Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.C(OC(=O)[N:13]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][C:34]2=[O:51])[CH2:27][CH2:26]1)[CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)(C)(C)C.[ClH:53].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:53].[CH2:44]([O:43][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:33]([CH2:32][CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([NH:13][CH2:14][C:15]3[CH:24]=[CH:23][C:18]4[O:19][CH2:20][CH2:21][O:22][C:17]=4[CH:16]=3)[CH2:30][CH2:29]2)[C:34](=[O:51])[CH:35]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccccc2)c2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixed solution of 1 mL ethyl acetate and 3 mL chloroform containing 0.20 g of tert-butyl(1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature for 24 hours, thereafter the resulting solid was filtered to give 0.15 g of 4-benzyloxy-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([N+:37]([O-:39])=[O:38])=[C:14]([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)=[CH:20][CH:19]=2)[CH:15]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.F>C1COCC1.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:14]3[CH:15]=[C:10]([C:9]#[C:8][CH2:7][OH:6])[CH:11]=[CH:12][C:13]=3[N+:37]([O-:39])=[O:38])=[O:36])=[CH:19][CH:20]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(NCc2ccc(C(=O)Nc3cc(C#CCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)ccc3[N+](=O)[O-])cc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: [F-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(NCc2ccc(C(=O)Nc3cc(C#CCO)ccc3[N+](=O)[O-])cc2)cc1OC
Reaction time: 12 h

Procedure:
A solution of compound 74 (871 mg, 1.24 mmol) in THF (3 mL) was treated with 1.0 M solution of tetrabutylammonium fluoride in THF (2.0 mL, 2.0 mmol) followed by 70% hydrogen fluoride in pyridine (0.1 mL), and the solution stirred under nitrogen for 12 h, diluted with ethyl acetate (200 mL) and washed with saturated NaHCO3 (50 mL) and then with water (6×100 mL), dried (Na2SO4), filtered and concentrated in vacuum. The crude material (647 mg) was pure enough for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][N:28]1[CH2:35][CH:34]2[CH:30]([CH2:31][CH2:32][CH2:33]2)[CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:27][N:28]3[CH2:35][CH:34]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NN3CC4CCCC4C3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].NC1C=CC(S)=CC=1.[C:15]([O:19][C:20]([NH:22][CH:23]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:25](=[CH2:41])[CH2:26][C:27]([NH:38][CH:39]=[O:40])(C(OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:15]([O:19][C:20]([NH:22][CH:23]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:25](=[CH2:41])[CH2:26][CH:27]([NH:38][CH:39]=[O:40])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=C(CC(NC(=O)OC(C)(C)C)C(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Agent: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(CC(NC=O)C(=O)OCC)CC(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 85 °C

Procedure:
2.21 g of cesium carbonate and 9.42 g of p-amino-thiophenol were added all at once to a solution of 17.25 g of the product of Step E in 250 ml of dimethylformamide and the mixture was heated at 85° C. for 3 hours and was then returned to room temperature. The solution was filtered and the filtrate was evaporated to dryness under reduced pressure. The oil residue was taken up in 300 ml of chloromethane and the solution was washed with hydrochloric acid and then with a saturated aqueous sodium bicarbonate solution. The oil was purified by HPLC and elution with a 6-4 cyclohexane-ethyl acetate mixture yielded the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:17][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:7][C:8]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cc(C(C)(C)C)c(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2,5-di-tert-butyl-4-methoxyphenol (9 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml). Cesium carbonate (13 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (9 mmol) was added to the solution. The reaction mixture was then stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between dichloromethane (DCM) and aqueous NaHCO3 (0.1 M). The organic portion was separated and dried over Na2SO4 and then the solvent was removed under vacuum. The crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to provide pure 1-methoxy-4-[2-(2-methoxyethoxy)ethoxy]-2,5-di-tert-butyl-benzene in an 87% yield. 1H NMR (300 MHz, CDCl3): δ/ppm 6.83 (s, 1H), 6.82 (s, 1H), 4.14 (t, J=4.5 Hz, 2H), 3.89 (t, J=4.5 Hz, 2H), 3.80 (s, 3H), 3.72 (t, J=4.5 Hz, 2H), 3.58 (t, J=4.5 Hz, 2H), 3.40 (s, 3H), 1.38 (s, 9H)), and 1.35 (s, 9H). The purity was over 99.5% based GC-mass spectroscopy, and the molecular weight was observed at 338.3, which is consistent with the theoretical value, 338.5.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[C:33]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:13])=[CH:2]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)n1cc(/C=C/C(=O)N(NC(=O)c2ccccc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (27 mg, 0.07 mmol, 1.0 equivalent), K2CO3 (32.2 mg, 0.23 mmol, 3.0 equivalent), DMAP (cat, 0.12 equivalent) were introduced and dissolved in DMF, after which acetic anhydride (0.015 ml, 0.15 mmol, 2.0 equivalent) was introduced. After stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=7:3:1) and dried so that solid form of (E)-N-(3-(1-acetyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (2.6 mg, 8.9%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.I[CH2:14][CH2:15][CH3:16].O>CN(C=O)C>[CH2:14]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH2:15][CH3:16]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
Sodium hydride (0.99 g, 50% in oil) was added to dry DMF (5 ml) and the resulting suspension was stirred at room temperature. A solution of 5-hydroxyindole (2.5 g) in dry DMF (15 ml) was added dropwise and a dark purple solution formed. After stirring the mixture for 30 min, 1-iodopropane (3.51 g) was added, and the resulting mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with ether (3x). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness to give a crude residue which was purified by chromatography (SiO2 ; hexane/ether). 5-n-Propyloxyindole was obtained as a yellow oil (2.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10]([CH:26]=[O:27])=[C:4]2[CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2C=O)cc1

