Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]=3[CH:22]=2)[C:9]=1[CH:10]=[O:11]>C1COCC1.O.[Cl-].[Na+].O.C(Cl)Cl>[F:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]=3[CH:22]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Cn1c(=O)oc2ccc(-c3cncc(F)c3C=O)cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(-c3cncc(F)c3CO)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
Sodium borohydride (6.3 mg, 0.17 mmol) was added to a solution of 3-Fluoro-5-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-4-carbaldehyde (47 mg, 0.17 mmol) in THF (0.5 mL) and water (0.1 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h. Brine was added to the reaction mixture. The resulting mixture was diluted with DCM and water. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-3%) and afforded the title compound (7 mg, 16%); ESI-MS m/z: 275 [M+1]+, Retention time 0.92 min; 1HNMR (MeOD, 400.3 MHz) δ 3.44 (s, 3H), 4.59 (s, 2H), 7.32 (dd, J=8.0, 1.2 Hz, 1H), 7.35 (d, J=1.2 Hz, 1H), 7.38 (d, J=80 Hz, 1H), 8.39 (s, 1H), 8.48 (d, J=1.2 Hz, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH:33](OC(=O)C)=[O:34]>>[CH:33]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:34]
Reactant: CC(=O)OC=O
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=CN1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH2:3]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:29]([O:28][C:26]([N:24]1[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH2:3][CH:2]([O:1][C:33](=[O:35])[CH3:34])[CH2:25]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(O)C3)cc1
Solvent: c1ccncc1
Product: CC(=O)OC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 4) (500 mg, 1.159 mmol) in pyridine (3 ml) was treated slowly with acetic anhydride (0.219 ml, 2.317 mmol) and the resulting yellow solution was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and purification of the crude material by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.COC(=O)C1C=CC(N2C=C(C3[C:46]([C:54]4[CH:59]=[CH:58]C=CC=4)=[N:47]OC=3C(F)(F)F)N=C2)=CC=1>>[CH:54]1([CH2:46][NH:47][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]3)=[N:6][CH:5]=2)[CH2:59][CH2:58]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 51 %

Procedure:
As described for Example 10, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), instead of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester was converted, to the title compound (50 mg, 51%) which was obtained as a white solid. MS: m/e=454.2 [M+H]+.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].CC[O:9][C:10]([CH:12]([C:21](OCC)=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=O>C(O)C>[NH2:5][C:4]1[N:6]=[C:10]([OH:9])[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[C:21]([OH:22])[N:3]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(O)c(-c2ccc(Cl)cc2Cl)c(O)n1

