Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[N:10]=[C:9]([C:27]#[N:28])[C:8]=2[N:7]=[CH:6]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.CO>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:27]#[N:28])[C:8]3[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]=3[CH:12]=2)=[CH:15][C:16]=1[C:23]([F:26])([F:25])[F:24])[CH3:22]
Reactant: C1COCCN1
Reactant: CCOc1ccc(-c2cc3c(ncn3CCCBr)c(C#N)n2)cc1C(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cc3c(ncn3CCCN3CCOCC3)c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
1-(3-Bromo-propyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile was dissolved in DMF (0.5 ml) and morpholine (19 mg, 0.22 mmol) was added. The mixture was heated to 120° C. in a Smith Creator microwave. Mixture was diluted with methanol and passed through an SCX cartridge, then eluted with 2M methanolic ammonia. Mixture was then prep HPLC purified and acetonitrile was removed under reduced pressure. Resulting aqueous solution was made basic with sodium bicarbonate, extracted into DCM (5 ml), then organics were dried and evaporated to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(3-morpholin-4-yl-propyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid (8 mg). 1H NMR (CDCl3) δ 8.25 (d, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.11 (d, 1H), 4.42 (t, 2H), 4.21 (q, 2H), 3.71 (m, 4H), 2.37 (m, 4H), 2.26 (t, 2H), 2.08 (m, 2H), 1.49 (t, 3H). MS m/z 460.6 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[NH3:16]>>[NH2:16][C:7]1[CH:6]2[CH2:13][CH2:14][CH2:15][CH:5]2[C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: N
Reactant: Fc1ccc2c(c1)C1CCCC1C(=S)N2
Product: NC1=Nc2ccc(F)cc2C2CCCC12
Yield: 95 %

Procedure:
Analogously to Example 4, 8-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (240 mg, 1.08 mmol) in 7N methanolic ammonia solution (30 ml) is reacted to form 210 mg (95%) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8](#[N:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][C:8]#[N:14])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCCC#Cc1cccnc1
Yield: 79 %

Procedure:
Argon was passed through a solution of 45 ml of 3-bromopyridine and 49.61 g of 5-hexynenitrile in 500 ml of dichloromethane and 150 ml of dry triethylamine for 15 minutes and 3.0 g of bis(triphenylphosphine)palladium dichloride and 0.45 g of cuprous iodide were added. The reaction flask was evacuated and refilled with argon and was heated to reflux for 12 hours. The resulting mixture was diluted with 1 L of dichloromethane and washed with 2×300 ml of water, 1×300 ml brine, dried over potassium carbonate and concentrated. The residue was distilled to afford 62.82 g (79%) of 6-(3-pyridinyl)-5-hexynenitrile as a yellow oil, bp 140°-170° C./0.2 mm., suitable for use in the next step. A portion was purified by chromatography over silica gel eluting with 1:1 ethyl acetate-hexane containing 1% triethylamine and was redistilled to give an analytical sample of 6-(3-pyridinyl)-5-hexynenitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6](C)([C:10]3=[CH2:11])[CH2:5][CH2:4][CH2:3]1.B(F)(F)F.[C:20]1(C)C=CC=CC=1>>[CH3:15][C:2]1([CH3:1])[C:7]23[CH2:8][CH:9]([C:10]([CH3:11])([CH3:20])[C:6]2=[CH:5][CH2:4][CH2:3]1)[CH2:12][CH2:13]3
Reactant: Cc1ccccc1
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Agent: FB(F)F
Product: CC1(C)C2=CCCC(C)(C)C23CCC1C3
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Over a period of 30 minutes 240 g (0.79 mol) of Longifolene (1) (80% ex Indian oil of turpentine [α]D +39.4°) were dropped into a heated solution (60° C.) of 90 g toluene and 10 g (0.07 mol) BF3 -etherate. This was stirred at 100° C. for 3 hours, than cooled down to room temperature and neutralized. After drying above Na2SO4 the solvent was distilled at reduced pressure. A raw product of 198 g (of 70.2% according to GLC) remained.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(OC([N:67]([CH2:76][CH2:77][S:78][S:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:68][CH2:69][C:70](OCC#N)=[O:71])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[C:80]([S:79][S:78][CH2:77][CH2:76][NH:67][CH2:68][CH2:69][C:70]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:71])([CH3:83])([CH3:82])[CH3:81]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CCC(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)SSCCNCCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h, 44.6 mg, 0.314 mmol) and cyanomethyl 3-((tert-butoxycarbonyl) (2-(tert-butyldisulfanyl)ethyl)amino)propanoate (Compound 6g-B, 236 mg, 0.628 mmol) were dissolved in DMF under ice-cooling, followed by addition of triethylamine (0.088 ml, 0.628 mmol). After stirring at room temperature for 1 hour, the reaction solution was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=70:30). TFA (1.5 ml) was added to the resulting residue, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=80:20) to afford the title compound (66.9 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:50][CH2:51][C@@:52]([OH:59])([C:55]([F:58])([F:57])[F:56])[CH2:53][OH:54]>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:50][CH2:51][C@:52]([OH:59])([CH2:53][OH:54])[C:55]([F:58])([F:57])[F:56])=[O:16]
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: NC[C@](O)(CO)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(C(=O)NC[C@](O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.4 %

