Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][N:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH:23]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:24]([OH:28])[C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[C:24]([CH:23]([NH:22][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)[CH2:29][CH2:30][CH2:31][CH3:32])=[O:28]
Reactant: O=C(O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CCCCC(N)C(O)C(N)=O
Agent: Cl
Product: CCCCC(NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1)C(=O)C(N)=O

Procedure:
Preparation in analogy to Example 5 by coupling 2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxylic acid and 3-amino-2-hydroxyheptanamide hydrochloride and subsequent oxidation afforded 40 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=O.[NH2:18][NH:19][C:20]([NH2:22])=[S:21].C(O)(=O)C>C(O)C>[CH:1](=[N:18][NH:19][C:20]([NH2:22])=[S:21])[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccccc1C=O)OCC
Reactant: NNC(N)=S
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(Cc1ccccc1C=NNC(N)=S)OCC

Procedure:
2.0 g (8 mmol) of the compound A and 0.73 g of thiosemicarbazide were dissolved or suspended in 200 ml of absolute ethanol. 2 ml of acetic acid were added and the mixture was boiled under reflux for 3 h. In the course of the slow cooling, the product D precipitated in crystalline form.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ccc(O)cc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ccc(OCCCCCCCCCCCBr)cc3)cc2)cc1
Yield: 97.7 %

Procedure:
A mixture of 3.5 g (8.4 mmol) of 4-Octyloxy-benzoic acid (4′-hydroxy-biphenyl-4-yl) ester, 7.88 g (25 mmol) of 1,11-Dibromoundecane, 3.45 g (25 mmol) of K2CO3 and 50 mL of dry butanone is refluxed for 24 h, then allowed to return to room temperature. The reaction mixture is filtered off and the butanone is distilled off under reduced pressure. The crude product purified by column chromatography on silica gel using CH2Cl2 as eluent gives a pure product as a white solid (5.35 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]([F:34])([F:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>O>[F:15][C:16]([F:33])([F:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 4-aminocinnamate, one equivalent of 15-(trifluoromethyl)pentadecyl bromide and one equivalent of anhydrous potassium carbonate in hexamethylphosporamide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the product as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[CH:32]=[C:33]([O:36][C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:35][C:27]=4[CH3:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)(F)F)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methyl-5-(trifluoromethoxy)benzoic acid (compound F5) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1.Cl[S:13]([N:16]=C=O)(=[O:15])=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][S:13](=[O:15])(=[O:14])[NH2:16])=[CH:7][CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 78.7 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 9.6 g (0.059 mole) of α,α,α-trifluoro-p-cresol, 5.7 ml (9.2 g, 0.065 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.2 g (70%) of white solid, mp 111°-112° C. (benzene).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][N:19]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][N:23]=1
Reactant: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Yield: 91.8 %

