Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH:17]=[CH2:18]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH2:4][CH2:3][CH:2]=[CH2:10])([CH2:15][CH2:16][CH:17]=[CH2:18])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C=CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC1(CCC=C)Cc2ccc(Br)cc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
To a stirred solution of 6-bromo-1-indanone (0.5330 g, 2.52 mmol) in dry THF (10 mL) was added NaH (0.3380 g, 60% in a mineral oil, 8.45 mmol) at 0° C. under nitrogen. After being stirred for 10 min, 4-iodobut-1-ene (1.3450 g, 7.39 mmol) was added and then the mixture was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C., quenched with 1 N HCl, extracted with ethyl acetate, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.1304 g of 6-bromo-2,2-di(but-3-en-1-yl)-2,3-dihydro-1H-inden-1-one. LC-MS tR=2.33 min in 3 min chromatography, m/z 319, 321 (MH+); 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 5.76-5.66 (m, 2H), 4.94-4.87 (m, 4H), 2.98 (s, 2H), 1.98-1.63 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 209.23, 151.43, 138.85, 137.85, 137.54, 127.94, 126.75, 121.55, 114.81, 52.87, 37.28, 36.58, 28.54.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[N:5]=1)#[C:2][CH3:3].[Li+].CC([N-]C(C)C)C.[B:19]([O:24]C)([O:22]C)[O:20]C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:20][B:19]([OH:24])[OH:22])=[C:6]([F:10])[N:5]=1)#[C:2][CH3:3]
Reactant: COB(OC)OC
Reactant: CC#Cc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC#Cc1ccc(OB(O)O)c(F)n1

Procedure:
0.05 mol of 10A, 0.08 mol of LDA and 0.08 mol of trimethyl borate are reacted with one another analogously to Example 1B. Aqueous work-up gives the unpurified product, which is processed further as in 10C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
To a cold (0° C.) mixture of 6-chloro-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (625 mg, 1.0 eq.), 1-Isopropyl-piperidin-4-ol (448 mg, 1.2 eq.) and triphenylphosphine (846 mg, 1.2 eq.) in tetrahydrofuran (8 mL) was added dropwise a solution of di-tert-butylazodicarboxylate (725 mg, 1.2 eq.) in tetrahydrofuran (7 mL). The reaction mixture was stirred for 20 h at room temperature. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol/ammonia from 98:2:0 to 90:9:1 as eluant to afford 635 mg (67%) of the tide compound as a light-yellow foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[N:26](COCC[Si](C)(C)C)[N:27]=[CH:28][CH:29]=3)[CH:20]=2)[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>Cl.O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][N:27]=[CH:28][CH:29]=3)[CH:20]=2)[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(OC(c2cccc(-c3ccnn3COCC[Si](C)(C)C)c2)c2nc3ccccc3s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC(c2cccc(-c3ccn[nH]3)c2)c2nc3ccccc3s2)CC1

Procedure:
A solution of 2-((1-Methyl-piperidin-4-yloxy)-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-phenyl}-methyl)-benzothiazole (500 mg) in 5N hydrochloric acid (4 mL) is stirred overnight at room temperature. 30% sodium hydroxide solution is added to reach pH 10, and the reaction is diluted with water. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 100/0 to 90/10) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole melting at 90° C.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH3:27])C1C=CC=CC=1.Cl>C(O)C>[Cl:21][C:20]1[C:15]([NH:14][CH2:13][C:12]2[CH:24]=[CH:25][C:9]([OH:8])=[C:10]([O:26][CH3:27])[CH:11]=2)=[N:16][C:17]([CH3:23])=[N:18][C:19]=1[CH3:22]
Reactant: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1O
Yield: 60.2 %

