Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(CC[C@H](C2C=CC=C(OCCCC(=O)NOC(C)(C)C)C=2)O)[CH:6]=CC=C[CH:2]=1.[O:29]=[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[C:44]([OH:46])=[O:45])[C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:36][C:32]([CH3:35])([CH2:33][CH3:34])[C:31](=[O:37])[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[C:44]([O:46][CH2:2][CH2:1][CH3:6])=[O:45])=[O:29]
Reactant: CC(C)(C)ONC(=O)CCCOc1cccc([C@H](O)CCc2ccccc2)c1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)[C@@H]1CCCCN1C(=O)C(=O)C(C)(C)CC
Reaction time: 8 h
Yield: 176.2 %

Procedure:
A solution of alcohol 2 (385 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipercolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-[3-9(3-tert-butyloxycarbamoylpropyl)oxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (524 mg, 84%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.35-6.90 (m, 9H), 5.80 (t, J=5.9 Hz, 1H), 5.32 (d, J=5.0 Hz, 0.82 H, pipercolate a-H of rotamer A), 4.80 (br. s, 1H), 4.02 (t, J=6.1 Hz, 2H), 3.40-3.25 (m, 3H), 3.12 (td, J=13.0, 3.3 Hz, 1H), 2.60 (m, 2H), 2.35 (d, J=14 Hz, 1H), 2.28 (m, 1H), 2.07 (m, 1H), 1.96 (t, J=6.3 Hz, 2H), 1.80-1.60 (m, 5H), 1.43 (s, 9H), 1.22 (s, 3H), 1.20 (s, 3H), 0.88 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 170.1, 167.6, 159.4, 156.4, 141.7, 141.3, 130.1, 128.9, 128.7, 1265, 119.4, 114.7, 113.2, 113.0, 66.1, 57.1, 51.7, 47.1, 44.5, 38.3, 32.9, 32.1, 30.0, 28.8, 26.8, 25.4, 24.9, 24.0, 23.8, 23.5, 21.6, 9.1. MS(FAB): (M+Na)+ 645, (M+H)+ 623.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=O)(C)(C)C.[ClH:45].O>C(OCC)(=O)C>[ClH:45].[ClH:45].[NH2:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@@H](N)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 250 mg of N-[N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-L-leucyl]-L-valyl]-L-phenylalanine, methyl ester (faster isomer) in 3 ml of ethyl acetate was cooled in an ice bath under nitrogen then treated with anhydrous hydrogen chloride gas to saturation. Once the reaction was saturated, the ice bath was removed, the reaction was stoppered, and stirred at ambient temperature. After one hour, the reaction was concentrated to dryness in vacuo, then recrystallized from methanol/ether at room temperature, and refrigerated overnight to afford 155 mg of the title compound as a hydrate with 1.0 mole of water, melting point 220°-223° C., dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH2:16])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([NH2:16])([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@](N)(CSCc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid methyl ester (30.7 g, 127.3 mmol) prepared in Step A was dissolved in DCM. Et3N (26.4 g, 190 mmol) and (BOC)2O (27.7 g, 127.3 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove DCM, and was used in the next reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]1[CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19].[C:22]([C:25]1[CH:80]=[CH:79][C:28]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH2:59][O:60][C:61]3[C:62]([O:77][CH3:78])=[CH:63][C:64]4[C:70](=[O:71])[N:69]5[CH2:72][CH2:73][CH2:74][CH2:75][C@@H:68]5[CH:67]=[N:66][C:65]=4[CH:76]=3)[CH:36]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:38]=2)=[CH:27][CH:26]=1)(=O)[CH3:23]>C(Cl)Cl>[CH3:78][O:77][C:62]1[C:61]([O:60][CH2:59][C:35]2[CH:34]=[C:33]([CH:38]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:36]=2)[O:32][CH2:31][CH2:30][O:29][C:28]2[CH:79]=[CH:80][C:25](/[C:22](=[N:21]/[NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:10]3[C:9](=[O:8])[CH:13]=[CH:12][C:11]3=[O:14])/[CH3:23])=[CH:26][CH:27]=2)=[CH:76][C:65]2[N:66]=[CH:67][C@@H:68]3[CH2:75][CH2:74][CH2:73][CH2:72][N:69]3[C:70](=[O:71])[C:64]=2[CH:63]=1
Reactant: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@@H]3C=N4)cc(OCCOc3ccc(C(C)=O)cc3)c1)N=C[C@H]1CCCCN1C2=O
Reactant: NNC(=O)CCCN1C(=O)C=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@H]3C=N4)cc(OCCOc3ccc(/C(C)=N/NC(=O)CCCN4C(=O)C=CC4=O)cc3)c1)N=C[C@@H]1CCCCN1C2=O
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide trifluoroacetic acid salt (246) (3 mg, 0.0096 mmol), (5Z,5′Z,6aR,6a′R)-3,3′-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one) (243) (7.5 mg, 0.0093 mmol) and 50 mg 4 Å molecular sieves was stirred in 2 ml of dry 5% HAc in DCM (one day earlier dried by 4 Å molecular sieves) for 2 h, neutralized with 0.5 ml of DIPEA, evaporated and purified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min and a gradient solvent system going from 80:20 solvent A:B at time 0-5 min to 50:50 A:B at 15 min then to 30:70 A:B at 25 min until to 10:90 A:B at 30 min. Solvent A—water, solvent B—methanol/dioxane (2:1)) and lyophilized to afford a white solid 5.6 mg (61%) of the title compound. MS m/z+1066.3 (M+2CH3OH+Na).
Reaction SMILES: C([NH:3][C@@:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:5]([OH:7])=[O:6])=O.C(N[C@:18](C1C=CC=CC=1)(C)[C:19](O)=O)=O>>[NH2:3][C@@:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: C[C@](NC=O)(C(=O)O)c1ccccc1
Reactant: C[C@@](NC=O)(C(=O)O)c1ccccc1
Product: CCOC(=O)[C@](C)(N)c1ccccc1