Procedure:
5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (1.0 g, 3.86 mmol) was treated with N,N-dimethylformamide (20 mL) and phosphorous oxychloride (0.54 mL, 7.8 mmol) as described in Example 12 to give 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde as a white crystalline solid, (0.9 g, 81%). 1H NMR (CDCl3): δ 10.12 (s, 1H), 8.52 (d, 1H), 8.47 (d, 1H), 7.76 (d, 2H), 7.11-7.06 (m, 3H), 3.93 (s, 3H); MS m/z 287 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:32]([CH3:35])(=[O:34])=[O:33])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].CCN(CC)CC>CN(C=O)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.[Cu]I>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:3]=[CH:4][C:5]=3[S:32]([CH3:35])(=[O:33])=[O:34])[C:21]2=[CH:20][CH:19]=1
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 214e, racemic (2′S,3R,4′S)-2′-[5-bromo-2-methylsulfonyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:1]([CH2:32][CH:29]2[CH2:31][CH2:30]2)[CH2:2][CH2:3][NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](NCCN(CC2CC2)CC2CC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and cyclopropanecarbaldehyde following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 498 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:16]1([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:36]#[N:37])[C:25]([CH3:35])=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3F)[N:23]=2)[CH2:18][CH2:17]1>CS(C)=O>[CH:16]1([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:36]#[N:37])[C:25]([CH3:35])=[C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:27]=3[N:6]3[CH2:7][CH2:8][C@H:4]([NH:3][CH2:1][CH3:2])[CH2:5]3)[N:23]=2)[CH2:18][CH2:17]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CCN[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C4CC4)oc23)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
(3S)-3-(Ethylamino)pyrrolidine (85 μl, 0.684 mmol) and triethylamine (95 μl, 0.684 mmol) were added to a dimethyl sulfoxide (2 ml) solution of 2-cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (100 mg, 0.342 mmol), followed by stirring in an oil bath at 95° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with isopropyl ether to obtain the entitled compound (31.0 mg, 23%) as a white solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)(O)[O-].[Na+].Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[N:7]=1
Reactant: CCOC(=O)CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Yield: 51.9 %

Procedure:
To 10 g of ice water was added 1.84 g of cyanuric chloride dissolved in 50 ml of acetone. To this solution kept at an internal temperature of 0° to 5° C. under stirring were added 1.68 g of sodium bicarbonate and 1.40 g of glycine ethylester hydrochloride and the mixture was stirred at said temperature for 30 minutes. The reaction product was extracted with ethyl acetate and dried with sodium sulfate. Then, ethyl acetate was distilled out and separated crystal was recrystallized from cyclohexane to obtain 1.3 g of 4,6-dichloro-2-ethoxycarbonylmethylamino-S-triazine which had a melting point of 89° to 90.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1nc(-c2ccc(F)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccc(F)cc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 86 %

