Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([O:6][CH2:3][C:4]#[CH:5])[N:11]=[CH:10][N:9]=1
Reactant: C#CCO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
In 12 ml of tetrahydrofuran was suspended 0.61 g of sodium hydride (60% in oil), to which 4 ml of a tetrahydrofuran solution containing 0.57 g of 2-propyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 4 ml of a tetrahydrofuran solution containing 1.5 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring for 2.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.61 g of 4-chloro-6-(2-propynyloxy)pyrimidine.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][O:8][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@]1(C(=O)COC(=O)c2ccccc2)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
In 4 ml of methylene chloride was dissolved 208 mg of 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method described in Example 6. To this solution was added 202 mg of triethylamine, and the mixture was ice-cooled. Next, 140 mg of benzoyl chloride was directly added to the solution and the mixture was stirred for one hour. To the solution was further added 1 ml of methanol, and the mixture was stirred for one hour. The reaction liquid was concentrated under reduced pressure and the resultant residue was directly subjected to preparative thin layer chromatography (silica gel) for purification whereby 204 mg (yield: 78.5%) of the title compound was obtained as a colorless amorphous solid. The structure of this compound was confirmed by the following physical properties and results of various analyses:
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:14])[NH:12][OH:13])=[CH:7][CH:6]=1)C.[CH2:16]([N:18]([CH2:29][CH3:30])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=O)[CH3:17].[OH-].[Na+]>C1COCC1>[CH2:29]([N:18]([CH2:16][CH3:17])[C:19]1[CH:20]=[C:21]([C:22]2[O:13][N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:15])=[CH:10][CH:9]=3)[N:14]=2)[CH:25]=[C:26]([CH3:28])[N:27]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(C(=N)NO)cc1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 8 starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester and 2-diethylamino-6-methyl-isonicotinic acid except that in the final step, the ethyl ester is cleaved under basic conditions (3 N aq. NaOH in THF); LC-MS: tR=0.77 min; [M+1]+=353.09; 1H NMR (D6-DMSO): δ 1.16 (t, J=6.8 Hz, 6H), 2.43 (s, 3H), 3.58 (q, J=6.5 Hz, 4H), 7.00 (s, 1H), 7.07 (s, 1H), 8.00 (d, J=8.0 Hz, 2H), 8.04 (d, J=8.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:7]=1>[Pd].CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: Cn1cc(Nc2cc(F)ccc2[N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2cc(F)ccc2N)cn1
Temperature: 20 °C
Reaction time: 6 h
Yield: 212 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)-(1-methyl-1H-pyrazol-4-yl)amine (102 mg, 0.43 mmol) and 10% palladium on carbon (25 mg) in EtOAc (10 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 6 h. A separate mixture of (5-fluoro-2-nitrophenyl)-(1-methyl-1H-pyrazol-4-yl)amine (0.19 g, 0.80 mmol) and 10% palladium on carbon (50 mg) in EtOAc (10 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 5 h. The catalyst was removed by filtration and the filtrates combined and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-8% (2M ammonia in methanol) in DCM) to give the title compound as a brown oil (0.188 g, 74%). LCMS (Method C): RT 1.61 min [M+H]+ 207.1
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]([N:12]([C:30](=[O:33])[CH2:31][CH3:32])[C:13]1[C:18]([S:19](O)(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH2:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)[Cl:35].CCOCC>ClCCl>[O:8]=[C:9]([N:12]([C:30](=[O:33])[CH2:31][CH3:32])[C:13]1[C:18]([S:19]([Cl:35])(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH2:10][CH3:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCC(=O)N(C(=O)CC)c1c(-c2cccc(C)c2)cccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)N(C(=O)CC)c1c(-c2cccc(C)c2)cccc1S(=O)(=O)Cl

Procedure:
To a solution of 3.6 g (7.6 retool) of the N,N-diethylethanamine salt of 2-[bis(1-oxopropyl)amino]-3'-methyl [1,1'-biphenyl]-3-sulphonic acid in 8 ml of dichloromethane, at 0° C., are added 1.6 g (7.6 mmol) of phosphorus pentachloride and the mixture is allowed to return to room temperature. The mixture is then heated for 4 hours at the reflux temperature and is then allowed to return to room temperature. Ether is added, the mixture is filtered, the filtrate is concentrated and the residue is purified on a column of florisil™, eluting with an ether/pentane mixture (1/1). The product is recrystallized from an ether/pentane mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([NH2:41])=[O:40]>C1COCC1.CN(C=O)C>[C:39]([CH2:38][NH:41][C:39](=[O:40])[CH2:38][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)(=[O:40])[NH2:41]
Reactant: NC(=O)CBr
