Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:21]1[CH:22]2[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]2)[CH2:20]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
(R)-2-((tert-Butoxycarbonyl)amino)-2-phenylacetic acid (5.0 g, 19.9 mmol), (R)-quinuclidin-3-ol (3.8 g, 29.8 mmol), N,N′-Dicyclohexylcarbodiimide (4.72 g, 22.9 mmol) and 1-hydroxybenzotriazole hydrate (3.09 g, 22.9 mmol) where mixed together in tetrahydrofuran (175 mL) and stirred at ambient temperature for 18 hours. After this time the reaction mixture was filtered through a pad of Celite® and concentrated in vacuo. The resulting crude was partitioned between ethyl acetate (100 mL) and 10% aqueous sodium carbonate solution (50 mL), the resulting organic fractions were dried over magnesium sulfate, filtered and the solvent was removed in vacuo. Trituration with cold methanol gave the title compound as a white solid (898 mg, 17%) as a single diastereoisomer.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.14 g) was added portionwise to a stirred solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-hydroxypropanoate (1.20 g) in dry N,N-dimethyl formamide (20 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes prior to the addition of benzyl bromide (0.6 mL). Stirring was continued at room temperature for 3 hrs, then at 80° C. for 17 hrs before the mixture was cooled, diluted with water (500 mL) and extract with ethyl acetate (3×200 mL). The combined ethyl acetate layers were washed with water (4×500 mL) and brine (500 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum, which was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[NH:4][CH2:5][CH3:6].Cl.[Cl:13][CH2:14][C:15](O)=O.N>>[CH2:5]([N:4]1[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[N:1]=[C:15]1[CH2:14][Cl:13])[CH3:6]
Reactant: O=C(O)CCl
Reactant: CCNc1ccc(C)cc1N
Agent: Cl
Agent: N
Product: CCn1c(CCl)nc2cc(C)ccc21
Yield: 27.9 %

Procedure:
2-amino-4-methyl-N-ethylaniline (2.15 g, 14 mmol), which is a known compound, hydrochloric acid (4N, 15 ml) and monochloroacetic acid (2 g, 21 mmol) were refluxed for 2.5 hours. After cooling, the reactant was neutralized with ammonia. The occurred oily substance was extracted with ethyl acetate and the product was treated as in a usual process to obtain the title intermediate (1.0 g, 3.9 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[C:5]([O:15][CH3:16])[CH:4]=1)[CH3:2].Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CCO.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(OC)c1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(OC)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To a solution of 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 18a) (100 mg, 0.43 mmol) in EtOH (2 mL) was added 2-(bromomethyl)pyridine hydrobromide (129 mg, 0.51 mmol). The suspension was heated at 60° C. for 22 h. The reaction mixture was diluted with EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 5% MeOH in DCM) to give 2-((5-(4-ethyl-2-methoxyphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine (95 mg) as a white powder (68%). 1H NMR (300 MHz, dMSO): δ 1.19-1.22 (t, 3H), 2.63-2.69 (dd, 2H), 3.93 (s, 3H), 4.48 (s, 2H), 6.93-7.03 (m, 2H), 7.25-7.29 (m, 1H), 7.49-7.5 (m, 1H), 7.71-7.75 (m, 1H), 7.93-7.95 (d, 1H), 8.50-8.51 (d, 1H), 13.65 (bs, 1H). MS (M+H, 327).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:15])([N+:12]([O-])=O)[CH3:11])=[CH:5][CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:15])([NH2:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
The crude 1-methoxy-4-(2-methyl-2-nitropropyl)benzene (200 mg, 0.96 mmol) was combined with palladium on carbon (40 mg) in methanol (30 mL). The suspension was vigorously stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through Celite and the filtrate was concentrated to give 1-(4-methoxyphenyl)-2-methylpropan-2-amine (150 mg, 88% yield) as a yellow oil which was used without further purification. (MS m/z: 180 (M+1)).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[C@@H:24]([CH3:25])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[CH3:18][N:16]1[CH:17]=[C:13]([C:11]2[N:12]=[C:6]3[C:5]([NH:19][C@H:20]4[C@@H:24]([CH3:25])[CH2:23][NH:22][CH2:21]4)=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]3[CH:10]=2)[CH:14]=[N:15]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate in DCM (4.5 ml) at 0° C. was added TFA (526 μl, 6.83 mmol) dropwise. The reaction was stirred at 0° C. for 10 minutes and at room temperature for 1.5 h. The reaction solution was concentrated to yield a yellow oil, which was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated to give 2-(1-methyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 TFA (333.5 mg, 0.587 mmol, 86% yield) as a yellow solid. ESI-MS (analytical LCMS Method B): m/z 341.2 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 1.847 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:19][CH3:20])=O.O>C1COCC1>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][NH:19][CH3:20]
Reactant: CNC(=O)c1cc2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
LAH (50 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 1-methyl-2-(methylaminocarbonyl)indole (2.33 g, 12.4 mmol) in anhydrous THF (10 mL) with cooling, and the resulting solution was stirred at RT under argon overnight. H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3), concentrated, and purified by silica gel flash chromatography to afford the title compound (430 mg, 20% yield) as a yellow solid. MS (ES) m/e 175 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([N:16]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:3]=1.[NH2:34][C@@H:35]([CH2:37][OH:38])[CH3:36]>CN1C(=O)CCC1>[CH2:9]([S:8][C:6]1[N:5]=[C:4]([N:16]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:3]=[C:2]([NH:34][C@H:35]([CH3:36])[CH2:37][OH:38])[N:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](N)CO
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(=O)(=O)N1CCOCC1
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCOCC2)nc(SCc2ccccc2)n1