Procedure:
--The nonynylpyrimidine 38 (1.50 g, 3.39 mmol) was hydrogenated over 5% Pd/C in ethyl acetate to give the nonylpyrimidine 39 (1.39 g, 92%) (from MeOH/EtOH), transitions/° C. K 42.8 SC 53.6 I; νmax /cm-1 (KBr) 2920, 2950, 1625, 1540, 1475, 1465, 1430, 1310, 1200 and 1080s; δ 0.90(6H, m, Me×2), 1.16-1.56 (22H, m), 1.67 (2H, quint, ArCH2CH2), 1.85 (2H, quint, OCH2CH2), 2.63 (2H, t, ArCH2), 4.10 (2H, t, OCH2), 6.82 (1H, ddd, J8.5, 8 and 2, 5'-H), 7.80 (1H, ddd, J8.5, 8 and 2, 6'-H) and 8.65 (2H, s, 4- and 6-H); m/z 446 (M+), 334, 305, 277, 263, 249, 235 and 222.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cn1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 2-bromo-5-pyridinecarboxaldehyde (2 Scheme 27, 12.0 g, 64.5 mmol) and ethylene glycol (5.4 mL, 96.8 mmol) and p-toluenesulfonic acid (100 mg) in benzene (150 mL) was refluxed in a Dean Stark apparatus for 16 h. The reaction mixture was cooled to room temperature, and the solution was extracted with cold water/ethyl acetate. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (1:4 ethyl acetate/hexanes) to afford a orange colored oil (10.5 g, 70%); 1H NMR (300 MHz, CDCl3) δ 3.82-3.96 (4 H), 5.64 (s, 1 H), 7.34 (d, J=8.10 Hz, 1 H), 7.49 (dd, J=8.10 Hz, 1 H), 8.29 (d, J=2.10 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 65.5 (2C), 101.2, 128.0, 133.4, 137.0, 142.8, 148.8. HRMS (EI) calcd for C8H8BrNO2 228.9738, found 230.9718.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26](F)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Cc1cnc(F)c(Br)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(C)cc4Br)cc3n2C)c1
Yield: 13.5 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10.0 mmol), 3-bromo-2-fluoro-5-methylpyridine (2.09 g, 11.0 mmol), copper iodide (0.19 g, 1.00 mmol), 1,10-phenanthroline (0.18 g, 1.00 mmol), cesium carbonate (9.77 g, 30.0 mmol) and DMF (50 mL) to obtain the title compound (0.65 g, 14%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1>C1(C)C=CC=CC=1>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Product: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 42 %

Procedure:
Dissolve 50 g of 2-(4-difluoromethoxyphenyl)-3-methylbutyric acid in 130 g of toluene and to this solution is added 0.24 mole of resolving agent quinine. Heat the solution with stirring under reflux for 6 hours, then cool, filter, and transfer the resulting solids to 49 g of 15% hydrochloric acid. Heat the mixture with stirring at 40° C. for 2 hours and then allow the mixture to cool to room temperature. The resulting mixture is extracted with benzene 2-3 times, and the solvent benzene is then removed by distillation to give 21 g (yield: 42%) of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid. [α]DRT =(+)40.5 (c=1.356 g/100 ml, CHCl2)
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].Br[C:8]([F:28])([F:27])[C:9]([NH:11][CH2:12][C:13]1(O)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[F:27][C:8]1([F:28])[CH2:1][C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][NH:11][C:9]1=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)C2
Yield: 30.7 %

Procedure:
To a stirring solution of potassium tert-butoxide (7.23 mL of 1 M, 7.23 mmol) in tetrahydrofuran (20 mL) at 70° C. was added a solution of tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.4 g, 3.62 mmol) in tetrahydrofuran (20 mL) over 15 min. After 20 min the reaction mixture was diluted with 1:1 brine/saturated NH4Cl and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (40 g silica, 30-100% ethyl acetate/hexane, product visualized by TLC with ninhydrin staining+heat) provided tert-butyl 4,4-difluoro-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (340 mg, 1.11 mmol, 31%) as a white solid. ESI-MS m/z calc. 306.1. found 307.5 (M+1)+; Retention time: 1.32 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 3.75 (d, J=13.3 Hz, 2H), 3.45 (d, J=3.2 Hz, 2H), 3.07 (br s, 2H), 1.79 (d, J=13.6 Hz, 2H), 1.72-1.60 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1.[CH:16]1([C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][CH:26]2[CH2:27][CH2:28][N:23]([C:21]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:22])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)C2CCCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(C1CCCC1)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C
Yield: 45.7 %