Procedure:
The title compound was prepared (1.12 g, 76%) by the procedure of Example 445C substituting the product of Example 450A for the product of Example 445B.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:25]1[C:24]2[NH:23][C:22](=[O:30])[C:21]3[S:31][CH:32]=[CH:33][C:20]=3[C:19]=2[C:18]([C:16]2[CH:15]=[CH:14][C:3]([CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:2]([F:1])[CH:17]=2)=[C:27]([O:28][CH3:29])[CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 73.1 %

Procedure:
Following General Procedure I, tert-butyl 2-fluoro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (1.1 g, 2.3 mmol) was reacted with NBS (540 mg, 3.1 mmol) to afford the desired product (920 mg, 70%) as a brown solid. ESI MS m/z 547 [C25H24BrFN2O4S+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH3:2].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1>C(O)C>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Reactant: CCNCCc1ccc(NS(C)(=O)=O)cc1
Solvent: CCO
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-Ethyl-4-methanesulphonamidophenethylamine (see Preparation 9(C)--1.7 g, 7.0 mmole) and 2-chloromethyl-6-nitroquinoline (0.78 g, 4.1 mmole) were heated at reflux temperature in ethanol (50 ml) for 4 hours. The solvent was then evaporated and the residue was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried (MgSO4), evaporated and the residue was purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.56 g.
Reaction SMILES: [Li][CH2:2][CH2:3]CC.CC1(C)CCCC(C)(C)N1.N#N.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25].C(=O)C>C1COCC1>[Br:18][C:19]1[C:27]2[CH:2]([CH3:3])[O:25][C:24](=[O:26])[C:23]=2[CH:22]=[N:21][CH:20]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: CC=O
Agent: N#N
Solvent: C1CCOC1
Product: CC1OC(=O)c2cncc(Br)c21
Temperature: -50 °C
Reaction time: 1 h

Procedure:
n-BuLi (1375 μl, 2.200 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (407 μl, 2.400 mmol) in THF (5 mL) at −78° C. under inert gas (N2). The resulting mixture was stirred at ˜−50° C. for 1 hr. 5-bromonicotinic acid (202 mg, 1 mmol) in THF (5 mL) was added at this temperature. The resulting mixture was stirred for 45 min at −50° C. acetaldehyde (56.5 μl, 1.000 mmol) was added and the resulting mixture was stirred for 60 min. The reaction was quenched by NH4Cl (saturated solution) and warmed up to room temperature. After acidified to pH 2 with HCl, the resulting mixture was heated to reflux for 8 hrs. After concentration, acid-base extraction and concentration again, the residue was purified by column (Heptane/ethyl acetate v/v, 10-20%) yielded colorless solid. 1H NMR (400.3 MHz, CDCl3): δ 1.77 (d, J=6.7 Hz, 3H), 5.56 (q, J=6.7 Hz, 1H), 8.91 (s, 1H), 9.08 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (Starting Material 1 supra) (0.3 g, 0.82 mmol) using (Ph3P)2PdCl2 (28.8 mg) and Cul (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85° C. for 18 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 0.23 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:25]3[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Reactant: Fc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Oc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:9][O:10][CH:11]([O:20][CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14](Br)[CH:13]=1>COCCOCCOC>[CH3:9][O:10][CH:11]([O:20][CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1
Reactant: COC(OC)c1ccc(F)c(Br)c1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(OC)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 155 °C
Reaction time: 7 h
Yield: 75.4 %

Procedure:
0.4 g of copper-I bromide and 43.5 g (0.375 mole) of sodium phenolate were added to 95 ml of diethylene glycol dimethyl ether (diglyme). The temperature of the mixture rose to about 80° C. To effect dehydration, 15 ml of diglyme (boiling point 160° C.) were distilled off under normal pressure. 57.3 g (0.23 mole) of 3-bromo-4-fluoro-benzaldehyde dimethyl acetal were then added dropwise in the course of 10 minutes, at 150°-155° C., and the reaction mixture was stirred for a further 7 hours at 155° C. Gas chromatography indicated that all of the precursor had then been converted. Subsequently, the solvent was distilled off at 40° C./10 mm Hg, the residue was dissolved in 300 ml of toluene and, after adding 10 g of "Celite" (Trade Mark) 545 as a filter aid, the mixture was filtered to remove the inorganic material. The filtrate was washed with twice 100 ml of 50% strength sodium hydroxide solution, the solvent was then stripped off in vacuo and the residue was distilled in vacuo. 45.5 g (75. of theory) of 3-phenoxy-4-fluoro-benzaldehyde dimethyl acetal were thus obtained in the form of a colorless oil with a boiling point of 128°-130° C./0.1 mm Hg.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:20])[CH:14]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 1 h