Procedure:
In analogy to the method described in example B1, 3.0 g (7.8 mmol) of (4-benzyloxy-3-methoxy-benzyl)(5-chloro-2,6-dimethylpyrimidin-4-yl)amine (from example A3) are reacted with 30 ml of 12.5N hydrochloric acid in 30 ml of ethanol. Extraction with ethyl acetate at a pH of 8 gives, after concentration, a solid residue which is chromatographed on silica gel (mobile phase: toluene/dioxane=5:1). Crystallization with toluene gives 1.38 g (60%) of the title compound as a beige crystallizate. m.p.: 179-181.5° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17])[CH2:2][CH2:3][CH3:4].[CH2:18]([O:20][C@H:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1)[CH3:19].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[F:17])[C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:20][CH2:18][CH3:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCNCc1ccc(C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of N-butyl-N-[2-fluoro-4-(trifluoromethyl)benzyl]amine (0.598 g, 2.40 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid, (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 20 g/70 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 0.785 g (74%) of a pale yellowish-white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Oc2ncccn2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (100 mg, obtained in Example 172) was added to a suspension of NaH (60% in mineral oil, 20 mg) in DMF (4 mL). Stirring was continued for 30 minutes at r.t. The mixture was cooled to 0° C. and 2-bromopyrimidine (59 mg, [CAS Reg. No. 4595-60-2]) was added. Stirring was continued for 4 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow solid (35 mg, 30%). MS (m/e)=480.1 [M+H+].
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:19][CH2:18]1)=[O:16])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.O.[OH-].[Li+].Cl.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.[PH2](Cl)=O>CO.O.C(Cl)Cl.C(N(CC)CC)C>[N:45]1([CH:42]2[CH2:43][CH2:44][N:39]([C:3](=[O:2])[CH:4]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:16])[CH2:5][C:6]3[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=3)[CH2:40][CH2:41]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COC(=O)C(Cc1ccc(OC)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=[PH2]Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(6-methoxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (160 mg) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (29 mg) in water (1 mL). The reaction was stirred at room temperature for 4 h and cooled to 0° C. The reaction was treated with 1N hydrochloric acid (0.6 mL), concentrated. The residue obtained was dissolved in methylene chloride (5 mL), and treated sequentially with 4-piperidyl-piperidine (75 mg), triethylamine (0.14 mL), and bis-2-oxo-3-oxazolidinyl)phosphinic chloride (104 mg). The reaction was stirred overnight, concentrated, and purified by prep HPLC to give 94 mg (45%). LC/MS: tR=1.86 min, 604.51 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:17]=1.[H][H]>CO.[C].[Pd]>[NH2:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:17]=1)[N:2]([CH3:1])[C:11]2=[O:12]
Reactant: Cn1c(-c2cccc(OCCCN3CCCCC3)c2)nc2ccc([N+](=O)[O-])cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2cccc(OCCCN3CCCCC3)c2)nc2ccc(N)cc2c1=O
Yield: 44 %

Procedure:
3-Methyl-6-nitro-2-[3-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone (105 mg, 0.248 mmol) was dissolved in methanol (3 mL), and 10% palladium-carbon (26.4 mg, 0.0248 mmol) was added thereto and stirred in a hydrogen atmosphere at room temperature for 4 days. The reaction solution was filtered through Celite, the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel column chromatography (chloroform/methanol=3/1) to obtain the intended compound (42.8 mg, 44%) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12](OC)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:19])=O.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:19][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CCCn2ccnc2)cn1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CCCn2ccnc2)cn1
Temperature: 100 °C
Reaction time: 10 h
Yield: 59.7 %

Procedure:
A mixture of 5-[3-(1-imidazolyl)propyl]-2-methoxypyridine(2.10 g), phosphorus oxychloride (7.44 g) and N,N-dimethylformamide (14.6 g) was stirred at 100° C. for 10 hours. To the reaction mixture was added saturated aqueous sodium acetate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel chloromatography. From the fraction eluted with ethyl acetate-methanol (20:1, v/v), 2-chloro-5-[3-(1-imidazolyl)propyl]pyridine (1.28 g, 60%) was obtained. Oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=2)[NH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To 5-aminoindolin-2-one (50 mg, 0.34 mmol) in DMF (1 mL) was added methanesulfonyl chloride (51 mg, 0.51 mmol) and DMAP (1 mg). The solution was stirred at rt for 16 h and the product was precipitated with ether, filtered and dried to give 10 mg, 13% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 3.55 (s, 2H), 2.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[NH:4][CH:5]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:6](=[O:36])[N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1.[C:44]([O:48][C:49](=[O:61])[NH:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57](Br)=[CH:56][CH:55]=1)=[O:53])([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:43])[NH:4][CH:5]([CH:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)[C:6]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:57]4[CH:58]=[CH:59][C:54]([C:52](=[O:53])[CH2:51][NH:50][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:61])=[CH:55][CH:56]=4)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)OC(C)(C)C)cc4)ccc3c2)[nH]1)C1CCOCC1