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)CNC(=O)COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in THF (1 ml) and DMF (5 drops) on ice was added sodium hydride (0.024 g, 0.6 mmol). To the flask was added bromoacetamide (0.083 g, 0.6 mmol). While warming to room temperature the reaction was allowed to sit for 6 hours. The reaction was quenched with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified by semipreparative HPLC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to yield the title compound (0.008 g, 7.0% yield):1H NMR (CDCl3) 6.6-7.3 (m, 11H), 6.0 (broad s, 2H), 5.55 (broad s, 1H), 4.7 (t, 1H), 4.5 (s, 2H), 4.1 (m, 4H), 3.5 (m, 2H), 3.05 (m, 1H), 2.9 (m, 4H), 2.65 (m, 1H), 2.55 (m, 4H), 1.65 (m, 4H), 1.5 (m, 2H); ES-MS (m/z) 575 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[C:8]=2[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[NH2:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[C:8]=3[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:3]=2)[CH2:26]1
Reactant: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC1CCN(c2ccc3c(NC(=O)CCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C
Yield: 84 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexanepropanamide (Example 90(a)) (0.24 g), (S)-3-aminopyrrolidine (0.18 g) and triethylamine (0.1 mL) were suspended in acetonitrile and heated at 100° C. in a microwave for 1 hour. The resulting precipitate was filtered and then washed with acetonitrile to give a brown solid. Purification (SiO2, methanol:dichloromethane:triethylamine 3:97:0.5) gave the title compound as a colourless solid (230 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([C:26]([F:29])([F:27])[F:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)-methoxy)benzoate (3.70 g, 8.88 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was triturated in hexanes (10 mL), the solid was filtered and dried to give the title compound (2.20 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.1 Hz, 1H), 6.59 (d, J=12.3 Hz, 1H), 4.11 (s, 2H), 2.03-1.88 (m, 3H), 1.76-1.60 (m, 5H), 1.50-1.21 (m, 3H), 0.94-0.83 (m, 2H), 0.64-0.55 (m, 2H); MS (ES+) m/z 361.1 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(=O)(O)[O-].[Na+:34].[OH-].[Na+].P([O-])([O-])([O-])=O>CC(C)=O.O>[Na+:34].[OH:27][N:26]=[C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]([NH:17][C@@H:16]1[C:15](=[O:29])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][OH:4])[CH2:7][S:8][C@H:9]12)=[O:28]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)C(=NO)c3ccccc3)C(=O)N12

Procedure:
To 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer) (5.0 g) was added sufficient saturated sodium bicarbonate solution to bring the pH to 7.0, during which time solution occurred. To this solution was added water (300 ml.) and defatted wheat germ (35 g.), and the suspension stirred vigorously whilst the pH was maintained at between 6.7 and 6.9 by frequent additions of 2 N-sodium hydroxide. After addition of ca. 6 ml, the pH remained constant at 6.9. The mixture was poured into acetone (400 ml.), filtered (kieselguhr), and the filtrate evaporated under reduced pressure to remove acetone, then refiltered (kieselguhr). The filtrate was washed with ethyl acetate, and the pH adjusted to 2.8. The aqueous phase was extracted with ethyl acetate, and the extracts were stirred with water (ca. 300 ml.) and the pH brought up to 7.0 with 2 N sodium hydroxide. Th phases were separated and the aqueous phase washed twice with ethyl acetate, once with ether, evaporated under reduced pressure to remove residual solvents, and freeze-dried. This gave the title acid (1.5 g: 31%), [α]D +93° (c 1.0, DMSO), λmax. (pH 6 phosphate buffer) 252 nm (ε 12,800), νmax. (Nujol) 1750 (β-lactam), 1650 and 1530 cm.-1 (amide), τ (DMSO-d6) values include 2.3 to 2.6 (multiplet; aromatic protons), 5.72 and 6.05 [two doublets (branches of a quartet), J 13 Hz; CH2OH], 6.44 and 6.68 [two doublets (branches of a quartet), J 18 Hz; C-2CH2 ].
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:15][C:16]1[N:17]=[C:18](Cl)[C:19]2[CH:24]=[CH:23][NH:22][C:20]=2[N:21]=1>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:8]=2[CH3:10])[C:19]2[CH:24]=[CH:23][NH:22][C:20]=2[N:21]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 4-cyclopropyl-2,6-dimethylphenol (259 mg, 1.60 mmol) in THF (3 mL) at 0° C. was added NaH (64 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol) in THF (2 mL) was added to the mixture. The mixture was heated at 80° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 79 mg (48%) of 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([F:20])([F:19])[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[N:8]=1.C[Si](C)(C)[Si](C)(C)C.II.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:25][C:2]([F:1])([C:21]([F:22])([F:23])[F:24])[C:3]([F:19])([F:20])[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])=[CH:9][C:7]=2[N:8]=1
Reactant: COC(=O)C(C)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A mixture of methyl 2-(2-heptafluoropropylbenzoxazol-5-yl)propionate (11.6 g, 0.0311 mol), hexamethyldisilane (6.81 g, 0.047 mol) and iodine (11.85 g, 0.047 mol) was stirred in refluxing toluene (110 ml) for 6 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with water, saturated aqueous sodium thiosulfate solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting initially with dichloromethane and then with ethyl acetate:dichloromethane 1:4, to give 2-(2-heptafluoropropylbenzoxazol-5-yl)propionic acid (6.3 g).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH2:24]([N:26]1[CH2:31][CH2:30][O:29][CH:28]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH2:31][CH2:30][O:29][CH:28]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:34][CH:33]=2)[CH2:27]1)[CH3:25]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(NS(C)(=O)=O)c3)n2n1
