Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:7][C:6]=2[CH:14]=1.O1CCCC1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].N>O.C(OC)(C)(C)C>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:14][C:6]=2[CH:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cc2cc(N)ccc2o1
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Yield: 100 %

Procedure:
100 g of 5-amino-2-butylbenzofuran, 192 ml of tetrahydrofuran and 96 ml of methyl tert-butyl ether are introduced into a round-bottomed flask. 59.35 g of methanesulfonyl chloride are added, at 20° C., followed by 43.23 g of 20% aqueous ammonia. 44.51 g of methanesulfonyl chloride are then introduced, followed by 86.47 g of 20% aqueous ammonia. 48 ml of water are then added, the medium is separated by settling and the organic phase is washed twice with 211 g of 10% aqueous sodium chloride solution. The medium is separated by settling and concentrated at 400° C. under vacuum, to give the desired compound in crude form (weight yield: 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:13][CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[CH3:12])=[CH:2]1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1)=O>C1(C)C=CC=CC=1>[F:18][C:15]([CH3:17])([CH3:16])[CH2:14][N:13]1[C@H:11]([CH3:12])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C@H:19]1[C:21]1[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:26]=1
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (obtained as described in Example 1, preparation of starting materials) (450 mg, 1.81 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (345 mg, 1.81 mmol) were dissolved in toluene (15 ml) acetic acid (5 ml) and molecular sieves were added. The reaction was stirred at 110° C. for 16 hours under nitrogen then cooled to room temperature. The crude product was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (317 mg, 41.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3, 30° C.) δ 1.09 (3H, d), 1.30 (3H, d), 1.47 (3H, d), 2.48-2.78 (4H, m), 3.30 (1H, m), 3.79 (3H, s) 5.09 (1H, s) 6.40 (1H, d), 7.12 (1H, td), 7.17 (1H, td), 7.29 (1H, d), 7.34 (2H, d), 7.43 (2H, d), 7.54 (1H, d), 7.66 (2H, nm). m/z: ES+ [M+H]+ 421.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH2:30][OH:31])[C:23](=[N:25]O)[NH2:24].CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[F:19][C:20]1[CH:21]=[C:22]([C:23]2[N:25]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:15])([F:14])[F:13])[O:17][N:24]=2)[CH:27]=[CH:28][C:29]=1[CH2:30][OH:31]
Reactant: NC(=NO)c1ccc(CO)c(F)c1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: OCc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1F
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A heterogeneous mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (1-E, 0.973 g, 3.75 mmol), 3-fluoro-N′-hydroxy-4-(hydroxymethyl)benzimidamide (0.691 g, 3.75 mmol), and Hunig's Base (0.852 mL, 4.88 mmol) in acetonitrile (7 mL) was stirred at room temperature over the weekend. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The dichloromethane was removed under reduced pressure to give an orange oily residue which was purified by flash silica gel chromatography using a 20% mixture of ethyl acetate in hexane to give (2-fluoro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (0.762 g, 1.88 mmol, 50% yield) as a pale yellow solid. The compound had an HPLC ret. time=3.33 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=406.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][O-].[K+].S(=O)(=O)(O)O.C(O)C>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (3.0 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (5.4 g), sulfuric acid (0.80 mL) and ethanol (60 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, and washed with water. The aqueous layer was neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent of IPE and hexane, and the obtained solid was collected by filtration to give the title compound (2.6 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][CH:17]([O:27][CH3:28])[C:18]1[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=1)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:23]([C:22]1[CH:25]=[C:18]([CH:17]([O:16][CH3:15])[O:27][CH3:28])[CH:19]=[CH:20][C:21]=1[F:26])[OH:24]
Reactant: COC(OC)c1ccc(F)c(C=O)c1
Reactant: c1ccc2scnc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(F)c(C(O)c2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
A total of 1.08 g of benzothiazole was dissolved in 15 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 6.4 ml of 1.56 M solution of n-butyllithium in hexane was added. After stirring for 5 minutes, 8 ml of a solution of 1.35 g of 5-(dimethoxymethyl)-2-fluorobenzaldehyde in dry tetrahydrofuran was added, followed by stirring for 10 minutes. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 1.8 g of the title compound as a yellow oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:24][CH:25]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4cccnc4)ccc3n2C)cc1
Yield: 35 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 35% of theory, C36H45N7O5 (655.8) Rf value: 0.28 (silica gel; dichloromethane/ethanol=19:1) ##EQU87##
Reaction SMILES: Cl[C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9].C(Cl)C[Cl:13]>[Zn].C(O)(=O)C>[Cl:13][C:8]([CH2:7][CH:6]([OH:10])[CH:3]=[CH:2][CH3:4])=[CH2:9]
Reactant: C/C=C/C=O
Reactant: C=C(Cl)CCl
Reactant: ClCCCl
Agent: [Zn]
Solvent: CC(=O)O
Product: C=C(Cl)CC(O)C=CC

