Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(C[CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)CC1>>[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.O.NN.C(Cl)(Cl)Cl>CO>[NH2:21][C:20]1[C:2]([CH3:1])=[C:3]([C:17]([CH3:24])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(C)ccc([N+](=O)[O-])c3C)c2n1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cccc(OCc3c(C)ccc(N)c3C)c2n1
Yield: 78.7 %

Procedure:
To a suspension of 8-(2,6-dimethyl-3-nitrobenzyloxy)-2-methylquinoline (2.34 g), ferric chloride (70.6 mg) and carbon (70.6 mg) in methanol (35 ml) was added hydrazine monohydrate (1.09 g) at 65° C., and the mixture was refluxed for 2 hours. Methanol (20 ml) was added thereto, and the mixture was refluxed for 1 hour. After cooling chloroform was added thereto, and the resulting precipitates were filtered off. The filtrate was concentrated and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was crystallized with ethyl acetate to give 8-(3-Amino-2,6-dimethylbenzyloxy)-2-methylquinoline (1.67 g) as a pale crystal.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:18].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:17](=[O:18])[N:3]([CH2:4][CH2:5][C@H:6]2[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]2)[CH3:2])=[CH:21][CH:22]=1
Reactant: CNCC[C@H]1CC[C@H](/C=C/CO)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CN(CC[C@H]1CC[C@H](/C=C/CO)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 150 mg (0.642 mmol) trans-3-[4-(2-methylamino-ethyl)-cyclohexyl]-(E)-prop-2-en-1-ol HCl-salt and 125 mg (0.654 mmol) 4-chlorophenyl chloroformate in 1.5 ml of dichloromethane was added at room temperature 0.55 ml (3.21 mmol) diisopropyl ethyl amine. The reaction mixture was stirred for 1 hour at room temperature, taken up in ether and washed with 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent giving 146 mg (64.7%) trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 369 (MNH4+, 1Cl).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:17]1([CH3:28])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[N:25]=[C:26]=[S:27]>CO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:13][C:26]([NH:25][C:18]2[C:17]([CH3:28])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=2[CH3:24])=[S:27])[CH:14]=[CH:15][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Solvent: CO
Product: Cc1cc(C)c(NC(=S)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)c(C)c1

Procedure:
To 0.45 g (1.9 mmol) of 3-(tert-butyldimethylsilyloxymethyl)aniline in 3 mL of methanol was added 0.67 g (3.8 mmol) of mesitylisothiocyanate. The mixture was heated at reflux for 18 h. The mixture was concentrated and purified by flash chromatography eluting with a 16% ethyl acetate/hexanes mixture to give 0.56 (71%) of the title compound as a sticky white solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>ClCCl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]
Reactant: C1=COCCC1
Reactant: N#Cc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(COC2CCCCO2)c1
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Add p-toluene sulphonic acid (2.11 g, 12.2 mmol) to a solution of 3-hydroxymethyl-benzonitrile (16.30 g, 122.4 mmol) and 3,4-dihydro-2H-pyran (51.5 g, 612 mmol) in dichloromethane (500 ml) and stir. After 90 minutes, pour reaction into saturated sodium bicarbonate, remove organics, dry with sodium sulfate, filter and concentrate to give a dark brown oil. Purify the residue by flash chromatography eluting with a gradient of 10-15% ethyl acetate:hexanes to yield the title product as a clear oil (16.20 g, 61%): 1H NMR (CDCl3) δ 1.53-1.91 (m, 6H), 3.56 (m, 1H), 3.88 (m, 1H), 4.53 (d, 1H), 4.72 (t, 1H), 4.81 (d, 1H), 7.45 (t, 1H), 7.58 (m, 2H), 7.69 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH:6]=[CH:7][CH2:8]OC(=O)C.[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])CC=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: C=CCC(NC(C)=O)C(=O)OC
Reactant: COC(=O)[C@H](CC=CCOC(C)=O)NC(=O)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C(CC=CCC(NC(=O)c1ccccc1)C(=O)OC)NC(C)=O

