Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.250 g, 0.964 mmol) in CH2Cl2 (10 mL) were added aniline (0.088 mL, 0.964 mmol), HOAt (0.131 g, 0.964 mmol) and EDC (0.222 g, 1.157 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (2×), and the organics were dried over Na2SO4 and concentrated to afford the title compound (0.247 g) as a brown oil. LC-MS (ES) m/z=240 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a stirred solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.24 mmol) in CH2Cl2 (5 ml) was added TFA (1 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 100 mg (93%) of the title product as a light yellow oil. ES-MS m/e: 435.8 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([NH2:22])[CH:21]=[C:15]2[CH2:14]1>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:22][C:20]2[CH:21]=[C:15]3[CH2:14][N:13]([CH3:12])[CH2:18][CH2:17][N:16]3[N:19]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CN1CCn2nc(N)cc2C1
Reactant: Clc1cc(Br)c2nccn2n1
Product: CN1CCn2nc(Nc3cc(Cl)nn4ccnc34)cc2C1

Procedure:
Following the procedures as described in Example 104b, and starting with 8-bromo-6-chloroimidazo[1,2-b]pyridazine 104a, 1.43 g, 6.2 mmol) and 124e (900 mg, 5.9 mmol) afforded 124f was as a yellow solid (800 mg, 44%). MS-ESI: [M+H]+ 304.1
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([C:15]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(SCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(SCc3ccccc3)n2)sc2ccccc12
Yield: 39.4 %

Procedure:
2-Benzylthio-6-cyanopyridine (1.63 g, 7.22 mmol) and methyl thiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml), and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (1.03 g, 44%) as white crystals.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.Cl.[CH3:20][N:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][N:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([O:18][CH2:17][CH2:16][CH2:15][C:4]1[N:3]=[N+:2]([O-:1])[C:7]2[CH:8]=[C:9]3[C:13]([CH2:12][CH2:11][CH2:10]3)=[CH:14][C:6]=2[N:5]=1)=[O:26]
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Reactant: CN(C)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCCC(=O)OCCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A mixture of alcohol 70 (100 mg, 0.41 mmol), 4-(dimethylamino)butanoic acid hydrochloride (68 mg, 0.41 mmol), DCC (93 mg, 0.45 mmol), DMAP (5 mg, 0.04 mmol) and Et3N (0.06 mL, 0.41 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/20% EtOAc/DCM, to give the ester 309 (137 mg, 94%) as a pale-brown oil: 1H NMR δ 8.25 (s, 1H, H-9), 7.74 (s, 1H, H-5), 4.21 (t, J=6.3 Hz, 2H, CH2O), 3.06-3.15 (m, 6H, H-6, H-8, CH2), 2.73 (br s, 2H, H-7), 2.56 [s, 6H, N(CH3)2], 2.37 (t, J=7.0 Hz, 2H, CH2), 2.18-2.29 (m, 4H, CH2), 1.92-1.99 (m, 2H, CH2); 13C NMR δ 172.6, 164.9, 154.9, 149.1, 147.4, 132.3, 122.7, 114.2, 63.7, 57.7, 43.9 (2), 33.6, 33.2, 32.8, 31.3, 26.8, 25.7, 21.0; HRMS calcd for C19H26N4O3 (M+) m/z 358.2005, found 358.2006.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)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>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:14][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:30])=[O:20]
Reactant: CC(C)(C)C(=O)Nc1cnc(N2CCOCC2)cc1I
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 3.50 g (9.0 mmol) N-(4-iodo-6-morpholin-4-yl-pyridin-3-yl)-2,2-dimethyl-propionamide, (0.27 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.34 g (9.9 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated. Purification by flash-chromatography gave 3.23 g (quantitative) of the title compound as a white foam.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>ClCCl>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
To a solution of 4-(4-methoxy-phenoxy)-biphenyl (3.2 g, 11.6 mmol) in anhydrous dichloromethane (60 mL) at −78° C. was added borontribromide (1M solution in dichloromethane) (7.52 g, 30 mmol) over a period of 15 min. The reaction mixture was stirred at −78° C. for 1 h, warmed to rt and stirred at rt for 1 h. The mixture was cooled to 0-5° C. Cold water (125 mL) was added over a period of 10 min and the mixture was extracted with dichloromethane (250 mL). The organic layer was dried over anhydrous Na2SO4. The crude mixture was purified by silica gel flash chromatography to obtain the title product (375 mg, 12%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].C(N(C(C)C)CC)(C)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:48]([CH:44]3[CH2:47][CH2:46][CH2:45]3)=[O:49])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing Example 22) (100 mg, 0.2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, mmol) and cyclobutanecarboxylic acid chloride (0.023 ml, 0.2 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure. The residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA): water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA) water (0.1% TFA) (100:0 by volume) to afford the title compound (Slmg). LCMS (electrospray): m/z [MH+] 547.26. 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.25(m, 8H), 7.20-7.15(m, 2H), 4.70(m, 1H), 4.50(m, 2H), 4.20(m, 2H), 3.95(m, 1H), 2.85(m, 1H), 2.30(m, 2H), 2.20(m, 2H), 2.05(m, 2H), 1.90(m, 1H)
Reaction SMILES: [Cl-].[CH3:2][C:3]([NH3+:7])([CH3:6])[CH2:4]Cl.[CH3:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]=[C:19]=[S:20]>>[CH3:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]=[C:19]1[NH:7][C:3]([CH3:6])([CH3:2])[CH2:4][S:20]1
Reactant: CC(C)([NH3+])CCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC(C)(C)CS1

