([C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:7]([CH3:8])[C:6]=2[CH3:14])=[O:4])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(C)c(C)c(C(=O)CBr)c1C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(C)c(C(=O)Cn2ccnc2)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture containing 2.55 g of 3-bromoacetyl-durene, prepared as described in Example 4, 3 ml of dimethylformamide and 3.40 g of imidazole, was stirred for 8 hours at 80° C. At the end of the reaction, the mixture was cooled to room temperature and 25 ml of water were added. The precipitate thus obtained was filtered off, dried and crystallized from benzene to give 1.5 g of the title compound. M.P. 176°-8° C., yield 62%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20]CCCO)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30](F)[CH:29]=2)[CH:7]=1)=[O:5])[CH3:2].C(OC(C1C2NC3C=C(O)C=CC=3C=2C(C)(C)C[N:44]([C:59](=[O:67])[C:60]2C=CC(F)=CC=2)C=1)=O)C.C(N(C(C)C)CC)(C)C.BrCCCO>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:60][C:59](=[O:67])[NH2:44])[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1cc(OCCCO)ccc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Agent: OCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OCC(N)=O)ccc21
Temperature: 75 °C
Reaction time: 10 h

Procedure:
To prepare 3-(3,4-difluoro-benzoyl)-1,1-dimethyl-8-(3-hydroxy-propoxy)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, A mixture of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]-indole-5-carboxylic acid ethyl ester (46 mg, 0.11 mmol), diisopropylethylamine (0.5 mL), and 3-bromo-1-propanol (1.4 mL) in dry acetonitrile (1 mL) was stirred at 75° C. for 10 hours. The solvent was removed in vacuo, and the residue was purified by preparative reverse-phase HPLC, which was then acylated in the manner described in Example 2A. 1H NMR (CDCl3): δ 10.51 (1H, s), 7.86 (1H, s), 7.82 (1H, d), 7.66-7.59 (2H, m), 7.15-7.09 (2H, m), 6.87 (1H, d), 6.74 (1H, m), 4.27-4.15 (4H, m), 4.09 (2H, brs), 3.90 (2H, m), 2.11-2.05 (2H, m), 1.60 (6H, s), 1.26-1.21 (3H, m). MS (ES): 481 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:25]2([CH2:29][CH:28]([OH:30])[CH2:27][O:26]2)[CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:22][C:25]4([CH2:29][CH:28]([OH:30])[CH2:27][O:26]4)[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC1COC2(CNC2)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2(CC(O)CO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-oxa-2-azaspiro[3.4]octan-7-ol hydrochloride in the presence of TBTU and DIEA to obtain the title compound as yellow oil; MS (EI): m/e=396.5 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (255 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (496 mg), potassium carbonate (415 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column. chromatography, and methyl [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (501 mg, yield 72%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Brc1ccccn1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccn2)CC1
Temperature: 150 °C

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (5.0 g, 25.0 mmol) (Aldrich) and 2-bromopyridine (1.98 g, 12.50 mmol) (Aldrich) were combined in a sealed tube and heated at 150° C. for 12 hours. The mixture was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48 (m, 9H), 1.88–2.02 (m, 2H), 3.20–3.48 (m, 2H), 3.52–3.70 (m, 4H), 3.72–3.83 (m, 2H), 6.45–6.59 (m, 2H), 7.47 (m, 2H), 8.11–8.18 (m, 1H); MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].ClS([N:43]=[C:44]=[O:45])(=O)=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:44]([NH2:43])=[O:45]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[3,5-Bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (40.3 mg, 0.073 mmol) (Example 20) was dissolved in CH2Cl2 (3 mL) and the solution was cooled to −78° C. Chlorosulfonyl isocyanate (32 μL, 0.367 mmol) was added dropwise by syringe. The reaction was stirred at −78° C. for 15 minutes, and then at 0° C. for 20 minutes. The reaction was then poured into H2O (15 mL) and saturated NaHCO3 (15 mL) was added. The mixture was extracted with CH2Cl2 (2×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 50% EtOAc/hexanes afforded N-[3,5-bis(trifluoromethyl)benzyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}urea. Rf=0.24 (40% EtOAc/hexanes). LCMS=593.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.75 (s, 1H), 7.66 (s, 2H), 7.60 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.5, 2.3 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.80 (d, J=15.8 Hz, 1H), 4.53 (s, 2H), 4.48 (d, J=15.8 Hz, 1H), 4.45 (d, J=17.8 Hz, 1H), 4.07 (d, J=17.8 Hz, 1H), 3.69 (s, 3H), 2.87 (m, 1H), 1.20-1.22 (m, 6H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([O:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)CC(=O)C>O>[OH:13][C:11]1([CH2:12][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 37.5 parts of 6-(phenylmethyl)-1-oxa-6-azaspiro[2.5]octane, 24.9 parts of ethyl 4-hydroxybenzoate, 20.7 parts of potassium carbonate and 200 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. After cooling, water was added. The precipitated product was filtered off, washed with water and crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 23 parts (41.5%) of ethyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzoate; mp. 100.2° C. (int. 78).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) were dissolved in dichloromethane (1000 ml), the solution was cooled in an ice bath and triethylamine (219 ml) was added portionwise such that the reaction temperature was kept below 20° C. Propionyl chloride (137 ml) was then added over 1 hour and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water followed by brine, then dried (anhydrous magnesium sulphate) and the solvent removed under reduced pressure to yield 4-bromophenyl propionate (344 g) as a green oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].I[CH2:25][CH3:26].[H-].[Na+].O>CN(C=O)C>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6])[CH3:26]
Reactant: CCI
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(I)ccnc21
Reaction time: 0.33 h
Yield: 78 %

Procedure:
Compound (158a) (1.50 g) and iodoethane (2.8 mL) were dissolved in DMF (35 mL), and sodium hydride (0.335 g, a 55% dispersion in paraffin liquid) was added to the resulting solution under ice cooling, followed by stirring for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 3-(ethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. This 3-(ethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (15 mL), and a hydrogen peroxide solution (30 wt %) (0.563 mL) and a 4 mol % aqueous sodium hydroxide solution (2.48 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (162a) (1.29 g, the second stage yield: 78%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:17]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:17]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3ccccc3s2)cc1I
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution in acetic acid (35 ml) of 2-(4'-aminophenyl) benzothiazole (2.98 g, 0.0132 mol) prepared as above was added dropwise a solution of iodine monochloride (2.78 g, 0.0171 mol) in acetic acid (35 ml) over 10 minutes at room temperature, followed by stirring for 11/2 hours. After evaporation of the solvent, 60 ml dichloromethane was added to the residue and the resulting suspension was neutralised with sodium hydrogen carbonate. Then 300 ml of water was added. The organic layer was washed with 10% sodium hydrogen carbonate solution (150 ml), water (100 ml×2) and dried (mgSO4). The solvent was removed under reduced pressure, absorbed onto silica gel, and placed on top of a column of silica gel. Flash elution using ethyl acetate-hexane (2:5) yielded brown crystals (3.32 g, 69.6%), m.p. 143-144° C.