Procedure:
2-Acetylamino-7-benzoylamino-oct-4-enedioic acid dimethyl ester 143 was synthesised using standard solution-phase metathesis conditions (refer to Section 7.5.2): 6-Acetoxy-2-benzoylamino-4-hexenoic acid methyl ester 142 (50 mg, 0.16 mmol), dichloromethane (10 mL), second generation Grubbs' catalyst (5 mol %, 7 mg, 8 μmol), methyl-2-acetylamino-4-pentenoate 21a (168 mg, 0.98 mmol), 50° C., 18 h. The desired compound was obtained as a brown oil and purified via column chromatography (SiO2; EtOAc:hexane; 2:1). 1H NMR (500 MHz, CDCl3, mixture of isomers (1:1.2)): δ 1.95, s (major isomer) and 1.97, s (minor isomer), 3H, CH3; 2.42-2.70, m, 4H, H3, 6; 3.62, s (minor isomer), 3.64, s (major isomer), 3.78, s (minor isomer) and 3.79, s (major isomer), 6H, 2×OCH3; 4.63-4.66, m, 1H, H2; 4.85-4.91, m, 1H, H7; 5.35-5.49, m, 2H, H4, 5; 6.20, d, J 7.7 Hz (major isomer) and 6.34, d, J 7.5 Hz, 1H, NH (minor isomer); 6.87, t, J 7.55 Hz, 1H, NH; 7.44, t, J 7.1 Hz, 2H, H4′, 6′; 7.50, t, J 6.9 Hz, 1H, H5′; 7.84, t, J 7.9 Hz, 2H, H3′, 7′. 13C NMR (75 MHz, CDCl3, mixture of isomers (1:1.2)): δ 22.83, CH3; 34.84, 35.05, 35.38 and 35.73, C3, 6; 51.51 and 51.55, C2; 52.35, 52.46, 52.53, 52.60 and 52.66, C7, 2×OCH3; 127.18 and 127.22, C3′, 7′; 128.57 and 128.62, C4′, 6′; 128.88 and 129.00, C4, 5; 131.86 and 131.91, C5′; 133.71, C2′; 167.06, COPh; 170.03 and 170.11, COMe; 172.20, 172.21, 172.24 and 172.43, 2×COOMe. Mass Spectrum (ESI+, CH3OH): m/z 399.2 (M+Na+) C19H24N2O6Na.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:18][CH2:19][CH:14]([C:13]([O:12][CH3:11])=[O:20])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCNCC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(Cc2ccc(OC)cc2)CC1
Reaction time: 72 h

Procedure:
4-Methoxybenzyl chloride (1.10 g, 6.98 mmol) was added dropwise to a solution of isonipecotic acid methyl ester (1.00 g, 6.98 mmol) and triethylamine (1.40 g, 14 mmol) in THF (30 ml), and stirring was carried out for 72 h at 60° C. 5% sodium hydrogen carbonate solution (50 ml) was then added to the reaction mixture, and extraction with ethyl acetate (3×50 ml) was carried out. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (2:1).
Reaction SMILES: [C-]#N.[K+].[CH2:4]([O:11][C:12]1[CH:30]=[CH:29][C:28]2=[CH:31][C:13]=1[CH2:14][C@H:15]([NH:55][C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C:16](=[O:54])[NH:17][C@@H:18]([CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:19](=[O:39])[N:20]([CH3:38])[C@H:21]([C:34](OC)=[O:35])[CH2:22][C:23]1[CH:32]=[C:27]2[CH:26]=[CH:25][C:24]=1[F:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[NH2:67][CH2:68][CH2:69][NH2:70]>>[NH2:67][CH2:68][CH2:69][NH:70][C:34]([C@H:21]1[N:20]([CH3:38])[C:19](=[O:39])[C@H:18]([CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:45])[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:17][C:16](=[O:54])[C@@H:15]([NH:55][C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])[CH2:14][C:13]2[CH:31]=[C:28]([CH:29]=[CH:30][C:12]=2[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:27]2=[CH:32][C:23](=[C:24]([F:33])[CH:25]=[CH:26]2)[CH2:22]1)=[O:35]
Reactant: NCCN
Reactant: COC(=O)[C@@H]1Cc2cc(ccc2F)-c2ccc(OCc3ccccc3)c(c2)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N1C
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CN1C(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(F)c(c2)C[C@H]1C(=O)NCCN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.46 mg (0.007 mmol) of potassium cyanide are added to a solution of 30 mg (0.036 mmol) of methyl (8S,11S,14S)-17-(benzyloxy)-14-{[(benzyloxy)carbonyl]amino}-11-(3-{[(benzyloxy)-carbonyl]amino}propyl)-5-fluoro-9-methyl-10,13-dioxo -9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaene-8-carboxylate (Example 23O) in 0.6 ml of 1,2-diaminoethane. The mixture is stirred at RT for 16 h. Water is added to the mixture. The precipitated solid is filtered off and dried under high vacuum.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C1[C:19]2[C:11]1=[C:12]([CH:16]=[C:17]([OH:21])[C:18]=2O)[C:13]([Cl:15])=[O:14].Cl.C[C:24](C)=[O:25]>C(Cl)(Cl)Cl.O>[ClH:15].[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:13](=[O:14])[C:12]1[CH:11]=[CH:19][CH:18]=[C:17]2[O:21][CH2:24][O:25][C:16]=12)[CH3:2]
Reactant: O=C(Cl)c1cc(O)c(O)c2c1C2
Reactant: CC(C)=O
Reactant: CCN1CCCC1CN
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1cccc2c1OCO2
Yield: 49.7 %