Procedure:
1,1-Dimethyl-2-hydroxyamine was converted to 1,1-dimethyl-2-chloroethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine HBr salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Temperature: 0 °C

Procedure:
Fuming H2SO4 (25 mL) is added dropwise to a solution of crude 3-chloro-pyridine-1-oxide in concentrated H2SO4 (25 mL) with cooling (0° C.) and stirring. HNO3 (fuming, 90%, 60 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and then allowed to warm up to room temperature slowly. The resulting mixture is then heated at 120° C. for 4 hours with stirring, cooled, and poured into ice-cold water, and extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 3-chloro-4-nitro-pyridine-1-oxide as an yellow solid (10 g) ; 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J=1.5 Hz, 1H), 8.13 (dd, J=1.5, 5.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:8][N:7]=1>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:8]1)=[O:4]
Reactant: Oc1nsc(OCc2ccc(Cl)cc2)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)n1sc(OCc2ccc(Cl)cc2)nc1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
5 ml of methyl isocyanate were added to a solution of 12.1 g of 3-hydroxy-5-(p-chlorobenzyloxy)-1,2,4-thiadiazole in 150 ml tetrahydrofuran and the mixture was stirred for 2 hours and 20° C and then concentrated to dryness. The residue was crystallized from ethyl acetate to obtain 7.3g of 2-(N-methylcarbamoyl)-5-(p-chlorobenzyloxy)-1,2,4-thiadiazole-3-one melting at 145° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid (25 g, 136 mmol) in DMF (125 mL) was added K2CO3 (37.8 g, 273 mmol). Then dimethyl sulfate (48.2 g, 382 mmol) was added dropwise to the mixture at rt. The mixture was stirred at rt overnight. Then the reaction was quenched by the addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×2). The combined organic layers were washed with water successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step A (26.8 g, 99.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.10-8.18 (m, 2H), 7.97-8.03 (br, 1H), 6.95-7.03 (m, 1H), 4.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[OH:31])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:9][C:8]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=O.[O-:34][C:35]#[N:36].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[OH:31])[CH2:5][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:11][CH:12]=2)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:36][C:35]1=[O:34]
Reactant: C#CCOc1ccc(NCc2cc(Cl)c(O)c(OC)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cc(Cl)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 43.1 mg (0.093 mmol) of [2-(3-Chloro-4-hydroxy-5-methoxy-benzyl-amino)-5-prop-2-ynyloxy-phenyl]-(4-isopropyl-phenyl)-methanone in 1 ml of acetic acid is added 12.1 mg (0.186 mmol) of sodium cyanate. After stirring for 12 h at r.t. the solvent is removed in vacuo and the residue partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography (SiO2, hexane/ethyl acetate) affords the title compound as an amorphous yellow solid.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:5][NH:6][C:7](=[NH:9])[NH2:8])=[O:17])[CH3:16]
Reactant: CCOC(=O)C(=O)Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)NNC(=N)N
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
To a solution of 1-aminoguanidine carbonic acid salt (12 g, 88 mmol) in pyridine (50 ml) was added ethyl 2-chloro-2-oxoacetate (10 g, 73.24 mmol). The resulting solution was stirred for 12 h at room temperature. The resulting solution was diluted with PE (200 ml). The solids were collected by filtration and then dissolved in water (50 ml), the pH was adjusted to 8 with NaOH (aq., 10N). The product precipitated and was filtered to afford ethyl 2-(2-carbamimidoylhydraziny)-2-oxoacetic acid as a white solid (2 g, 19%).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[F:30])[CH3:21].[H-].[Na+]>C1COCC1>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:2][CH:3]2[CH2:8][CH2:7][CH:6]([CH:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]3)[CH2:5][CH2:4]2)=[CH:25][C:24]=1[F:30])[CH3:21]
Reactant: CCOc1ccc(O)cc1F
Reactant: CCCCCC1CCC(C2CCC(CI)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(COc3ccc(OCC)c(F)c3)CC2)CC1
Yield: 39 %