Procedure:
Sodium (4.52 g, 0.196M) was added in portions to ethanol (150 ml). After all the sodium had dissolved guanidine hydrochloride (12.44 g, 0.13M) was added followed by diethyl 2,4-dichlorophenyl malonate(20 g, 0.0655M). The mixture was refluxed for 6 hours, EtOH was removed under reduced pressure and the residue partitioned between 2N NaOH (400 ml) and EtOAc (400 ml). The aqueous layer was acidified with concentrated hydrochloric acid with cooling and the precipitated solid was filtered and dried (11 g, 62%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[F:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].[OH-].[K+].[Cl-].[NH4+]>O.CO>[F:10][C:11]1[C:16]([CH:17]([OH:18])[C:9]2[C:5]3[CH:4]=[N:3][CH:2]=[N:1][C:6]=3[NH:7][CH:8]=2)=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: c1ncc2cc[nH]c2n1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncncc23)c1F
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To 7H-pyrrolo[2,3-d]pyrimidine (6, 0.100 g, 0.839 mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (9, 0.258 g, 0.982 mmol), 1.4 mL of methanol was added. This suspension was allowed to stir for 10 minutes, followed by the addition of potassium hydroxide (0.153 g, 2.73 mmol). The reaction was allowed to stir at room temperature for 8 hours, then poured into 5 mL of water and 5 mL of saturated ammonium chloride and extracted with 2×5 mL of ethyl acetate. Organic layers were combined and concentrated under vacuum and the resulting residue was purified by silica gel column chromatography eluting with a gradient of 60 to 100% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to give the desired compound (P-0001, 150 mg), with some 7H-pyrrolo[2,3-d]pyrimidine impurity, used in the next step without further purification. MS(ESI)[M+H+]+=383.2, [M−H+]−=381.5.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:25]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][F:34])[CH2:28][CH2:27]2)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:25]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][F:34])[CH2:30][CH2:31]3)=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: FCCN1CCC(c2nccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2C2CCN(CCF)CC2)cc1)c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (78 mg, 0.326 mmol), 2-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazine (37 mg, 0.163 mmol), and cesium carbonate (106 mg, 0.326 mmol) in DMSO (0.5 mL) was heated at 80° C. for 20 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, followed by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 95% over 15 min then neutralization to provide (1H-benzo[d]imidazol-2-yl)(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl) as white solid. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[C:6]1([S:12]([O:14][Na])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[C:6]1([S:12]([CH2:2][C:3]([NH2:5])=[O:4])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)CBr
Reactant: O=S(O[Na])c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of α-bromoacetamide IV in anhydrous DMF, is added PhSO2Na at 0° C. The reaction mixture is stirred for 1 hour at room temperature and is then poured into water. The organic layer is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica gel column chromatography to give α-phenylsulfonylacetamide III.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14]([O:20]C)=[N:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=3[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=2)[CH:6]=[N:5]1)#[N:2].[I-].[Na+].Cl[Si](C)(C)C>>[C:1]([CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14](=[O:20])[NH:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=3[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=2)[CH:6]=[N:5]1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(-c1cnn(CC#N)c1)cn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Product: N#CCn1cc(-c2cn(C3CCCC3)c3c(C#N)c[nH]c(=O)c23)cn1
Yield: 25.1 %

Procedure:
3-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (13.7 mg), sodium iodide (11.9 mg) and chloro(trimethyl)silane (25 μL) were stirred at 50° C. for 1 hr. The precipitated crystals were collected by filtration, and washed with ethyl acetate to give the title compound (3.3 mg).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([CH:25]3[O:29][CH2:28][CH2:27][O:26]3)[N:22]=[CH:21]2)=[CH:16][CH:15]=1.IC>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH:24]=[C:23]([CH:25]3[O:29][CH2:28][CH2:27][O:26]3)[N:22]=[C:21]2[CH3:1])=[CH:18][CH:19]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc(-n2cnc(C3OCCO3)c2)cc1
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(C2OCCO2)cn1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 0.37 mL, 0.60 mmol, 1.5 equiv) was added to a solution of N,N-diisopropylamine (0.085 mL, 0.60 mmol, 1.5 equiv) in THF (1.5 mL) at −78° C. The solution was stirred at −78° C. for 10 min and then a solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (100 mg, 0.40 mmol) in THF (1 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min, and then iodomethane (0.042 mL, 0.68 mmol, 1.7 equiv) was added. The solution was allowed to warm to room temperature and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic extract was washed with saturated aqueous sodium chloride (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give crude 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.09 (s, 1H), 5.88 (s, 1H), 4.20 (m, 2H), 4.03 (m, 2H), 2.35 (s, 3H). MS m/z 265.0 (M+H)+; Rt-0.57 min.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].CCN(C(C)C)C(C)C>CCCCO>[C:10]1([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:19][CH2:18][CH2:16][OH:17])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: Clc1cc(Nc2ccccc2)ncn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2ccccc2)ncn1
Temperature: 200 °C
Yield: 97 %

Procedure:
50 mg of 6-chloro-N-phenylpyrimidin-4-amine hydrochloride, 14 mg of ethanolamine and 69 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(Phenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:9]1[CH:14]([Cl:15])[CH2:13][CH2:12][CH2:11][O:10]1.Cl.O>CCOCC>[Cl:15][CH:14]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: ClC1CCCOC1Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: ClC1CCCOC1c1ccccc1
Yield: 93 %