Procedure:
134 g of 1-ethyl-2-aminomethyl-pyrrolidine, 950 cm3 of chloroform and, gradually, 183 g of 2,3-methylenedioxyl benzoyl chloride, with the temperature being maintained at from 5°-10° C., were introduced into a balloon flask provided with an agitator and a thermometer. After the addition of 1 liter of water, chloroform was distilled and then the remaining solution was filtered. After the addition of 120 cm3 of 20% ammonia and extraction with ether, the ethereal solution was dried on potassium carbonate and then the ether was distilled. The base produced was dissolved in 30 cm3 of acetone and then a solution of 34 g of hydrochloric acid in 330 cm3 of acetone was added. The hydrochloride precipitate was dried, washed with acetone and then dried. After recrystallization from isopropyl alcohol, 154 g of N-(1-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxybenzamide hydrochloride was produced (M.P.: 127.5°-128.5° C.; yield: 49.7%).
Reaction SMILES: C([NH:8][C:9]1[C:14]([F:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[F:20])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[F:15][C:14]1[C:13]([O:16][CH3:17])=[CH:12][C:11]([O:18][CH3:19])=[C:10]([F:20])[C:9]=1[NH2:8]
Reactant: COc1cc(OC)c(F)c(NCc2ccccc2)c1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(N)c1F
Temperature: -10 °C
Yield: 94.9 %

Procedure:
N-Benzyl-2,6-difluoro-3,5-dimethoxyaniline (6.0 g, 21.5 mmol) was dissolved in THF (40 mL) and the solution hydrogenated over 20% palladium hydroxide on carbon catalyst (0.6 g) at 20° C.–25° C. 48–50 psi hydrogen pressure for 16 hours. The mixture was filtered, the catalyst washed with THF (2×15 mL) and the combined filtrates concentrated to a solid. This was recrystallized from heptane (10 mL) and toluene (4.5 mL). The mixture was cooled to −10° C. before filtering. The crystals were washed with heptane (2×10 ML) and vacuum dried at 35° C. to give 2,6-difluoro-3,5-dimethoxyaniline as off-white needles (3.85 g, 20.4 mmol). mp: 78° C.–79° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reaction time: 2 h

Procedure:
A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (20.0 g) in DMF (50 ml) was slowly added to a solution of sodium hydride (3.4 g) in DMF (190 ml) under ice cooling. Thereafter, 2-(trimethylsilyl)ethoxymethyl chloride (13.3 ml) was added thereto, and stirred at the same temperature for 2 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (1.3 ml) was additionally added to the reaction mixture, and stirred at room temperature for 1 hour. The reaction mixture was poured into water (600 ml), and stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration and washed with water and diisopropyl ether, followed by dissolution with ethyl acetate again. Insoluble matter was then filtered off by filtration. The solvent of the filtrate was distilled off under reduced pressure. Heptane was added to the resulting residue to collect the precipitate by filtration. The precipitate was washed with heptane, and dried under reduced pressure to obtain the title compound (21.2 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:27][C:28]([Cl:33])([Cl:32])[C:29](Cl)=[O:30].O>C(Cl)(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:2]=1[NH:1][C:29](=[O:30])[C:28]([Cl:33])([Cl:32])[Cl:27])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of 762 mg of 2-amino-5-trifluoromethylbenzophenone in 10 ml of chloroform was added dropwise 349 mg of triethylamine, and then 627 mg of trichloroacetyl chloride was added dropwise under ice-cooling. After stirring at the same temperature for 30 minutes, 50 ml of water was added, thereby separating the solution. The organic layer was collected and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 1.08 g of 2′-benzoyl-2,2,2-trichloro-4′-trifluoromethylacetanilide. 1H NMR (CDCl3): 7.53-7.58 (2H, m), 7.66-7.75 (3H, m), 7.90-7.95 (2H, m), 8.81 (1H, d, J=8.6 Hz), 12.38 (1H, br. s).
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]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NCCO)ncn2)cc1
Temperature: 200 °C