Procedure:
A solution of 88 parts of 3,4,5,6-tetrahydrophthalic anhydride in 2000 parts of glacial acetic acid was treated with 84 parts of 4-chloro-2-fluoroaniline at once and stirred for one hour. After refluxing for 19 hours, 1000 parts of acetic acid were distilled from the reaction mixture. The residue from the distillation was poured over 3000 parts of ice. The resulting crystals were filtered and recrystallized from 700 parts of methanol at -40° after activated carbon treatment, to yield 117 parts off-white crystals of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 76.5-78.0°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O.[CH3:18][C:19]([S:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[N:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Temperature: 80 °C

Procedure:
To a solution of (2-Amino-5-bromo-phenyl)-(4-chloro-phenyl)-methanone (13.87 g, 0.05 mol) in THF (200 mL) is added 2-Methyl-propane-2-sulfinic acid amide (6.5 g, 0.05 mol) and Ti(OEt)4 (20.5 g, 0.09 mol).The stirred mixture is refluxed at 80° C. The mixture is quenched with H2O, filtered. THF is removed, extracted with ethyl acetate, dried over NaSO4 and concentrated then purified by silica gel. This produces the desired compound.
Reaction SMILES: C([Li])CCC.[S:6]1(=[O:12])(=[O:11])[CH:10]=[CH:9][CH2:8][CH2:7]1.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:10]1[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][CH:9]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=S1(=O)C=CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
n-Butyllithium (6.72 mL of a 1.6 M solution in hexanes, 10.7 mmol) was added over 5 min to a solution of 2,3-dihydro-thiophene 1,1-dioxide (1.21 g, 10.2 mmol, prepared as described in J. Organomet. Chem., 665, 167 (2003)) in tetrahydrofuran (60 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then tributyltin chloride (3.04 mL, 11.2 mmol) was added over 5 min. After stirring at −78° C. for 45 min, the mixture was warmed to 25° C. and stirred for an additional 45 min then was concentrated in vacuo. The residue was diluted with chloroform (50 mL) and filtered. The filtrate was partitioned between water (100 mL) and a 1:1 mixture of ethyl acetate and hexanes (1×200 mL). The organic layer was dried over sodium sulfate, filtered and was concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 20-30% ethyl acetate in hexanes) afforded the desired product, tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (1.13 g, 2.77 mmol, 27% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 0.90-0.95 (9H, m), 1.15-1.21 (6H, m), 1.29-1.40 (8H, m), 1.50-1.67 (6H, m), 2.96-3.00 (1H, m), 3.11-3.14 (1H, m), 6.57 (1H, t, J=3.1 Hz).
Reaction SMILES: C(O)=O.[C:4]1([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]=O.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[CH3:26][N:12]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)[CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: c1ccc(CCNC2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
136 ml of formic acid was added to 210 g of 4-(2-phenylethylamino)-1-benzylpiperidine. Since the temperature of the mixture increased to about 90° C., the mixture was ice-cooled. To the reaction mixture was added 64 ml of 37% formalin at 50-60° C.; the ice bath was removed; and the mixture was stirred for 1 hour. To the resulting reaction mixture were added 1 liter of ethanol and 120 ml of concentrated hydrochloric acid, followed by concentration under reduced pressure. To the residue was added 1 liter of ethanol. The resulting insolubles were collected by filtration and then washed with ethanol to obtain 251.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine dihydrochloride as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NC[C:36](N)=[O:37]>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH2:36][OH:37])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(+)-3-amino-1,2-propanediol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.81 (m, 1H), 3.54 (m, 3H), 3.39 (m, 1H), 2.20 (s, 3H). ESHRMS m/z 480.1117 (M+H calculated for C22H21ClF2N3O5 requires 480.1132).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1>CO.[Ru]>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][C@H:11]2[CH2:13][CH3:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: [Ru]
Solvent: CO
Product: CC[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Reaction time: 20 h

Procedure:
A hydrogenation vessel was charged with a solution of tert-butyl ((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)carbamate 87 (prepared as described in WO 03/099274) in MeOH followed by Ru/C (7.5 wt %). The vessel was placed under N2 (20 psig) and vented to atmospheric pressure three times to remove residual oxygen. The vessel was then placed under H2 (50 psig) and the reaction was complete in <5 h based on H2 consumption. After 20 h, the vessel was vented to atmospheric pressure. The reaction slurry was then filtered and evaporated to a yellow oil which was brought to the following step without further purification. MS (ES+) m/z 333 (M+H+).