Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To a solution of 1.4 g (6.7 mmol) of tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate in 20 mL of anhydrous THF are added portionwise under argon, at room temperature, 0.27 g (6.7 mmol) of sodium hydride at 60% in oil. After stirring for 45 minutes, the medium is cooled to 0° C. and 0.8 mL (6.7 mmol) of benzyl bromide is added. After stirring for 1 hour at room temperature, the medium is hydrolysed with 30 mL of water and extracted with 2×100 mL of EtOAc, dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 1.53 g of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}carbamate are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[CH:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:10]([I:19])=[C:6]2[N:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)cc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-1A-3g; 370 mg, 1.33 mmol) in 5:1 methylene chloride/chloroform (9 ml) cooled in an ice bath was added N-iodosuccinimide (449 mg, 2.0 mmol), portionwise, to give a heterogeneous mixture. After 1.5 hours, the ice bath was removed and the reaction was stirred an additional 2.5 hours to give a homogenous, pink solution. The reaction was extracted from aqueous NaHCO3 with methylene chloride. The combined extracts were washed with saturated aqueous Na2S2O4 and brine, dried (MgSO4), and then concentrated, in vacuo, to afford product I-1A-3h as a tan solid (535 mg, quantitative): +ESI MS (M+1) 403.9; 1H NMR (400 MHz, CD2Cl2) δ 7.57–7.40 (m, 4H), 6.99 (s, 1H), 2.66 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)c1cc(O)cc(=O)[nH]1
Reactant: O=[N+]([O-])O
Product: CC(C)c1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 0 °C
Reaction time: 84 h

Procedure:
A solution of 4-hydroxy-6-isopropyl-1H-pyridin-2-one (1.76 g, 11.5 mmol) in 55-60 mL of 50% aq HNO3 is stirred at 70° C. for 2.5 h. After cooling, the reaction mixture is poured into ice-cold H2O (˜100 mL). The resulting solution is allowed to sit in the refrigerator for 3.5 days. The solid that precipitates is collected by filtration, washed with water, and dried to afford 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one as yellow crystals. 1H NMR (DMSO-d6, 300 MHz) δ 12.30 (br s, 1H), 11.82 (br s, 1H), 5.82 (d, J=1.2 Hz, 1H), 2.71 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[CH3:21][NH:22][CH3:23].[OH-].[Na+]>O>[CH3:21][N:22]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(N(C)C)ccc3C[C@@H]21
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (1.00 g, 3.32 mmol) and dimethylamine hydrochloride (15 g) was heated to 200° C. to form a homogeneous molten semi-solid. After 30 minutes, the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-dimethylamino-6-propyl-5,5a,6,7,8, 9,9a,10-octahydropyrido[2,3-g]quinoline (Rf =0.54, 568 mg, 63% yield) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH2:25])[C:5]=2[NH2:26].[NH:27]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:28]([C:30](O)=[O:31])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C>CCOC(C)=O.CN(C)C=O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH:25][C:30]([C@@H:28]([NH:27][C:33](=[O:34])[O:35][CH2:36][CH:37]1[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:44]3[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:29])=[O:31])[C:5]=2[NH2:26]
Reactant: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(N)c3N)cc(Br)c1OC
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)[C@H](C)NC(=O)OCC2c4ccccc4-c4ccccc42)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To an oven-dried carousel reaction flask charged with a magnetic stir bar at room temperature under argon was added (R)-2,7,8-triamino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene (0.200 g, 0.479 mmol), Fmoc-Ala-OH (0.179 g, 0.575 mmol), dimethylformamide (2.4 mL), HOBt 0.084 g, 0.62 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) (0.119 g, 0.623 mmol). The black solution was stirred at room temperature overnight. The solution was diluted with EtOAc (50 mL), washed with water (3×30 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to give the crude product as a brown residue. Purification by flash column chromatography (silica gel 12 g pre-packed column, gradient elution with EtOAc:Hexanes, 1:9 to 1:4 to 1:1) gave 0.046 g (13%) of the title compound as a yellow solid: mp: 212-217° C. (dec); 1H-NMR (DMSO-d6): δ 9.37 (br s, 1H), 7.89 (d, J=7.7 Hz, 2H), 7.76-7.69 (m, 3H), 7.44-7.39 (m, 2H), 7.35-7.30 (m, 2H), 6.98 (d, J=1.9 Hz, 1H), 6.88 (br s, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 6.31 (d, J=8.3 Hz, 1H), 4.79 (br s, 2H), 4.69 (s, 1H), 4.31-4.23 (m, 4H), 3.80 (s, 3H), 3.70 (s, 3H), 1.32 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(C(=O)c2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid (0.12 g) was reacted with 2-(piperidin-4-yl)propan-2-ol (1.2 eq), HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq) and DIPEA (3 eq) in DMF (3.2 mL) for 1 hour. The reaction was then extracted with EtOAc and bicarbonate solution and the organic layer was dried with Magnesium sulfate, filtered and concentrated to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone in quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([OH:15])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(OC)([C:21]1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([O:15][CH3:21])[C:10]2([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: OC1CN(Cc2ccccc2)CC12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(Cc2ccccc2)CC12CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Benzyl-5-azaspiro[2.4]heptan-7-ol (200 mg) was dissolved into DMF (4 ml) and cooled at 0° C. NaH (120 mg) was added to the reaction and stirred for 10 minutes. To the reaction was added TsOMe (200 mg), the solution was heated at 80° C. for two hours. The reaction was quenched with water and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4 and evaporated to give the titled product. Mass: (M+1), 158
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:10][C:4]1[C:5]([O:9][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1cc(Cl)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A solution of 4-amino-2-chloro-5-fluorophenol (6.0 g, 37 mmol), 2,4-dichloro-pyridine (5.3 g, 37 mmol) and K2CO3 (5.2 g, 37 mmol) in DMSO (100 mL) was heated at 80° C. under nitrogen overnight. The mixture was cooled to RT, poured into water (300 mL), and extracted with EtOAc (3×200 mL). The combined organics were washed with brine (3×100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/petroleum ether) to give 5-chloro-4-(2-chloro-pyridin-4-yloxy)-2-fluoro-phenylamine as a white solid (3.0 g, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (d, J=5.7 Hz, 1H), 7.34-7.31 (m, 1H), 7.01-6.82 (m, 3H), 5.63 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33](=[O:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:35]([CH2:34][C:33]([O:32][CH3:31])=[O:39])(=[O:37])=[O:36])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.1 %