Procedure:
47.50 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 20.00 g of crotonaldehyde, 40 g of ethylene dichloride, 60 g of 3% acetic acid and 18.65 g of zinc powder at 40° C., and the resultant mixture was allowed to react at the same temperature for 5 hours. After the reaction was completed, zinc-derived insolubles were filtered off and, the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over magnesium sulfate. The desiccant was filtered off, and the ethylene dichloride was distilled off under reduced pressure to give 37.15 g of 2-chloro-1,5-heptadien-4-ol; nD25 =1.471, FI-MS m/e 146(M+), 148(M+2+).
Reaction SMILES: [CH3:1][C:2]12[CH:10]([CH:11]([CH3:19])[CH:12]=[CH:13][CH:14]([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8][CH:7]1[CH:6]([OH:20])[CH2:5][CH2:4][CH2:3]2.N1C=CN=C1.Cl[Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29]>CN(C)C=O>[CH3:1][C:2]12[CH:10]([CH:11]([CH3:19])[CH:12]=[CH:13][CH:14]([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH2:9][CH2:8][CH:7]1[CH:6]([O:20][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:5][CH2:4][CH2:3]2
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)C(C)C=CC(C)C1CCC2C(O)CCCC12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC1CCCC2(C)C(C(C)C=CC(C)C(C)C)CCC12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.95 g of [1R-[1α[1R*,4S*-(E)],3aβ,4α,7aα]]-octahydro-7a-methyl-1-(1,4,5-trimethyl-2-hexenyl)-1H-inden-4-ol 1 is introduced into 220 ml of dimethylformamide [H. H. Inhoffen et al. Chem. Ber. 91, 781 (1958)], 5.33 g of imidazole and 10.78 ml of chlorotriethylsilane are added, and it is stirred for 24 hours at room temperature. It is quenched with sodium chloride solution, extracted with ethyl acetate, the organic phase is washed with sodium chloride solution and dried on sodium sulfate. After the solvent is removed, the residue is purified by chromatography on silica gel with ethyl acetate/hexane, whereby 14.6 g of title compound 2 is obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:8]([CH2:22][C:23]#[N:24])[C:7]=2[CH:25]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]([CH2:22][CH2:23][NH:24][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[C:7]=2[CH:25]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)N(CC#N)C(c1cccc(C(F)(F)F)c1)CO2
Product: COc1ccc2c(c1)N(CCNC(=O)C1CC1)C(c1cccc(C(F)(F)F)c1)CO2

Procedure:
The procedure is as in Example 15, starting from the compound obtained in Step A and with the replacement of benzoyl chloride with cyclopropylcarbonyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:27])[CH3:26]>>[N:27]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:9][CH2:10][CH2:5][CH2:6][CH2:26][CH2:25]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(OCCN2CCCCCC2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, hexamethyleneimine and acetonitrile essentially as described above in example 40. Purity by LC/MS (APCI)=99%, [M+H]+=343.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)C(OC)=O)[CH:6]=1.BrCC1C=C(C=CC=1)C(OC)=O.BrC(C1C=CC=CC=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:10][CH:9]=2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:6]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Agent: COC(=O)c1cccc(CBr)c1
Product: CCOC(=O)C(c1ccccc1)n1cc(Br)cn1

Procedure:
The title compound was prepared using a procedure analogous to methyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoate except that methyl 3-(bromomethyl)benzoate was replaced with ethyl 2-bromo-2-phenylacetate. LCMS, [M+H]+=308.9. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.45-7.36 (m, 6H), 6.14 (s, 1H), 4.34-4.23 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>CCOCC>[CH2:14]([N:16]([CH2:17][CH3:18])[C:11]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8])=[O:12])[CH3:15]
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)C(=O)c1sc(Cl)nc1C(F)(F)F
Yield: 89.4 %

Procedure:
To a well-stirred solution of 4.0 g (0.0160 mole) of the acid chloride of Example 16 in 20 ml. of ether was added dropwise 2.34 g (0.032 mole) of diethylamine in 5 ml. of ether. The insoluble salt was filtered. The ether solution was washed with water, dried and concentrated under reduced pressure. The residue was crystallized from hexane at low temperature to give 4.1 g of the desired product, m.p. 40°-41° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:19])=[O:8]
Reactant: Nc1ccccc1N
Reactant: N#Cc1cccc(C(=O)O)c1
Product: NCc1cccc(C(=O)Nc2ccccc2N)c1
Yield: 29 %

Procedure:
The title compound (140 mg, 58% yield) was prepared as a grey solid from 3-cyano-benzoic acid (294 mg, 2 mmol) and o-phenylenediamine (432 mg, 4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 242 (M+1).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[Cl-:19].[NH4+:20]>CO>[ClH:19].[C:13]1([CH:12]=[CH:11][CH2:10][CH:8]2[NH:9][C:3](=[NH:20])[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC1=NC(CC=Cc2ccccc2)CCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: Cl
Product: N=C1CCCCC(CC=Cc2ccccc2)N1
Yield: 47.5 %