Procedure:
To a solution of 2-(4-chlorophenoxy)phenylamine (100 mg, 0.45 mmol), 1-cyclopentylcarbonyl-4-piperidone (144 mg, 0.735 mmol) and acetic acid (147 mg, 2.45 mmol) in DCE (1.5 ml) was added sodium triacetoxyborohydride (260 mg, 1.23 mmol). This solution was then heated at 100° C. for 15 minutes in a CEM discover microwave (fixed hold time set to on). The reaction mixture was then quenched with saturated aqueous sodium bicarbonate solution (5 ml) and extraction with ethyl acetate (3×5 ml) followed. The combined organics were concentrated in vacuo and purification by flash chromatography proceeded (eluant: 8:2 hexane:ethyl acetate) to provide the title compound as a transparent oil (82 mg, 43%). 1H NMR (300 MHz, CDCl3): δ 1.16-1.36 (2H, m, 2×CH), 1.47-1.56 (2H, m, 2×CH), 1.59-1.78 (6H, m, 6×CH), 1.93-2.08 (2H, m, 2×CH), 2.76-2.87 (2H, m, 2×CH), 3.07-3.18 (1H, m, CH), 3.43-3.52 (1H, sept, J=3.9 Hz, CH), 3.78-3.89 (1H, bd, J=13.8 Hz, CH), 3.97-4.10 (1H, m, CH), 4.31-4.42 (1H, bd, J=13.5 Hz, NH), 6.55-6.62 (1H, td, J=1.5, 1.2, 1.2, 7.7 Hz, ArH), 6.68-6.71 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.73-6.77 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.79-6.84 (2H, m, ArH), 6.95-7.01 (1H, td, J=1.5, 0.6, 1.5, 7.7 Hz, ArH), 7.16-7.22 ppm (2H, m, ArH). 13C NMR (67.93 MHz, CDCl3): δ 19.5, 19.6, 30.2, 32.2, 33.2, 40.6, 44.1, 49.9, 112.2, 117.2, 118.8, 119.6, 125.3, 127.9, 129.8, 138.9, 143.1, 156.1, 175.4 ppm LCMS: M+H, 421.46 HPLC: 98.41% (3.124 min, isocratic 90% acetonitrile, 10% water at 1 ml/min).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH:14]1([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH:9]=[N:10]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc2cnn(C3CCCC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cnn(C3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.3 %

Procedure:
A mixture of 3.93 g (16.1 mmol, 1.0 equiv) of 1-cyclopentyl-1H-indazole-6-carboxylic acid methyl ester, 100 mL CH3OH and 50 mL 1N NaOH was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and most of the CH2OH removed on a rotary evaporator. The residue was diluted with 325 mL H2O and acidified to pH=1 with 2N HCl. After stirring 5 minutes, the mixture was filtered, and the solid washed 2×H2O and dried overnight to give 3.42 g (92%) of a yellow powder: mp 172-175° C.; Anal. calcd for C13H14N2O2: C, 67.79; H, 6.13; N, 12.16. Found: C, 67.62; H 5.82; N, 12.19.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl([F:20])(=O)(=O)=O.O>CCCCCC>[F:20][C:9]1[S:8][C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1
Reactant: Cc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: Cc1cccc2cc(F)sc12

Procedure:
To a solution of 7 g of 7-methylbenzo[b]thiophene in abs. tetryhydrofuran are added dropwise at -78°, 30 ml of a 1.6M solution of n-butyllithium in hexane. After 20 minutes 5.5 g of perchloryl fluoride are introduced whereby the reaction temperature is maintained below -60°. After 30 minutes at -78° the temperature is slowly raised to 0°. The mixture is then mixed with water and the organic phase separated, washed, dried and concentrated under vacuum. The residue is chromatographed (eluant: n-hexane) to obtain the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17]#[N:18])[C:15]2[S:14][CH2:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Na+]>CCOCC>[OH:1][C:2]1([CH2:16][CH2:17][NH2:18])[C:15]2[S:14][CH2:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: N#CCC1(O)C2=C(C=CCS2)Oc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: NCCC1(O)C2=C(C=CCS2)Oc2ccccc21