Procedure:
[2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester (200 mg, 0.34 mmol), [2-(4-Bromo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (106 mg, 0.34 mmol), Pd[PPh3]4 (39.2 mg, 0.034 mmol), potassium carbonate (117 mg, 0.85 mmol) was heated at 120 C in the microwave for 22 minutes in DME (2.5 mL) and water (0.3 mL). Brine (1 mL) was added and the organic layer was isolated and the volatiles were removed. The product was purified via flash chromatography on silica gel (eluent: EtOAc/hexanes) to yield 183 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].FC(F)(F)C(O)=O.CO[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C>C(Cl)Cl>[CH2:25]([N:19]1[CH2:20][CH:4]2[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[CH:5]2[CH2:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
N-Methylmaleimide (23.3 g, 21 mmol; Aldrich) was dissolved in CH2Cl2 (400 mL) in a 3-neck flask, chilled to 0° C. under nitrogen, and treated with trifluoroacetic acid (1.6 mL, 21 mmol; Aldrich). A solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (49.8 g, 21 mmol; Aldrich) in CH2Cl2 (60 mL) was then added slowly at a rate to maintain the temperature below about 5° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 24 h. The solution was concentrated under vacuum, and the residue was diluted with CH2Cl2 (125 mL), washed with saturated aqueous NaHCO3 (2×100 mL) and brine (2×100 mL). The organic phase was concentrated under vacuum to afford the title compound as a white solid (51.2 g, 21 mmol; 100% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.37 (m, 5H), 3.57 (s, 2H), 3.28 (d, J=10.2 Hz, 2H), 3.13-3.21 (m, 2H), 3.01 (s, 3H), 2.32-2.42 (m, 2H); MS (DCl/NH3) m/z 245 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30])(=[O:25])[CH3:24]>C(O)(C)C>[ClH:20].[C:23]([O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH:30][C:14]1[C:13]2[C:18](=[CH:19][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:11]([O:21][CH3:22])[CH:12]=2)[N:17]=[CH:16][N:15]=1)(=[O:25])[CH3:24]
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: CC(=O)Oc1cc(N)ccc1C
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (2.18 g, 6.47 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and isopropanol (50 ml) was stirred and heated at reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was filtered off, washed with isopropanol and ether to give 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline hydrochloride (2.69 g, 89%).
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:25](=[O:26])[CH2:24][C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[Cl:15])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3]
Reactant: COc1ccc(CC(=O)Cl)c(Cl)c1
Reactant: C=CCN1C(=O)COc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: C=CCN1C(=O)COc2ccc(C(=O)Cc3ccc(OC)cc3Cl)cc21

Procedure:
In analogy to Example 56, step 1, 4-allyl-4H-benzo[1,4]oxazin-3-one (18.8 g) was reacted with (2-chloro-4-methoxy-phenyl)-acetyl chloride and AlCl3 in 1,2-dichloroethane 3 h at 0° C. The crude product was purified by column chromatography (silica gel, heptane/AcOEt 6:1) to give the title compound (10.6 g) as a white solid. MS (m/e)=372.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([NH:20][OH:21])=[NH:19])[N:9]=2)=[CH:4][CH:3]=1.[S:22]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=O)(=[O:25])(=[O:24])[NH2:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]3[N:19]=[C:29]([C:28]4[CH:27]=[C:26]([S:22]([NH2:23])(=[O:25])=[O:24])[CH:34]=[CH:33][CH:32]=4)[O:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1cccc(-c2nc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)no2)c1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16 g, 0.5 mmol) and commercially available 3-sulfamoyl-benzoic acid (0.1 g, 0.5 mmol) according to the general procedure VI. Obtained as a white solid (0.1 g, 43%). MS (ISP) 482.1 [(M+H)+]; mp 273° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])=[C:4]([CH3:36])[CH:3]=1.[C:37](Cl)(=[O:39])[CH3:38].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH:21][C:37](=[O:39])[CH3:38])(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[O:23])=[C:4]([CH3:36])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(N)(=O)=O)cnn12
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 50 °C
Yield: 13.5 %

Procedure:
7-(4-Fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.098 g, 0.175 mmol) obtained in Example 1 step 5 was dissolved in pyridine (2 mL), 4-(dimethylamino)pyridine (0.023 g, 0.189 mmol) and acetyl chloride (0.25 mL, 3.50 mmol) were added, and the mixture was stirred with heating at 50° C. for 2 hr. 1 mol/L Hydrochloric acid was added dropwise to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (0.013 g, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[F:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:29]2[CH2:30][CH2:31][CH:26]([F:25])[CH2:27][CH2:28]2)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: FC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCC(=O)N1CCC(F)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and 4-fluoro-piperidine (60.0 mg, 0.59 mmol). The title compound was obtained as a solid (50.0 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.07 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 4.93 (1H, m), 4.10 (2H, m), 3.54 (2H, m), 3.44 (2H, m), 1.92 (1H, m), 1.74 (2H, m), 1.61 (1H, m). MS m/z: 491.39, 493.37 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[OH:26][N:25]=[C:12]([C@@H:11]1[C@:15]2([CH3:23])[C@H:8]([C:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]2)=[CH:5][CH:6]=3)[CH2:9][CH2:10]1)[CH3:13]
Reactant: CC(=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
The crude 3β-hydroxy-5,7-pregnadien-20-one (1.3 g) prepared in (a) was dissolved in 30 ml of pyridine, and after addition of hydroxylamine hydrochloride (863.2 mg), the solution was stirred for 5 hours at room temperature. After distilling off the pyridine under vacuum, methanol was added to the residue and the precipitating crystal was collected by filtration to obtain 1.04 g of the desired oxime compound.