Procedure:
The subtitle compound was prepared as a yellow oil by the method of Example 43 step by reacting the subtitle product of step i) (11.75 g) with (R)-alaninol (3.4 ml) in NMP (30 ml). Yield: 12.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Product: Fc1ccccc1-n1nccc1-c1ccc2noc(-c3ccc(Br)cc3)c2c1

Procedure:
The title compound, light yellow solid (108 mg, 71%), MS (ISP) m/z=434.2 [(M+H)+], mp 202° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-bromo-phenyl)-acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:12]([C:15]1[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1>O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:46][C:45]2[CH:48]=[CH:49][C:42]([F:41])=[CH:43][CH:44]=2)[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 15.2 %

Procedure:
A mixture of (±)-(3-{(4-methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]-amino}-propyl)-carbamic acid tert-butyl ester (Example 3 A, 38 mg, 0.08 mmol) and cesium carbonate (40 mg, 0.12 mmol) in dioxane (1 mL) was stirred at 40° C., under Ar, for 45 min. To the mixture was added 4-fluorobenzyl bromide (22 mg, 0.12 mmol) and the reaction mixture was stirred at 40° C. for 24 h before being diluted with ethyl acetate. The ethyl acetate layer was washed twice with water and once with brine, before being dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 74–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (7 mg, 15%): 1H NMR (CDCl3) δ 7.44–6.99 (m, 10H), 6.61 (m, 1H), 5.91 (m, 1H), 5.88 (m, 1H), 4.83 (m, 1H), 3.86 (m, 1H), 3.33 (m, 2H), 2.71 (m, 2H), 2.39 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 1.62 (m, 2H), 1.39 (s, 9H), 0.71 (m, 3H); MS (ESI+), 576.17 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].B.CO>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Br

Procedure:
4-Bromo-3-methoxybenzoic acid (23.1 g, 0.1 m) dissolved in tetrahydrofuran (200 ml) is added to 1M borane in tetrahydrofuran (150 ml) stirred at 5°. The mixture is refluxed, cooled, treated with methanol, refluxed and concentrated in vacuo to give 4-bromo-3-methoxybenzyl alcohol.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1>>[CH3:28][C@@H:6]1[C@:5]2([O:29][CH2:30][CH:2]([CH3:1])[CH2:3][CH2:4]2)[O:9][C@H:8]2[CH2:10][C@H:11]3[C@@H:16]4[CH2:17][CH2:18][CH:19]5[CH2:24][CH:23]([OH:25])[CH2:22][CH2:21][C@:20]5([CH3:26])[C@H:15]4[CH2:14][CH2:13][C@:12]3([CH3:27])[C@@H:7]12
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Product: CC1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CCC5CC(O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C

Procedure:
A variety of structurally related saponins are known, the most variable structural feature being the glycosylation pattern. Saponins also may contain additional modifications, such as the sarasaponins which are saponins with asteroid attached, and saponin structure can be modified by any number of enzymatic, chemical and/or mechanical means known in the art. Saponins from Yucca schidigera contain steroidal saponins with the major sapogenins being sarsapogenin and tigogenin. The sarsaponin yields on hydrolysis, sarsasapogenim (sarsasapogenim 5-beta, 20-betaF, 22-deltaF, 25-betaF; also known as spirostan-3-beta-01 and parigenin), glucose and galaclose. The sarasapogenim has a molecular formula of C27H44O3. Nobel, Park S., Agaves, Oxford Univ. Press, New York, 1994.
Reaction SMILES: F[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>>[N:10]1([C:2]2[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: OCc1cccnc1F
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cccnc1N1CCNCC1

Procedure:
A mixture of (2-fluoro-pyridin-3-yl)methanol (1 g, 8 mmol, Asymchem), piperazine (1.3 g, 15 mmol) and N,N-diisopropylethylamine (1 mL, 5.8 mmol, Aldrich) was reacted under the conditions of Example 43a to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 194 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:16][C:17]3[CH:28]=[CH:27][C:20]4[N:21]=[C:22](S(C)=O)[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[OH:39].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:16][C:17]3[CH:28]=[CH:27][C:20]4[N:21]=[C:22]([NH:32][C@@H:33]5[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]5[OH:39])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 138 °C
Yield: 59.5 %

