Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:33]N)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.N(OCCC(C)C)=O.N1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56]([NH2:58])=[O:57].C(N(CC)CC)C>O1CCOCC1.CN(C)C=O>[NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([N:33]1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56]([NH2:58])=[O:57])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)NN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound XIII (1.25 g, 2 mmoles) in dimethylformaide (8 ml) is chilled to -40° C to -50° C in a Dry-ice-acetone bath and 3.66M hydrogen chloride in dioxane (1.37 ml) is added. To this is then added dropwise isoamyl nitrite (0.29 ml, 2.2 mmoles) and the mixture is stirred at -10° C to -20° for 10 minutes. The mixture is again chilled to -40° C to -50° C and an ice-cold solution of XIV (0.30 g, 2 mmoles) and triethylamine (1.1 ml, 7.7 mmoles) in dimethylformamide (10 ml) is introduced. The temperature is allowed to rise to 0° C, at which the mixture is stirred for 3 hours. After the pH have been adjusted to about 8 with an additional quantity of triethylamine (0.27 ml, 2 mmoles) the reaction mixture is kept at 4° C for 2 days. The solvent is removed by evaporation in vacuo at a bath temperature of 40° C. The resulting residue is dissolved in ethyl acetate and the solution is washed with ice-cold M hydrochloric acid and M sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. Repeated precipiration of the residue obtained above yields the desired tripeptide XV; yield 1.29 g (91%), mp. 85°-90° C, [α]D22 - 40.5°±0.4° (c 2.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:35]S(C)(=O)=O)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[C:40](Cl)(=[O:42])[CH3:41].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:35][C:40](=[O:42])[CH3:41])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1
Reactant: CC(=O)Cl
Reactant: CCc1nc2cc(NS(C)(=O)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2cc(NC(C)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphere at 0° C., and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH (30 mL), brine (30 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([C:30](=[O:31])[NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[CH:38]=[CH:39][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.53 min, MH| 527. NMR: δH [2H6]-DMSO 12.73,(1H, b), 11.70,(1H, b), 9.26,(1H, d), 8.43,(1H, dd), 8.33,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.93,(1H, d), 7.58,(1H, d), 7.54,(1H, d), 7.36,(1H, t), 7.30,(2H, m), 7.12,(1H, t), 3.78,(2H, s), 2.67-2.25,(11H, b), 2.14,(3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:36]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[F:23])=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoro-aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, butylamine (24 μl) was added, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 25 mg (yield 38%) of the title compound.
Reaction SMILES: BrC1C=C2C(C(C)(C)CCC2=O)=CC=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](OCC)=[O:24])[CH:19]=[CH:20][CH:21]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][CH:23]=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
Compound G can be obtained as described in J. Med. Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([Cl:37])[CH:31]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].CCOCC>C(Cl)Cl.CN(C=O)C>[C:17]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13])=[C:32]([Cl:37])[CH:31]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(N)c(Cl)c2)cc1
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
Oxalyl chloride (0.047 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.077 g) in DCM (2.5 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 2 hours and was then added to a solution of 4-(4-acetamidophenylsulphonyl)-2-chloroaniline (Method 10) (0.160 g) in DCM (2.5 ml) and stirred a further 2 hours. Ether (50 ml) was added and the mixture was washed with water (2×50 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-70% ethyl acetate/toluene to give the title compound (0.025 g) as a solid. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.1-7.3 (brm, 1H), 7.8 (d, 2H), 7.9 (m, 3H), 7.97-8.05 (brs, 2H), 8.25 (d, 1H), 10.36 (brs, 1H); MS (ESP−): 463; EA: found: C, 47.8; H, 3.6; N, 5.4%; C18H16ClF3N2O5S.0.2 C7H8 requires: C, 48.2; H, 3.7; N, 5.8%.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([O:25][CH2:26][O:27][CH3:28])[CH:12]=2)=[CH:8][CH:7]=1)=O.[OH-].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>CO>[CH3:28][O:27][CH2:26][O:25][C:13]1[CH:12]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([S:5][CH2:34][CH:36]3[CH2:37][O:38]3)=[CH:30][CH:29]=2)[CH:16]=[CH:15][C:14]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: COCOc1cc(Oc2ccc(SC(=O)N(C)C)cc2)ccc1NC(=O)OC(C)(C)C
