Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([CH2:16][C:17]2[CH:18]=[C:19]([O:31][CH3:32])[CH:20]=[C:21]3[C:26]=2[O:25][C:24](=[O:27])[C:23]([C:28](O)=[O:29])=[CH:22]3)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:57]1[C:58]([C:66]2[CH:67]=[C:68]([NH2:72])[CH:69]=[CH:70][CH:71]=2)=[CH:59][N:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=12>CN(C)C=O>[N:57]1[C:58]([C:66]2[CH:67]=[C:68]([NH:72][C:28]([C:23]3[C:24](=[O:27])[O:25][C:26]4[C:21]([CH:22]=3)=[CH:20][C:19]([O:31][CH3:32])=[CH:18][C:17]=4[CH2:16][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:29])[CH:69]=[CH:70][CH:71]=2)=[CH:59][N:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1cc(CN2CCOCC2)c2oc(=O)c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN2CCOCC2)c2oc(=O)c(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)cc2c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
DIEA (0.030 mL, 0.17 mmol) was added to 8-(4-morpholinylmethyl)-3-carboxy-6-methoxy-coumarin (0.050 g, 0.16 mmol) and HATU (0.065 g, 0.17 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.033 g, 0.16 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.047 g of 1541D in a 59% yield: LCMS (ESI) m/z 511 (MH+).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[Cl:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][CH:26]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(Cl)c2)C1
Yield: 88.4 %

Procedure:
The title compound (D124) (85 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 3-Chlorophenol (0.035 ml, 0.338 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:56]1[CH2:61][CH2:60][NH:59][CH2:58][C:57]1=[O:62].ClCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:59]1[CH2:60][CH2:61][NH:56][C:57](=[O:62])[CH2:58]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C1CNCCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CCN1
Yield: 44 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and piperazinone in DMF. Yield: 44%; C20H17Cl2N5O3 (446.29); mass spectrum: (M+H)+=446/448/450 (chlorine isotope).
Reaction SMILES: Cl([O-])=O.[Na+].[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)=[CH:10][C:9]([C:21]2[CH:22]=[C:23]([C:27]([NH:30][S:31]([CH2:34][C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:32])([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=2)=[N:8]1)[CH3:6].CC(=CC)C.P([O-])(O)(O)=[O:45].[Na+]>CO>[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:45])=[O:20])=[CH:17][CH:18]=2)=[CH:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:29])([NH:30][S:31]([CH2:34][C:35]([F:38])([F:36])[F:37])(=[O:32])=[O:33])[CH3:28])[CH:22]=2)=[N:8]1)[CH3:6]
Reactant: O=P([O-])(O)O
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CO
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
Sodium chlorite (71 mg, 0.78 mmol, 4.0 equiv) was added to a mixture of N-(1-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (97 mg, 0.20 mmol, 1 equiv), 2-methyl-2-butene (1 mL), aqueous sodium dihydrogenphosphate solution (20% w/w, 0.7 mL) and methanol (2.8 mL). The biphasic mixture was stirred for 90 minutes, then was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 4-({1-ethyl-3-[3-(1-methyl-1-{[(2,2,2-trifluoroethyl)sulfonyl]amino}ethyl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid. Calcd (M+1)+: 512.1. Found: 512.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: -70 °C

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.), and potassium carbonate (5.5 g., 0.04 mole) is added and the mixture stirred and heated on a steam bath for 30 minutes. Ethyl 7-bromoheptanoate is added dropwise over 10 minutes with stirring and heating on a steam bath for two hours. The mixture is poured into a mixture of ice and water (300 g., total) and then extracted with ether. The ether extract is dried over Na2SO4, filtered and the ether removed at reduced pressure. The residue is dissolved in petroleum ether and cooled to -70° C. to obtain ethyl 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate, 17.7 g., m.p. 47°-50° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=5)[O:20][CH2:19][CH2:18]4)[C:13]([NH2:28])=[CH:12][N:11]=3)[C:6]=2[CH:29]=1.N[C:31](N)=[S:32]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]4[C:13]([NH:28][C:31](=[S:32])[N:16]4[C@H:17]4[C:26]5[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=5)[O:20][CH2:19][CH2:18]4)=[CH:12][N:11]=3)[C:6]=2[CH:29]=1
Reactant: NC(N)=S
Reactant: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCOc2c(F)cccc21
Solvent: CC#N
Product: Fc1ccc2ncn(-c3ncc4[nH]c(=S)n([C@@H]5CCOc6c(F)cccc65)c4n3)c2c1
Temperature: 200 °C
Yield: 14.1 %