Procedure:
250 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 62 mg of ethanolamine and 296 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated. The evaporation residue was subjected to crystallization from an n-BuOH/EtOH solvent mixture.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([C:17]([OH:19])=O)[CH2:6]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C(Cl)Cl>[C:13]([O:12][C:10]([N:8]1[CH2:9][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C@@H:7]1[C:17](=[O:19])[NH:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)O[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1C[C@H](C(=O)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
The crude product (2R,4R)-4-acetoxy-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid from Step A (5.9 g, 21.6 mmol) was dissolved in methylene chloride (22 ml) and treated with EDC (4.5 g, 23.8 mmol) and HOBt (3.2 g, 23.8 mmmol). The mixture was stirred at r.t. for an hour before the addition of 4-chlorobenzylamine (2.9 ml, 23.8 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with DCM (25 ml) and washed with NaHCO3 (sat'd) and brine, dried (Na2SO4), filtered, evaporated and the residue purified by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100% EtOAc) to afford the desired product as a white amorphous solid (6.5 g, 76% over two steps).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[CH:12][C:7]=2[CH:6]=1.N[C@@H]1CC[O:34]C[C@H]1O.C(OCC)(=O)C>CN1CCCC1=O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH:15]3[OH:34])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: CCn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3)nc21
Reactant: N[C@@H]1CCOC[C@H]1O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3O)nc21
Yield: 21.9 %

Procedure:
A mixture of the sulfone (see example 95 for preparation) (0.50 g, 1.31 mmol) and trans-4-amino-3-hydroxy-tetrahydropyran (0.23 g, 1.97 mmol) (see following ref for preparation: (a) Marquis, Robert W et al J. Med. Chem. (2001), 44(5), 725-736. (b) Gribble, Andrew D et al PCT Int. Appl. (1998), 74 pp. (c) Mochalin, V. B et al Zh. Org. Khim. (1971), 7(4), 825-8). in 2 mL of 1-methyl-2-pyrrolidinone was heated at 100° C. for 12 h. The reaction mixture was cooled, ethyl acetate (15 mL) was added and the organic solution was washed with water (3×, 15 mL), brine and then dried (MgSO4). Evaporation of the solvent under reduced pressure and column chromatography (CH2Cl2/methanol—97/3) afforded 120 mg of product (mpt. 174.9-176.3° C., MS (M+H)=419)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH:13]1[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][CH:14]=1.O>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:19][CH2:18][C:16]2[O:15][CH:14]=[CH:13][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccco1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)NCc2ccco2)cc1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
4-Cyanobenzenesulfonyl chloride (1.77 g, 8.78 mmol) was dissolved in 8 mL of anhydrous pyridine and 2-furfurylamine (1.04 g, 9.66 mmol, 0.98 mL) was added. After 2 h, the reaction solutions were added to 100 mL cold water and stirred for 10 min. Filtration and washing with water provided the title compound as a yellow solid (2.04 g, 7.78 mmol, 89%). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.18 (s, 1H), 6.19 (m, 1H), 6.10 (m, 1H), 4.95 (m, 1H), 4.28 (d, J=6.0 Hz, 2H) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13](=O)[CH3:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:17][O:18][NH2:19]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: CON
Reactant: CC(=O)c1ccccc1N1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=C(C)c1ccccc1N1CCOCC1
Yield: 93.4 %

Procedure:
A mixture of Example 49A (1.22 g, 5.94 mmol) and methoxyamine hydrochloride (550 mg, 6.59 mmol) in pyridine (20 mL) was stirred at room temperature for 12 h. The reaction was diluted with ethyl acetate and washed sequentially with 3 N HCl, 1 N HCl and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give 1.3 g of the title compound. MS (ESI+) m/z 235 (M+H)+.