Procedure:
1-Iodomethyl-4-(4-pentylcyclohexyl)cyclohexane (9.8 g, 26 mmol) was reacted with 4-ethoxy-3-fluorophenol (3.7 g, 24 mmol) in THF (60 ml) in the presence of NaH (ca. 24 mmol) used as a base. After treatment was carried out by the same method as in Example 3 to obtain 1-ethoxy-2-fluoro-4-(4-(4-pentylcyclohexyl)cyclohexyl)methyloxybenzene (yield: 39%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@H]1CCNC1

Procedure:
To (3 S)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((S)-pyrrolidin-3-yl)acetamide. (33 mg, 0.069 mmol)
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Product: Cc1cccc(-c2ccccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3′-Methyl-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=471.2.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[CH3:24][N:25]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CC(N(C)C)=O>[CH3:24][N:25]([CH:33]1[CH2:34][CH2:35][N:36]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)[CH2:37][CH2:38]1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
DIPEA (1.355 mL, 7.78 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.865 g, 3.89 mmol) and tert-butyl methyl(piperidin-4-yl)carbamate (1 g, 4.67 mmol) in DMA (15 mL). The resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was evaporated and diluted with DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl methyl[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]carbamate (1.500 g, 96%) as a solid.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([C:16]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>COCCO>[OH:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([C:16]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COCCOc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1
Solvent: COCCO
Product: O=C(Nc1nnn[nH]1)c1nc2ccccc2nc1OCCO

Procedure:
3-(2-Methoxyethoxy)-N(1H-tetrazol-5-yl)-2-quinoxalinecarboxamide, m.p. 246°-247°, from 2-methoxyethanol (85%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:19])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC1(C)CN(c2ccc(Cl)nn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(Cl)nn2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(6-chloropyridazin-3-yl)-4,4-dimethylimidazolidin-2-one (Example 154, step 2) (140 mg, 618 μmol) in DMF (3 ml) was added 60% sodium hydride suspension (37.1 mg, 926 μmol, 1.5 equiv.). After stirring at room temperature for 10 min, iodomethane (132 mg, 57.9 μl, 926 μmol, 1.5 equiv.) was added and the suspension was stirred for 1 hour at room temperature. The solvent was removed in vaccuo and the residue was worked up with ethyl acetate/water. The title compound was obtained as a crystalline light brown solid (129 mg, 87% yield), MS: m/e=241.2, 243.4 (M+H+).
Reaction SMILES: [Br:1]Br.[CH:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[C:5]([OH:11])[CH:4]=1>C1C=CC=CC=1>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][Br:1])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: BrBr
Solvent: c1ccccc1
Product: Oc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dried bromine gas (Br2) was blown through a mixed solution of 33 g of p-hydroxybenzyl alcohol ##STR133## and 900 ml of benzene for 2 hours while cooling the solution with ice water. Thereafter, the solution was stirred for 2 hours, and then distilled to obtain p-hydroxybenzyl bromide ##STR134## The boiling point of this compound was 125°-126° C./15 mmHg.