Procedure:
In a microwave vial, to the solution of 50 mg (0.13 mmol) 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)N4—((R)-8-fluorochroman-4-yl)pyrimidine-4,5-diamine (known compound, e.g. WO 2006/108103) in 0.75 mL anhydrous acetonitrile was added 24 mg (0.32 mmol) thiourea. The vial was capped and the mixture was heated in an Emrys Optimizer microwave at 200° C. for 30 minutes. The resulting red dark suspension was concentrated in vacuo, and partitioned between water and EtOAc. Extract this aqueous phase with EtOAc three more times, and the combined organic layer was concentrated in vacuo, and purified by silica gel column chromatography eluting with DCM and MeOH to yield 8 mg (14%) the titled compound as a pale yellow solid. (Note: On similar diamines, cyclization with 1,1′-thiocarbonyl-diimidazole at 0° C., then slowly warm up to room temperature was found to give improved yields.)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]2[N:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35][CH2:34][O:33]2)[CH:29]=[CH:30][CH:31]=1>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=4)[N:36]([CH2:35][CH2:34][OH:33])[CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: Clc1cccc(C2OCCN2Cc2ccccc2)c1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(OC)c(O)c(C(c3cccc(Cl)c3)N(CCO)Cc3ccccc3)c1)O2
Yield: 26.6 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofuran and 32.8 g of 2-(3-chlorophenyl)-3-benzyl-1,3-oxazolidine are held in 260 ml of absolute alcohol for 60 hours at 70° C. and subsequently the solvent and excess of 2-(3-chlorophenyl)-3-benzyl-1,3-oxazolidine are removed, finally in vacuum. After purification by means of a chromatographic column there is obtained 9.8 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenyl-(3-chlorophenyl)-methyl)-N-(2-hydroxyethyl)-N-benzylamin, a bright yellow oil.
Reaction SMILES: C(O[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](C1C=C(SC2N(C3C=CC=C(C(O)=O)C=3)N=NN=2)C2C(=CC=CC=2)C=1O)=[O:24])CCCCCCCCCCCCC.C(NN[C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:23]([NH:61][CH:58]1[CH2:57][CH2:56][CH2:55][CH2:60][CH2:59]1)([NH:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16]1)=[O:24]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)O)c2)c2ccccc2c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h
Yield: 55.5 %

Procedure:
13.9 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-1-naphthol and 3.0 g of 1-formyl-2-(4-aminophenyl)hydrazine were dissolved in 20 ml of DMF and to the solution was added dropwise with stirring 5 ml of a DMF solution containing 4.1 g of dicyclohexylcarbodiimide at 0° C. under nitrogen atmosphere. After the completion of the addition, the mixture was stirred for 2 hours and then further stirred at room temperature for 2 hours. Dicyclohexylurea formed was removed by filtration and the filtrate was poured into 1.5 liters of water. The crystals thus deposited were collected by filtration and dissolved in 50 ml of DMF. After treating with active carbon the DMF solution was poured into 400 ml of methanol and the crystals thus deposited were collected by filtration to obtain 9.2 g of the desired Compound (15). Yield: 55.5%. Melting Point: 173° to 180° C.
Reaction SMILES: [F:1][C:2]1[C:3]([F:16])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[NH:6][C:5]2=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1.Cl.[CH3:18]O>>[CH3:18][O:14][C:13]([C:11]1[CH:12]=[C:2]([F:1])[C:3]([F:16])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[NH:6][C:5]=12)=[O:15]
Reactant: CC1COc2c(F)c(F)cc(C(=O)O)c2N1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(F)c(F)c2c1NC(C)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.1 g (9.1 mmol) of 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid Example 31) in 50 mL of methanol is cooled to 0° C. and saturated with hydrogen chloride gas. The reaction is stirred at room temperature for 18 hours, recooled to 0° C. and resaturated with hydrogen chloride gas. After stirring an additional 24 hours at room temperature, the solvent is removed in vacuo and the residue is partitioned between dichloromethane/5% aqueous sodium bicarbonate (200:100 mL). The organic layer is separated, washed with 5% aqueous sodium bicarbonate, water, dried (MgSO4), filtered, and concentrated in vacuo affording 1.9 g of the title compound. 1H NMR (400 MHz, CDCl3): 7.27 (bs, 1H), 7.24 (m, 1M), 4.26 (m, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.62 (m, 1H), 1.22 (d, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)Oc2ccccc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (0.050 g, 0.130 mmol), phenyl chloroformate (0.020 mL, 0.59 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.574 mmol) in CH2Cl2 (10 mL) was stirred at room temperature, then concentrated to dryness. The crude product was purified using preparative reverse-phase HPLC to provide 7-chloro-4-oxo-3-(phenoxycarbonylamino-methyl)-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester. MS calcd. for C25H20ClN2O5 [(M+H)+] 463.1, obsd. 462.9.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH3:33])[C:25]([F:27])([F:28])[F:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC)C(F)(F)F)c23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100 mg, 0.224 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 14 mg, 0.35 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodomethane (0.0697 mL, 1.12 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (79.1 mg, 0.172 mmol, 77%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([OH:17])[CH2:19]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: OC1CCCNC1
Product: CC(C)(C)OC(=O)N1CC(N2CCCC(O)C2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see International Patent Application Publication no. WO93/19059) (1.5 g, 4.78 mmol) and 3-hydroxypiperidine (1.9 g, 4 mol. equiv.) was heated at 110° C. for sixteen hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and 5% aqueous sodium bicarbonate solution (100 ml). The layers were separated and the aqueous phase was extracted with a further portion of ethyl acetate (100 ml). The combined organic layers were dried over anhydrous magnesium sulphate. The solution was filtered, the solvent removed from the filtrate under reduced pressure and the crude product purified by column chromatography using silica gel eluting with methanol:dichloromethane (1:9, by volume) to give the title compound (1.4 g). TLC Rf=0.3 (silica, methanol:dichloromethane, 1:9, by volume).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCCC)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][O:37][C:38](=[O:49])[CH2:39][NH:40][C:41]([CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1)=[O:42]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:45]4[CH2:46][CH2:47][O:48][C@H:43]([C:41]([NH:40][CH2:39][C:38]([O:37][CH3:36])=[O:49])=[O:42])[CH2:44]4)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)CNC(=O)C1CNCCO1
Product: COC(=O)CNC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
Methyl N-({(2S)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}carbonyl)glycinate was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [(Morpholine-2-carbonyl)-amino]-acetic acid methyl ester following General Procedure B.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCC(=O)NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 87% yield. MS: 335.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][CH2:23][OH:24].CS(O)(=O)=O>CO>[OH:24][CH2:23][CH2:22][C:21]1[CH:20]=[C:19]([CH:27]=[CH:26][CH:25]=1)[NH:18][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: COc1ccc2c(Cl)c3ccccc3nc2c1
Reactant: Nc1cccc(CCO)c1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccc2c(Nc3cccc(CCO)c3)c3ccccc3nc2c1