Procedure:
This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 26 step 6 (180 mg, 86% yield). 1H NMR (CDCl3) δ 8.51 (1H, t), 8.22 (1H, dt), 8.04 (1H, dt), 7.85-7.81 (2H, m), 7.64 (1H, m), 7.59 (1H, t), 7.31 (1H, s), 7.06-7.02 (2H, m), 3.97 (2H, q), 3.35 (2H, t); MS (ESI) m/z: Calculated for C21H14F4N4O2S: 462.08. found: 463.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E1 of 3-(3,4-difluorophenyl)-pyrrolidin-3-ol (0.26 g, 1.3 mmol), acetonitrile (3 mL), potassium carbonate (0.269 g, 1.95 mmol) and iodopropane (0.22 g, 1.3 mmol). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 45:55 to 60:40). Yield: 0.156 g. [α]D=+19.0° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 127-129° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 9), 212, (bp), 182 (32), 141 (17), 84 (58).
Reaction SMILES: O=S(Cl)Cl.[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[CH:8][C:7]=1[CH3:19].[CH3:20]O>>[Cl:5][C:6]1[C:7]([CH3:19])=[CH:8][C:9]([CH2:13][C@@H:14]([OH:18])[C:15]([O:17][CH3:20])=[O:16])=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1cc(C[C@@H](O)C(=O)O)cc(C)c1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](O)Cc1cc(C)c(Cl)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.4 mL (59.9 mmol) SOCl2 were added dropwise to a solution of 12.45 g (54.4 mmol) of (R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid in 300 mL MeOH cooled to 0° C. and the reaction mixture was stirred for 1 h at RT. The reaction solution was evaporated down i. vac. and the residue was purified by chromatography (silica gel, cyc/EtOAc 4:1).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].C[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([OH:20])(=[O:19])=[O:18].[C:21](=O)([O-:23])[O-:22].[K+].[K+]>O>[C:21]([C:10]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=[CH:8][C:9]=1[S:17]([OH:20])(=[O:18])=[O:19])([OH:23])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c([N+](=O)[O-])cccc1S(=O)(=O)O

Procedure:
400.0 g (2.53 mol) of potassium permanganate are added in portions at 80° C. over a period of 2 h to a solution of 106.0 g (0.40 mol) of 2-methyl-5-nitrobenzenesulfonic acid and 80.0 g (0.58 mol) of potassium carbonate in 1300 ml of water. The reaction temperature is maintained at between 80° and 95° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][CH2:20][CH:21]=[CH2:22])=[CH:16][CH:15]=1)#[N:13]>C(Cl)Cl>[O:9]1[CH2:22][CH:21]1[CH2:20][CH2:19][O:18][C:17]1[CH:23]=[CH:24][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCOc1ccc(C#N)cc1
Solvent: ClCCl
Product: N#Cc1ccc(OCCC2CO2)cc1

Procedure:
mCPBA (15.9 g; 65 mmol) was added to a stirred solution of 4-(4′-cyanophenoxy)but-1-ene (7.5 g; 56 mmol; prepared according to the method described in J. Chem. Soc. Perkin Trans. 1, 9 (1992) 1145-1148) in CH2Cl2 (175 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with NaHCO3 (aq.) and the organic layer separated, dried and concentrated to give the sub-title compound (7.23 g; 38 mmol).
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][NH2:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][NH:32][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1>C(C#N)(C)=O>[Cl:4][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: COc1cc(NC(C)=O)cc(OC)c1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(=O)C#N
Product: COc1cc(NC(C)=O)c(Cl)c(OC)c1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Sulfurylchloride (26.9 ml, 325 mmol, 1.93 eq.) is added (in 7 min) to a cold (0° C.) suspension of N-(3,5-dimethoxyphenyl)-acetamide (32.9 g, 169 mmol) in AcCN (500 ml), under an inert atmosphere. The resulting yellowish is allowed to stir 30 min and quenched by dropwise addition of a saturated aqueous solution of sodium bicarbonate (250 ml). The resulting precipitate is collected by vacuum filtration, washed with water (300 ml) and dried to afford 20 g of the desired product (batch 1). The filtrate is diluted with a saturated aqueous solution of sodium bicarbonate (300 ml) and extracted with EE (2×300 ml). The organic phase is washed with water and brine, dried (sodium sulphate), filtered and concentrated. The residue is purified by silica gel column chromatography (EE/Hx, 1:1→2:1) to provide 8.8 g of product (batch 2). Batch 1 and 2 are combined and stirred in hexane. The solid is collected by filtration, washed with hexane and dried to afford 25.8 g of the title compound as a white solid. ESI-MS: 264.0/266.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: Nc1cncnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cc(Br)cc(Nc2cncnc2)c1
Temperature: 100 °C
Yield: 55.3 %

Procedure:
1-chloro-3,5-dibromobenzene (0.30 g, 1.1 mmol, 1.0 eq), 5-aminopyrimidine (106 mg, 1.11 mmol, 1.00 eq), Cs2CO3 (506 mg, 1.55 mmol, 1.40 eq), Pd2(dba)3 (51 mg, 0.089 mmol, 0.080 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77 mg, 0.13 mmol, 0.12 eq) and toluene (3.7 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 173 mg (55%) of the title compound as a light-orange solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.77 (s, 1H), 8.62 (s, 2H), 7.18 (t, J=1.8 Hz, 1H), 7.15 (t, J=1.7 Hz, 1H), 7.09 (t, J=1.9 Hz, 1H); ES-MS [M+1]+: 284.0.