Procedure:
Into a dry flask fitted with dropping funnel reflux condenser, drying tube and mechanical stirrer was placed 51 g of magnesium turnings, followed by the addition of 200 ml of dry ether. A small portion of bromobenzene was added to initiate the reaction, followed by the remainder of 330 g (2.1 mole) of bromobenzene in 1 liter of dry ether at a rate sufficient to maintain reflux. The mixture was cooled in an ice-salt bath to which was added dropwise the cold ethereal solution of 2,3-dichlorotetrahydropyran. After completing the addition, the slurry was refluxed for 3 hours, cooled in an ice-water bath and 300 ml of cold 20 percent hydrochloric acid added slowly to the stirred mixture. The addition of 500 ml of water dissolved the precipitated salts, the layers were separated, the aqueous phase extracted with ether (2×200 ml) and the combined ethereal layers washed with brine (200 ml) and dried over anhydrous potassium carbonate. In vacuo removal of solvent left an amber liquid which was distilled through a 20 cm Vigreux column, whereby 256 g was collected at 77°-90°/0.25 mm Hg. The product was redistilled at 153-154/16 mm Hg, the distillate crystallizing to give needles m.p. 39.5°-40.5°. The crude yield was 256 g (93% yield based on dihydropyran).
Reaction SMILES: C([CH2:3][CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=O.[Cl-].[NH4+].S(=O)(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:16][O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:5]([CH2:4][CH2:3][CH:12]=[CH:13][O:15][CH3:16])[CH:14]=1
Reactant: COc1cc(CCC=O)c(OC2CCCCO2)c2ccccc12
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC=CCCc1cc(OC)c2ccccc2c1OC1CCCCO1
Reaction time: 0.5 h
Yield: 260.7 %

Procedure:
A 50 ml oven-dried 2-necked (14/20) round bottom flask, equipped with magnetic stirring bar, nitrogen inlet and serum cap is charged with methoxymethyltriphenylphosphonium chloride (90%) (2.5 g). This material is suspended in 10 ml tetrahydrofuran and the resulting mixture is placed under a nitrogen atmosphere and cooled to 0°-5° C. n-Butyllithium reagent (1.65 M in hexane, 4.0 ml) is added dropwise to the stirred mixture via syringe over 2-3 min. The solids gradually dissolve to give a deep red colored solution (some solids remain). This solution is stirred at 0°-5° C. for 30 min and then is treated with a solution of 2-(2-formylethyl)-4-methoxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]naphthalene (0.958 g) in 5 ml tetrahydrofuran in one portion. The resulting deep red colored solution is stirred at 0°-5° C. for 15 min at which time TLC analysis indicates no remaining starting material. The solution is poured into saturated aqueous ammonium chloride, the pH adjusted to 7 with 10% sodium bisulfate and this mixture extracted first with Skellysolve B and then with ether. Each of these extracts is washed two times with water, dried with magnesium sulfate, filtered and concentrated. TLC analysis of the ether extract indicates the presence of the product mixture suggesting that the Skellysolve B extraction is not efficient. The separate extracts are combined to give 1.36 g of the title compound mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[S:27][C:26]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[N:25][C:24]=4[CH3:34])=[O:22])[CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:34])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2cnc3cc(Cl)ccc3c2O)CC1
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2cnc3cc(Cl)ccc3c2Cl)CC1

Procedure:
A suspension of 1-(7-chloro-4-hydroxyquinoline-3-sulfonyl)-4-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]-piperazine (200 mg) in phosphoryl chloride (6 ml) was refluxed for 2 hours. The reaction mixture was concentrated, and ice water was added to the residue. To the mixture was added an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The extract was dried and concentrated to give brown crystals of the title compound (223 mg).
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](C)[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH:27]([F:29])[F:28])C1C=CC=CC=1.Cl.[CH2:31](O)C>>[Cl:21][C:20]1([CH3:31])[CH:19]=[N:18][C:17]([CH3:23])=[N:16][CH:15]1[NH:14][CH2:13][C:12]1[CH:24]=[CH:25][C:9]([OH:8])=[C:10]([O:26][CH:27]([F:28])[F:29])[CH:11]=1
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OC(F)F)c2)n1
Reactant: CCO
Agent: Cl
Product: CC1=NC(NCc2ccc(O)c(OC(F)F)c2)C(C)(Cl)C=N1
Yield: 41 %