Procedure:
A mixture of 9-chloro-3-methoxyacridine, (975 mg, 4 mmol), 3-aminophenethyl alcohol (549 mg, 4 ml) and methanesulfonic acid (0.32 ml, 5 mmol) in methanol (30 ml) is stirred under reflux for 2 hours. The mixture is concentrated in vacuo, and the residue is dissolved in methanol (10 ml). The solution is diluted with ether (150 ml). The precipitates are collected by filtration, washed with ether to give 9-[3'-(β-hydroxyethyl)anilino]-3-methoxyacridine, as the methanesulfonate (1.15 g, 65%), mp 186°-188° C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([C@@H:21]([CH3:24])[CH2:22][OH:23])[CH:20]=1>C(Cl)Cl.CCOC(C)=O>[C:6]([Si:10]([O:23][CH2:22][C@@H:21]([C:19]1[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=1[O:25][CH3:26])[CH3:24])([CH3:13])[CH3:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(F)cc1[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(F)cc1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (3.55 g, 52.1 mmol) and tert-butyldimethylchlorosilane (10.21 g, 33.9 mmol) were added to a solution of 25A (4.8 g, 26.1 mmol) in CH2Cl2 (125 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc (150 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (loading in chloroform, 0% to 20% ethyl acetate in hexane) to yield 25B as a clear oil.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=C1NCCc2nc(O)ccc21
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2nc(Cl)ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 2-hydroxy-7,8-dihydro-6H-[1,6]naphthyridin-5-one (17 g, 73.1 mmol) in phosphorus oxychloride (30 mL) was stirred at 100° C. for 8 h. The solvent was evaporated in vacuo. The mixture was basified with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 1/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one (4.81 g, 36%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(Cl)c1F
Yield: 99.3 %

Procedure:
3-Chloro-2-fluorobenzoic acid (10.0 g, 0.06 mol), thionyl chloride (31 ml, 50 g, 0.4 mol) and dry toluene (40 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (11.5 g) as a clear yellow oil.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=O)[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.[OH:22][NH2:23]>N1C=CC=CC=1>[CH2:1]([C:5]12[CH2:17][CH2:16]/[C:15](=[N:23]\[OH:22])/[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CC/C(=N\O)C(C)=C1c1ccc(O)cc1C2
Temperature: 60 °C

Procedure:
A solution of 9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (60 mg, 0.22 mmol) and hydroxyl amine hydrochloride (77 mg, 1.11 mmol) in anhydrous pyridine (0.5 mL) was stirred under a nitrogen atmosphere at room temperature for 4.3 hours and then heated in an oil bath at 60° C. for 30 minutes. The reaction mixture was evaporated under vacuum to an oil which was taken up in EtOAc (10 mL), washed with 1N HCl (2×6 ml), water (6 mL) and brine (6 ml), dried over MgSO4, filtered, and evaporated under vacuum. The residue was lyophilized from benzene (3 mL) to afford (3E)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one oxime as an amorphous solid.