Procedure:
A stirred mixture of 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.48 g, 3.4 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol hydrochloride (1.29 g, 8.5 mmol), and DIEA (2.19 g, 17 mmol) in DMA (44 mL) was heated at 138° C. for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 6% MeOH in DCM to afford (1R,2R)-2-((6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (0.98 g, 59%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.43-7.46 (m, 3H), 7.29-7.39 (m, 4H), 7.25 (s, 1H), 7.13-7.16 (m, 2H), 6.96 (m, 1H), 5.75 (br s, 1H), 5.31 (s, 2H), 5.09 (s, 2H), 3.46-3.56 (m, 2H), 2.07-2.18 (m, 2H), 1.71-1.77 (m, 2H), 1.26-1.40 (m, 4H); LCMS (ESI) m/z 485 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](C2N=CNN=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(Nc2ccccc2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (367 mg, 1 mmol) in dioxane (20 ml) was added aniline (186 mg, 2 mmol). The solution was stirred overnight at 60° C. The solvents were evaporated in vacuo yielding crude 2-acetamido-4-anilino-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The residue was redissolved in a mixture of dichloromethane and ethanol (in a ratio of 80/20, 10 ml). A sodium ethoxide solution (0.2 N solution) was added till pH 12 and the resulting mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo. The crude residue was purified by preparative TLC on silica, using a methanol/dichloromethane mixture in a ratio of 10:90 as mobile phase, yielding the pure title compound (160 mg, 50%) which was characterised as follows:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([OH:16])[CH:3]=1.O1CCCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([OH:16])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(Cl)c(Cl)cc1O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reaction time: 0.5 h
Yield: 111.5 %

Procedure:
To a solution of ethyl 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetate (2 g, 7.6 mmol) in of 4:1 mixture of tetrahydrofuran and water (30 mL) at room temperature, LiOH.H2O (3.2 g, 76 mmol) were added and the resulting mixture was stirred for 30 min and then acidified with aqueous HCl (1N) to adjust the pH to 3-5. The mixture was extracted with ethyl acetate (40 mL×3). The combined organic layer was washed with brine (40 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (2 g) which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=2)[N:8]([CH2:24][C:25]([O:27]CC)=[O:26])[N:7]=1)=[O:5])[CH3:2].[Li+].[OH-].Cl>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:15]([F:23])[CH:14]=2)[N:8]([CH2:24][C:25]([OH:27])=[O:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1nc(C(=O)OCC)cc1OCc1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCc2cc(F)cc(C(F)(F)F)c2)n(CC(=O)O)n1
Temperature: 25 °C

Procedure:
To an ice cold solution of 1-ethoxycarbonylmethyl-5-(3-fluoro-5-trifluoromethyl-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (2) in 1 mL of tetrahydrofuran and 0.2 mL of water was added 0.21 mL (0.21 mmol) of 1 M LiOH solution, and the mixture was allowed to warm up to rt for 2 h. The reaction mixture was then acidified with 0.25 mL (0.25 mmol) of 1 M HCl solution, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated to give 58.5 mg (0.150 mmol) of 1-carboxymethyl-5-(3-fluoro-5-trifluoromethyl-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (3) as crude product.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])[N:7]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.C1COCC1.C(Cl)Cl.O.C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])[N:7]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42])=[O:33])[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NCC(O)CO
Reactant: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(C(=O)O)c3)c(F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(C(=O)NCC(O)CO)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of 3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid (100 mg, 0.20 mmol), 3-aminopropane-1,2-diol (22 mg, 0.24 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in THF and DCM was stirred at room temperature overnight. Ethyl acetate and water were added, and the organic phase was washed with brine, dried over MgSO4, and evaporated at reduced pressure. HPLC purification (10-90% aqueous acetonitrile) afforded pure title compound (23 mg, 20%). 1H-NMR (DMSO-d6) δ 8.97 (s, 1H), 8.91 (s, 1H), 8.55 (t, J=5.7 Hz, 1H), 8.29 (d, J=7.2 Hz, 1H), 8.11 (t, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.18 (d, J=9.0 Hz, 1H), 6.94 (d, J=12.0 Hz, 1H), 6.76 (s, 1H), 4.81 (s, 1H), 4.57 (s, 1H), 3.62 (t, J=5.7 Hz, 1H). 3.40 (m, 2H), 3.18 (m, 2H), 2.36 (s, 3H), 1.80 (s, 9H), MS LC-MS [M+H]+=577.3, RT=1.54 min.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH2:3][CH2:4]Br.[I-:18].[Na+]>CC(C)=O>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH2:3][CH2:4][I:18]
Reactant: [I-]
Reactant: CC(=CCCc1ccc2c(c1)OCO2)CCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=CCCc1ccc2c(c1)OCO2)CCI

Procedure:
3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 19.0 g. of 3-methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C3) and 10.5 g. of sodium iodide in 125 ml. of acetone, to give 21 g. of product as a yellow oil.