Procedure:
In analogy to the method described in example B1, 6.9 g (16.4 mmol) of [4-benzyloxy-3-(1.1-difluoromethoxy)benzyl](5-chloro-2,6-dimethylpyrimidin-4-yl)amine (from example A6) are reacted with 70 ml of 12.5N hydrochloric acid in 70 ml of ethanol. Extraction with ethyl acetate at a pH of 8 gives, after concentration, a solid residue. Extraction by stirring with petroleum ether and drying give 2.2 g (41%) of the title compound as a beige crystallizate. m.p.: 167-168.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.N1C=CC=CC=1.[C:59](OC(=O)C)(=[O:61])[CH3:60]>ClCCl>[C:59]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:26][CH:27]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1)(=[O:61])[CH3:60]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCNC(C)=O)c3c2Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 0.185 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.1 ml of dichloromethane is admixed successively with 0.50 ml of pyridine and 0.21 ml of acetic anhydride and stirred at room temperature for 2 hours. The reaction mixture is poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed successively with 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (EtOAc-heptane=4:1); Rt=5.89.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]1=O.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1.C[Li]>CO>[CH2:20]([C@@H:3]1[N:2]([CH3:1])[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH2:16][CH2:17][CH3:18]
Reactant: CN1C(=O)CC[C@H]1COc1cccnc1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CO
Product: CCCC[C@H]1CC[C@@H](COc2cccnc2)N1C
Temperature: -78 °C
Reaction time: 44 h

Procedure:
A 1.24 g (6.0 mmol) sample of 3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as in Example 22b above, was dissolved in mL of THF and cooled to -78° C. To this solution was added 6.0 mL (12 mmol) of 2 M methyl lithium, and the solution was warmed to room temperature, then stirred for 44 hours. Two mL of methanol were added, and the mixture concentrated under vacuum. Another 10 mL of methanol was added, followed by 65.6 mg of NaBCNH3 and a trace of bromocresol green indicator. HCl (4M) was added slowly until the solution remained a yellow color, then the reaction mixture was stirred for 1 hour. The mixture was then adjusted to basic pH with satd NaHCO3, concentrated, and extracted with ethyl acetate. The extract was dried, concentrated and chromatographed on silica gel to give 86 mg of title compound. MS (DCI/NH3) m/e: 248 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.33-8.31 (m, 1H), 8.23-8.19 (m, 1H), 7.23-7.19 (m, 2H), 4.11-4.04 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.77 (m, 1H, 2.46 (s, 3H), 2.40-2.27 (m, 1H), 2.05-1.20 (m, 10H), 0.92 (t, J=6.0 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]3[C:25]([CH3:30])=[N:26][O:27][C:28]=3[CH3:29])=[CH:22][C:21]([CH2:31][CH2:32][CH3:33])=[N:20]2)=[CH:15][CH:14]=1.C(Cl)Cl>C1(C)C=CC=CC=1.O>[CH3:30][C:25]1[C:24]([C:23]2[N:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)[N:20]=[C:21]([CH2:31][CH2:32][CH3:33])[C:22]=2[CH:8]=[O:9])=[C:28]([CH3:29])[O:27][N:26]=1
Reactant: CN(C)C=O
Reactant: CCCc1cc(-c2c(C)noc2C)n(-c2ccc(OC)cc2)n1
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=O
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
Phosphorus oxychloride (599 μL, 6.42 mmol) was added dropwise to dry N,N-dimethylformamide, (497 μL, 6.42 mmol) in toluene (0.6 mL) at 0° C. The mixture was stirred for 5 minutes. Then 4-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)-3,5-dimethylisoxazole (160 mg, 0.51 mmol) was added, dissolved in toluene (0.5 mL) and the reaction mixture was heated at 150° C. for 20 minutes in the microwave. CH2Cl2 and water were added, a phase separator was used to separate and dry the organic phase. Filtration through a short silica plug gave semi-crude 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde which was used as such in the next step without further purification.