Procedure:
5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (104 mg) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (0.33 ml) was added followed by the addition of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (196 mg). The reaction was stirred at room temperature, under nitrogen, for 20 minutes. (S)-2-(Aminomethyl)-3,3,3-trifluoro-1,2-propanediol (90 mg) in dry dimethylformamide (2 ml) was added and the reaction was stirred at room temperature for 3 hours. The reaction was partitioned between ethyl acetate (50 ml) and water (50 ml) and the separated aqueous phase was re-extracted with ethyl acetate (50 ml). The combined organics were washed with water, 1M hydrochloric acid, 10% lithium chloride solution (2 times), bicarbonate and brine. The organics were dried using a hydrophobic frit and evaporated to give a pale yellow oil (200 mg). This was dissolved in dichloromethane (ca. 5 ml) and left to stand at room temperature for 4 hours wherein a precipitate formed. The precipitate was filtered and washed with a small amount of dichloromethane to give the title compound as a white solid (93 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8]CCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]1([S:28]CC(Cl)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)CSc1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Yield: 64 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-(phenylthio)acetyl chloride (0.222 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.102 g, 1.19 mmol) and triethylamine (0.240 g, 2.37 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-(phenylthio)acetamide (0.179 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.29 (m, 4H), δ 7.18 (m, 2H), δ 3.60 (s, 2H), 3.34 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 134.8, 129.5, 128.6, 127.1, 50.8, 39.3, 37.7 ppm; HRMS (ESI) calcd for C10H12N4OS (M+) 236.0732. found 236.0729.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: COc1cccc(N)c1C(N)=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: COc1cccc(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1C(N)=O

Procedure:
Using General Protocol II with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 8.8 mmol) and 2-amino-6-(methyloxy)benzamide (3.10 g, 18.7 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-(methyloxy)benzamide was isolated as white solid (1.15 g, 28% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 3.81 (s, 3 H), 6.55 (s, 1 H), 6.94 (d, J=7.87 Hz, 1 H), 7.37-7.49 (m, 4 H), 7.63 (d, J=4.03 Hz, 3 H), 7.94 (d, J=8.24 Hz, 2 H), 10.98 (s, 1 H).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[C:5]2[C:10]([CH3:11])=[N:9][O:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][S:1][C:2]3[N:3]([CH3:13])[C:4](=[O:12])[C:5]4[C:10]([CH3:11])=[N:9][O:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1noc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1noc2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of 6-mercapto-3,5-dimethylisoxazolo-[5,4-d]pyrimidin-4(5H)-one (800 mg) and sodium hydroxide (165 mg) in 50% ethanol (10 ml)-DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.25 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to provide the title compound as colorless solid (470 mg). 1H-NMR (CDCl3) 8: 2.57(3H,s), 3.55(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.6Hz), 7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:29])[CH:12]([NH:13][C:14](=[O:28])[C:15](=[N:24][O:25][CH2:26][CH3:27])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.[ClH:30]>CO>[ClH:30].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:29])[CH:12]([NH:13][C:14](=[O:28])[C:15](=[N:24][O:25][CH2:26][CH3:27])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: CO
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
A solution of 2-methyl-7-[2-ethoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-ethoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (3.0 g) in methanol (40 ml) was cooled in an ice-water bath and thereto was added dropwise a solution of concentrated hydrochloric acid (3.8 g) in methanol (12 ml) with stirring and then stirring was continued at room temperature. After 35 minutes stirring a homogeneous solution was formed and then 2 hours later precipitates appeared and thereafter diethyl ether (300 ml) was added thereto. The precipitates were collected by filtration, washed with diethyl ether and then dried over phosphorus pentoxide under reduced pressure to give powder of 2-methyl-7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), which can be represented as 2-methyl-7-[2-ethoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), (2.6 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])C.O.[NH2:29][NH2:30]>C(O)C>[CH2:20]([N:6]([CH2:5][C:4]([NH:29][NH2:30])=[O:3])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 22 h
Yield: 93.3 %