Procedure:
To product of example 205 (21.5 mg, 0.05 mmol) in methylene chloride (1 mL) was added chlorosulfonyl-acetic acid methyl ester (35 mg, 0.2 mmol) and triethylamine (30 μl, 0.22 mmol) and the resulting mixture was stirred at room temperature for 3 days. Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was chromatographedon silica gel eluting with 199:1 dichloromethane:methanol. The product was dissolved in dichloromethane and added two drops of acetic acid, then stirred at rt for 10 min, washed with water. The organic layer was dried with magnesium sulfate and evaporated in vacuo to give the title compound (2 mg, 7%). 1H NMR (300 MHz, DMSO-d6): δ 0.99 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 3.65 (s, 3 H) 4.40 (s, 2 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.59 (dd, J=8.82, 2.57 Hz, 1 H) 7.66 (d, J=2.57 Hz, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.41, 1.84 Hz, 1 H) 10.73 (s, 1 H) 14.15 (s, 1 H). MS (ESI−) m/z 562 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:20]#[C:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[O:1]([CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]([C:20]#[C:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:13]=2)[CH2:5][CH2:4]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC#CC(CC(=O)OC)c1ccc(OCC2(CO)CC2)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC#CC(CC(=O)OC)c1ccc(OCC2(COc3ccccc3)CC2)cc1
Reaction time: 0.17 h

Procedure:
100 mg of methyl 3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate were dissolved in 10 ml of DCM and used to charge a microwave vessel, then 46.7 mg of phenol and 130 mg of triphenylphosphine (polymer-bound, Reagentplus 99%) were added, and the mixture was stirred for 10 min to swell the resin. Subsequently, 98 μl of diisopropyl azodicarboxylate were added and the mixture was stirred at 120° C. under microwave irradiation for 15 min. The cooled reaction mixture was filtered and the filtercake was washed 3× with 10 ml each time of DCM. The combined filtrates were washed with 30 ml of water, then dried using a ChemElut cartridge and concentrated under reduced pressure. The residue was purified by means of RP-HPLC. This gave 68 mg of methyl 3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate.
Reaction SMILES: [IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7](SC)=[N:8][CH3:9].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[C:23]2[CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][NH2:40])[CH2:34][CH2:33]2)=[CH:17][CH:16]=1>CC(O)C>[IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7]([NH:40][CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([CH2:31][C:23]2[N:22]([CH2:21][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH2:33][CH2:34]1)=[N:8][CH3:9]
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CN=C(NCC(OC)OC)SC
Agent: I
Solvent: CC(C)O
Product: CN=C(NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)NCC(OC)OC
Yield: 99 %