Reactant: CCN1CCOC(c2ccc(N)cc2)C1
Product: CCN1CCOC(c2ccc(Nc3ncc4ccc(-c5cccc(NS(C)(=O)=O)c5)n4n3)cc2)C1

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using N-[3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide and 4-(4-ethyl-morpholin-2-yl)-phenylamine to give N-(3-{2-[4-(4-ethyl-morpholin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}phenyl)methanesulfonamide as a yellow foam (47.3, 31.4% yield). LCMS (E/I+) 493 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.01 (s, 1H), 7.89 (d, 1H, J=7.8 Hz), 7.58 (d, 2H, J=8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.36 (m, 3H), 7.02 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 4.57 (d, 1H, J=10.2 Hz), 4.05 (d, 1H, J=11.4 Hz), 3.85 (t, 1H, J=11.4 Hz), 3.03 (s, 3H), 2.98 (d, 2H, J=11.6 Hz), 2.83 (d, 1H, J=11.5 Hz), 2.47 (q, 2H, J=7 Hz), 2.23 (t, 1H, J=11.5 Hz), 2.08 (t, 1H, J=10.5 Hz), 1.12 (t, 3H, J=7 Hz).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:31]>ClCCl.CO.C(OCC)C>[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc(F)c4)cc3c2C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1cccc(F)c1)c1ccc2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the product from step C (135 mg, 0.30 mmol) in dichloromethane (1 mL) and methanol (0.5 mL) was added 2M HCl in diethyl ether (4 mL). After stirring for 14 h at ambient temperature the reaction mixture was diluted with diethyl ether to induce precipitation. The reaction mixture was concentrated in vacuo to give 8-(3-fluorophenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (96 mg, 96%, AUC HPLC>99%) as an off-white solid: mp 262-272° C. dec; 1H NMR (CD3OD, 300 MHz) δ 8.31-8.27 (m, 1H), 7.97 (dd, J=8.7, 2.1 Hz, 1H), 7.84-7.78 (m, 1H), 7.76-7.69 (m, 2H), 7.64-7.56 (m, 1H), 7.42-7.35 (m, 1H), 4.49 (s, 2H), 3.69 (t, J=6.0 Hz, 2H), 3.23-3.17 (m, 2H); APCI MS m/z 332 [M+H]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[OH-].[Na+]>ClC1C=CC=CC=1>[CH:10]1([NH:13][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: Clc1nc(Cl)nc(NC2CC2)n1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
133 g of cyanuric chloride are suspended in 720 ml of chlorobenzene and cooled to -10° C. To this suspension are added with stirring 50 ml of cyclopropylamine dropwise over a period of 25 minutes. Keeping the temperature at -10° C., 96 ml of aqueous sodium hydroxide (30% NaOH) are added dropwise. The reaction mixture is then stirred at -10° C. for 11/2 hours and allowed to stand for a further 16 hours at room temperature, after which it is washed with water (2×400 ml), dried over anhydrous sodium sulphate and filtered. The excess chlorobenzene is then removed by water jet vacuum distillation. 138 g of 2-cyclopropylamino-4,6-dichloro-s-triazine in the form of white crystals are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:40])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:39])[C:17]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[C:18]([CH:32]=2)[CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:12])=[C:4]([CH3:41])[CH:3]=1.CC1(C)C[O:47][B:46](B2OCC(C)(C)CO2)[O:45]C1.C([O-])(=O)C.[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:32]=[C:14]([NH:13][C:11]([O:10][CH2:9][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([B:46]([OH:47])[OH:45])=[CH:3][C:4]=2[CH3:41])[CH3:40])=[O:12])[CH:15]=[C:16]([F:39])[C:17]=1[O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH3:31])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(B(O)O)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a tube was added 28C (373 mg, 0.591 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (160 mg, 0.709 mmol), potassium acetate (145 mg, 1.477 mmol), Pd(dppf)Cl2 (97 mg, 0.118 mmol) in DMSO (1.5 ml). The tube was filled with Ar, sealed and stirred at 85° C. for 2 h. The mixture was quenched with water, extracted with EtOAc (3×20 ml). The combined organic layer was filtered though silica gel and concentrated. The crude product was purified by flash chromatography to give 28D (210 mg, 0.352 mmol, 59.6% yield). MS (ESI) m/z: 597.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].[CH2:31]([NH2:33])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:33][CH2:31][CH3:32])=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8]
Reactant: CCN
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Product: CCNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Yield: 62.5 %

Procedure:
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid and 70% aqueous ethylamine solution as the raw materials, the same operation as the example 212(2) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[C:5]([CH3:13])[N:4]=1>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:13])[C:6]([NH2:10])=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)c([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1nc(C)c(N)c(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 2-methoxy-4,6-dimethyl-5-nitropyrimidine (3.37 g, 18.4 mmol) in tetrahydrofuran (80 mL) was added 10% palladium on carbon (50% wet, 330 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (2.82 g, 18.4 mmol, 100%).