Procedure:
18.5 g. 9-hydroxy-9-cyanomethyl-thiaxanthene (0.07 mol) are substantially dissolved in 150 ml. ether and slowly added dropwise, with stirring and external cooling, to a suspension of 3.8 g. lithium aluminum hydride (0.1 mol) in 50 ml. ether. The reaction mixture is subsequently vigorously stirred for 2 hours at room temperature and carefully decomposed by the addition of saturated, aqueous sodium chloride solution. The precipitated precipitates of the metal hydroxides agglomerate and, in this form, can be filtered off with suction. The filter cake is thoroughly washed through with ether and from the combined ethereal filtrates one obtains, after drying with potassium carbonate, 9-hydroxy-9-(2-aminoethyl)-thiaxanthene in the form of the hydrochloride by the dropwise addition of ethereal hydrochloric acid. The yield amounts to 17.0 g. (82% of theory) of m.p. 180°. After recrystallisation from isopropanol, the yield drops to 12.5 g. (61% of theory); the melting point thereby increases to 188°.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:38]=[CH:37][N:15]4[C:16](=[O:36])[C:17](/[CH:27]=[CH:28]/[C:29]([O:31]C(C)(C)C)=[O:30])=[C:18]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>C(O)=O>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:38]=[CH:37][N:15]4[C:16](=[O:36])[C:17](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[C:18]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Solvent: O=CO
Product: O=C(O)/C=C/c1c(N2CCCC(O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (E)-3-[8-[2-(4-Cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-(3-hydroxy-piperidino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (76 mg, 0.142 mmol) was added with formic acid (3 ml) and stirred at room temperature for 2 hours and 30 minutes. After the formic acid was evaporated under reduced pressure, the residue was purified by thin layer silica gel chromatography (chloroform:methanol=15:1) to obtain 39 mg (55% for the three steps) of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36].[CH2:37](O)[C:38]#[CH:39].C1(C)C=CC=CC=1.CCOCC>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][C:28]([CH3:33])([CH3:32])[C:29]([O:31][CH2:39][C:38]#[CH:37])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36]
Reactant: Cc1ccc(OC(C)(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCOC(=O)C(C)(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
A mixture of 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}-2-methylpropionic acid (0.500 g, 0.000960 mol), p-toluenesulfonic acid (0.0100 g), propargyl alcohol (0.0538 g, 0.000960 mol) and toluene is stirred one day at 50° C., cooled to room temperature and concentrated in vacuo to obtain a residue. Chromatography of the residue on silica gel with ether:methylene chloride affords the title compound (0.360 g, 67.2%) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>[OH-].[Na+]>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:11])=[N:7]2
Reactant: Nc1ccccc1O
Reactant: Clc1ccc2nccn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1ccccc1Oc1ccc2nccn2n1
Temperature: 120 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), 2-aminophenol (1419 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 3 days. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=70/30→0/100). The objective fraction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→75/25), and precipitated from diisopropyl ether to give the title compound (307 mg, 1.4 mmol, yield 14%) as a pale-brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12](=O)[NH:13][CH2:14][CH:15]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH:27]1[C:28]2[C:24](=[CH:23][C:22]([CH:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][NH:13][CH3:12])=[CH:30][CH:29]=2)[CH:25]=[CH:26]1
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNCC(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (54 mg, 1.4 mmol) was added, under nitrogen atmosphere, to a solution of [2-(1H-indol-5-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester CCLXXV (100 mg, 0.30 mmol) in tetrahydrofuran (3 mL) and the resulting mixture was heated at reflux for 95 minutes. The reaction mixture was cooled to room temperature and then at 0° C., freshly crushed sodium sulfate decahydrate (3 g) was then added portionwise and the resulting mixture was stirred for 1.5 hours. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to a light yellow oil. This crude residue was purified by flash chromatography (DCM/(DCM/MeOH/NH4OH) 100/0 to 25/75) to give [2-(1H-indol-5-yl)-2-phenyl-ethyl]-methyl-amine CCLXXVI. MS=251 [M+H]+.