Procedure:
A mixture of 6.4 parts of methyl N-(2,2-dimethoxyethyl)-N'-methylcarbamimidothioate monohydroiodide, 7.3 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine and 80 parts of 2-propanol was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 12.77 parts (99%) of N-(2,2-dimethoxyethyl)-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]N"-methylguanidine monohydroiodide (450).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:41][C:40]3[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (230 mg, 0.494 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (75.6 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (34.5 mg, mp =105° C.). 1H NMR (360 MHz, CDCl3) δ 1.36 (3H, t, J=7.3 Hz), 1.53-1.91 (8H, m), 2.87 (3H, s), 3.41 (1H, m), 4.10 (2H, q, J=7.3 Hz), 5.45 (2H, s), 7.23-7.36 (2H, m), 7.58-7.75 (2H, m), 7.88 (1H, s); MS (ES+) m/e 422 [MH]+. Anal. Found C, 62.56; H, 5.67; N, 23.18%. C22H24FN7O requires C, 62.69; H, 5.74; N, 23.26%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.BrCC1CCCCO1>>[F:52][C:51]([F:54])([F:53])[C:48]1[O:47][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:50][CH:49]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 64-68° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.8, 7.7, 1.0 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.07 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.76-6.72 (m, 1H), 6.50 (s, 1H), 6.38 (d, J=3.3 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.5 Hz, 1H), 4.89 (d, J=16.5 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (d, J=267 Hz), 112.8 (d, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: C[O-].[Na+].O=[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][CH2:7][CH:8]=O.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl>CO>[CH2:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:17]2[C:18]=1[CH:19]=[CH:20][CH2:21]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1=CCC=C1
Reactant: CCCCCCCC(=O)CCC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCc1cccc2c1C=CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
20.4 ml of a 30 percent strength solution of sodium methanolate (111 mmol) in methanol were initially introduced into the reaction vessel at 0° C., and a mixture of 9.0 g (44.5 mmol) of 4-oxoundecylaldehyde and 4.0 ml (49 mmol) of cyclopentadiene was added in the course of 30 minutes. After the mixture had been stirred at 0° C. for 2 hours and at room temperature for a further 3 hours, it was hydrolyzed, methylene chloride was added and the mixture was filtered over Corolite. The organic phase was separated off, dried over MgSO4 and evaporated. Column chromatography with hexane as the mobile phase gave 3.2 g (34%) of the indene 17. For the NMR data, see Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:31]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]3[C:30]=1[N:21]=[CH:22][CH:23]=[CH:24]3)(=[O:32])=[O:33])[CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc3cccnc23)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.8 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 8-quinolinesulfonyl chloride (25 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 11%) as a white solid. MS (ESI+) for C21H21N3O3S m/z 396 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[C:10]=2[F:23])=[C:4]([Cl:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]([CH:49]=[O:50])=[CH:35][C:36]3[N:40]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[N:38][C:37]=3[C:47]=2[F:48])=[C:28]([Cl:51])[CH:27]=1.C([O-])([O-])=O.[K+].[K+].S([CH2:68][N+:69]#[C-:70])(C1C=CC(C)=CC=1)(=O)=O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[C:10]=2[F:23])=[C:4]([Cl:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]([C:49]3[O:50][CH:70]=[N:69][CH:68]=3)=[CH:35][C:36]3[N:40]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[N:38][C:37]=3[C:47]=2[F:48])=[C:28]([Cl:51])[CH:27]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Agent: Fc1c(Nc2ccc(Br)cc2Cl)c(-c2cnco2)cc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(-c3cnco3)cc21
Temperature: 25 °C
Yield: 4 %

Procedure:
(4-Bromo-2-chloro-phenyl)-(4-fluoro-6-oxazol-5-yl-1H-benzoimidazol-5-yl)-amine 10×: 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.025 g, 0.053 mmol) is suspended in MeOH (2 mL) and K2CO3 (0.015 g, 0.105 mmol) is added followed by tosylmethyl isocyanide (0.011 g, 0.058 mmol). The reaction mixture is heated to reflux under N2 for 16 hours. After cooling, additional tosylmethyl isocyanide (0.011 g, 0.058 mmol) is added and the reaction mixture heated to reflux under N2 for 16 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure and dissolved in ethyl acetate. The organic solution is washed with water and brine. The combined aqueous washes are extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 20:1 methylene chloride:MeOH provides 4 mg (18%) desired product 10× and 1 mg (4%) (4-bromo-2-chloro-phenyl)-[4-fluoro-1-(2-methanesulfonyl-ethyl)-6-oxazol-5-yl-1H-benzoimidazol-5-yl]-amine.