Procedure:
The product of Example 33 (0.50 g, 2.05 mmol) in 18 mL of MeOH was reacted with ammonium chloride (144 mg, 2.7 mmol) by the method of Example 5 to yield 258 mg (30%) of the title material.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 140 °C
Yield: 85.2 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1.64 g, 0.01 mol), p-toluidine (1.07 g, 0.01 mol) in dioxane (2 mL) was heated in a sealed tube for 30 minutes at 140° C. The crude product was treated with NaOH (50 ml, 2M) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (2 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@H:11]([CH2:13][OH:14])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]2[N:17]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C@@H:11]([CH2:13][OH:14])[N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]3[N:17]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: OC[C@@H]1CC[C@H](c2cncc(F)c2)N1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Temperature: 90 °C
Yield: 14 %

Procedure:
A mixture of ((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol (0.910 g, 4.64 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 1.05 g, 4.64 mmol) and DIEA (1.10 mL, 6.00 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by reverse phase column chromatography (0-50% acetonitrile/water) followed by normal phase column chromatography (2-5% MeOH/DCM) to afford ethyl 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.250 g, 14% yield) as a viscous, clear oil. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[CH3:41][O:42][CH2:43][C:44](=[O:46])[CH3:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[C:15]([C:44]([OH:46])([CH3:45])[CH2:43][O:42][CH3:41])=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COCC(C)=O
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC(C)(O)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, Step 2) (350 mg, 0.95 mmol) was dissolved in THF (10 mL) and cooled to −78° C. 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (2.0 mL, 2.0 mmol) was added slowly to the solution at −78° C. The reaction was stirred at −78° C. for 2 hours. Then methoxyacetone (168 mg, 2.0 mmol) was added into the reaction mixture at −78° C. The reaction was allowed to warm to room temperature and stirred for 8 hours under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl solution (5 mL) at −78° C. and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (0 to 100% EtOAc/hexanes) to afford 4-(5-chloropyridin-3-yl)-2-(2-hydroxy-1-methoxypropan-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS APCI calcd. for C24H28ClN5O2 [M+H]+ 454. found 454.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([F:26])=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[CH3:29][NH:30][CH2:31][C:32]#[CH:33]>CN(C=O)C>[F:26][C:17]1[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:30]([CH3:29])[CH2:31][C:32]#[CH:33])=[C:6]([O:27][CH3:28])[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:25])[NH:21]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCBr
Reactant: C#CCNC
Solvent: CN(C)C=O
Product: C#CCN(C)CCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (250 mg, 0.56 mmol), (prepared as described for the starting material in Example 17), in DMF (2.5 ml) was treated with N-methylpropargylamine (116 mg, 1.68 mmol) and stirred at ambient temperature overnight. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8). The relevant fractions were combined and evaporated under vacuum to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{2-[N-methyl-N-(2-propynyl)amino]ethoxy}quinazoline as a white solid. (165 mg, 68%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:32](=[O:33])[N:5]2[C:6]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:17])=[C:7]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:8][S:9][C@H:4]12.[C:34]([NH:53][C:54]1[S:55][CH:56]=[C:57](/[C:59](=[N:63]/[O:64][C:65]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)/[C:60](O)=[O:61])[N:58]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([NH:53][C:54]1[S:55][CH:56]=[C:57](/[C:59](=[N:63]/[O:64][C:65]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)/[C:60]([NH:2][CH:3]2[C:32](=[O:33])[N:5]3[C:6]([C:16]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[S:17])=[C:7]([CH:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)[CH2:8][S:9][C@H:4]23)=[O:61])[N:58]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C3CCOCC3)CS[C@H]12
Agent: Cl
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C3CCOCC3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 77.4 %

Procedure:
Diphenylmethyl 7-amino-3-(tetrahydropyran-4-yl)thio-3-cephem-4-carboxylate hydrochloride (290 mg) was reacted with (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (403 mg), followed by purifying the reaction product in accordance with the procedure of Example 1(d), affording the titled compound (500 mg; 88%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([F:17])=[C:6]([C:12]([F:16])=[CH:13][C:14]=1F)[C:7]([O:9]CC)=[O:8])([O-])=O.FC1C=C(F)C=C(F)[C:20]=1[C:21]([O:23]CC)=O.[N+]([O-])(O)=O.O.O[S:38](O)(=O)=O>>[F:17][C:5]1[C:4]2[NH:1][C:21](=[O:23])[CH2:20][S:38][C:14]=2[CH:13]=[C:12]([F:16])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(F)cc(F)c([N+](=O)[O-])c1F
Reactant: CCOC(=O)c1c(F)cc(F)cc1F
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C1CSc2cc(F)c(C(=O)O)c(F)c2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Ethyl 3-nitro-2,4,6-trifluorobenzoate. To a suspension of ethyl 2,4,6-trifluorobenzoate (3.93 g, 19.2 mmol) in conc. H2SO4 at 0° C. was added conc. HNO3 (70% HNO3) dropwise via pipet. After the addition was complete, the reaction was allowed to warm to RT and stir for 4 h. The biphasic mixture was poured into H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4) and concentrated to provide 4.71 g (98%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): 6.96 (ddd, J=9.2, 9.2, 2.2, 1H), 4.45 (q, J=7.2, 2H), 1.40 (t, J=7.2, 3H).