Procedure:
To a stirred solution of [benzyl-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid ethyl ester (2.52 g) in ethanol (15 mL) was added hydrazine monohydrate (1.60 g). The mixture was stirred for 5 h at r.t. and for 22 h at 50° C. The mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give N-benzyl-N-hydrazinocarbonylmethyl-2-trifluoromethyl-benzenesulfonamide (2.27 g) as a colorless oil. MS: 388.4 ([M+H]+)
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[Li+].[OH-].Cl.Cl[CH2:22][C:23]1[C:24]([NH:36][CH3:37])=[N:25][C:26]2[CH:27]=[C:28]3[O:35][CH2:34][O:33][C:29]3=[CH:30][C:31]=2[CH:32]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:22][C:23]2[C:24]([NH:36][CH3:37])=[N:25][C:26]3[CH:27]=[C:28]4[O:35][CH2:34][O:33][C:29]4=[CH:30][C:31]=3[CH:32]=2)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc4c(cc3nc2NC)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (284 mg, 1.22 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. LiOH solution (1.20 mL, 2.40 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (350 mg, 1.22 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave 1-ethyl-6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (6 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum. Recrystallization from a mixture of MeOH:Et2O afforded 1-ethyl-6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol dihydrochloride 61 as a pale brown solid (104 mg, 16% yield).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[OH-].[K+].[CH2:14](Br)[CH3:15]>CS(C)=O.O>[CH2:14]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:15]
Reactant: CCBr
Reactant: CN(CCO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.5 %

Procedure:
To a solution of the product from step 1 (850 mg, 506 mmol) in DMSO (4 mL) and KOH (1.2 g, 22.0 mmol) was added ethyl bromide (0.85 mL, 11.4 mmol). After stirring 1.5 hours at ambient temperature, the reaction mixture was diluted with water and the product extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a yellow oil (950 mg, 95%). MS (ES+) m/z 180 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
A mixture of 6-methylquinoxaline (2.0 g, 13.9 mmol), N-bromosuccinimide (3.0 g, 16.9 mmol), and benzoyl peroxide (411 mg, 1.7 mmol) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux for 2 days. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (1×100 mL) and brine (1×100 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-30% EtOAc/hexanes), affording 6-(bromomethyl)quinoxaline (1.10 g, 35% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][O:32][C:31]4=[O:38])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.ClC1C=C(C2C=NN3C=CC(N4[C@@H](C(C)C)COC4=O)=NC=23)C=CC=1C1N(COCC[Si](C)(C)C)N=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([CH:35]([CH3:36])[CH3:37])[CH2:33][O:32][C:31]4=[O:38])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)c(Cl)c3)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)c(Cl)c3)c2n1
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(Cl)c3)c2n1
Yield: 25 %

Procedure:
(S)-3-(3-(3-Chloro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.051 g, 25%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (S)-3-(3-(3-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one and (S)-3-(3-(3-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.270 g, 0.487 mmol), to produce a yellow solid. LCMS (APCI+) m/z 424.6 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 14.21 (broad s, 1H), 9.13 (d, J=7.8 Hz, 1H), 8.83 (s, 1H), 8.67 (s, 1H), 8.39 (m, 1H), 8.09 (m, 1H), 7.95-7.82 (m, 2H), 4.96-4.92 (m, 1H), 4.56-4.50 (m, 2H), 2.80-2.76 (m, 1H), 1.07 (d, J=7.1 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:20]1[CH:24]=[CH:23][CH:22]=[N:21]1.CC(C)([O-])C.[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccnc(-c2ccc(-n3cccn3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
212 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and 68 mg of pyrazole were dissolved in 4 ml of DMSO, and 102 mg of potassium tert-butoxide was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=67:33) to obtain 251 mg of methyl 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[N:12][OH:13])[C:3]1([CH3:10])[CH3:9]
Reactant: CC1(C)C(=O)CCCC1O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=NO)CCCC1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.8 %

Procedure:
A mixture of 3-hydroxy-2,2-dimethylcyclohexanone (1.6 g, crude), hydroxylamine hydrochloride (2.98 g, 42.9 mmol) and sodium carbonate (4.54 g, 42.9 mmol) in EtOH (30 mL) and water (3 mL) was stirred at 25° C. for 6 h. After removal of EtOH, the residue was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (1.8 g, crude). MS (ESI) m/z 158.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH:6]([CH3:10])[C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH:6]([O:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[CH:3]=1)[CH3:10])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1cccc(Cl)c1)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CC(Oc1cccc(Cl)c1)C(=O)NCCO[N+](=O)[O-]
Yield: 56.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-(3-chlorophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.58 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).