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOc1cc(Oc2ccc(SCC3CO3)cc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of compound 18 (0.65 g, 1.5 mmol) in anhydrous MeOH (10 mL) was added potassium hydroxide (0.42 g, 7.5 mmol). The mixture was refluxed for 4 h and then cooled to room temperature. Epichlorohydrin (0.21 g, 2.3 mmol) was added dropwise and the mixture was stirred at room temperature for 15 min, after which the solvent was removed under reduced pressure. The concentrate was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the suspension was filtered, followed by concentration of the filtrate in vacuo. Purification by silica gel chromatography (hexanes/EtOAc=4/1) gave 19 in 68% yield (0.43 g) 1H NMR (500 MHz, CDCl3) δ 1.53 (s, 9H), 8.03 (br. s., 1H), 2.47 (dd, J=2.6, 5.0 Hz, 1H), 2.77 (t, J=4.4 Hz, 1H), 2.85 (dd, J=6.1, 13.9 Hz, 1H), 3.12-3.05 (m, 1H), 3.18-3.12 (m, 1H), 5.18 (s, 2H), 3.48 (s, 3H), 6.66 (dd, J=2.6, 8.8 Hz, 1H), 6.92-6.85 (m, 3H), 6.98 (br. s., 1H), 7.44-7.37 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 28.5, 38.2, 47.6, 51.3, 56.5, 80.6, 95.4, 106.8, 113.1, 118.4, 119.4, 125.1, 128.0, 131.8, 133.8, 146.6, 151.2, 152.9, 157.9. HRMS (FAB) calcd for C22H28NO4S (M+H+) 434.1632. found 434.1637.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([O:50][C:51](=[O:61])[NH:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([NH2:60])[CH:54]=1)([CH3:49])([CH3:48])[CH3:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:59][C:56]1[CH:57]=[CH:58][C:53]([NH:52][C:51](=[O:61])[O:50][C:46]([CH3:47])([CH3:49])[CH3:48])=[CH:54][C:55]=1[NH:60][C:10]([C:8]1[S:7][C:3]2=[N:4][CH:5]=[CH:6][N:1]=[C:2]2[CH:9]=1)=[O:12]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: O=C(O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (1.01 g, 5.61 mmol), HATU (1.8 g, 5.61 mmol) and DIPEA (1.953 mL, 11.21 mmol) in DMF (8 mL) was stirred for 15 min. (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl 27 (1.246 g, 5.61 mmol), DIPEA (1 eq) in DMF (8 mL) were added and stirred overnight at rt. Citric acid solution (3%) was added and extracted with EtOAc. Organic layer was washed with NaHCO3 solution, brine, dried and evaporated. Purification by chromatography (0-20% EtOAc in CH2Cl2) gave tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate 28 (1.43 g, 66.4%). (m/z)=385 (M+H)+.
Reaction SMILES: C[Li].[N+:3]([C:6]1[CH:49]=[CH:48][CH:47]=[CH:46][C:7]=1[CH2:8][O:9][C:10]([CH:12]([PH:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:13]1[CH:16]([CH2:17][C:18]([C:20]2C=CC=CC=2)=S)[CH2:15][C:14]1=[O:26])=[O:11])([O-:5])=[O:4].[NH4+].[Cl-].CC[O:54]CC>C1COCC1.C(Cl)Cl>[N+:3]([C:6]1[CH:49]=[CH:48][CH:47]=[CH:46][C:7]=1[CH2:8][O:9][C:10]([CH:12]([PH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[N:13]1[CH:16]([CH2:17][C:18]([CH3:20])=[O:54])[CH2:15][C:14]1=[O:26])=[O:11])([O-:5])=[O:4]
Reactant: CCOCC
Reactant: O=C(OCc1ccccc1[N+](=O)[O-])C(N1C(=O)CC1CC(=S)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)CC1CC(=O)N1C(C(=O)OCc1ccccc1[N+](=O)[O-])[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Cuprous iodide (0.380 g) is suspended in 10 ml anhydrous ether under N2, in a dry flask and cooled to 0°. Methyl lithium (3.0 ml, 1.3 Molar) is added dropwise and the mixture is stirred at 0° for 5 min to give a yellow suspension. The mixture is then cooled to -50°. 1-(o-nitrobenzyloxycarbonyl-triphenylphosphoranylmethyl)-4-(phenylthiocarbonylmethyl)-2-azetidinone (0.674 g) in 10 ml THF is added dropwise over 5 min. The mixture is stirred at -50° for 5 min and allowed to come to -20° over 20 min and stirred at -20° for 5 min. Saturated NH4Cl solution 5 ml is added and the mixture is diluted with CH2Cl2. Stirred at r.t. for 5 min. The organic phase is separated, dried and evaporated. The residue is chromatographed on silica gel using EtOAc as eluant to give 0.162 g of the product 0.112 g of recovered thio ester.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C@@H:6]([OH:20])[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]>C1COCC1.O>[OH:20][CH:6]([CH2:7][CH2:8][N:9]1[C@@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[C:5]([O:4][CH3:3])=[O:21]
Reactant: COC(=O)[C@@H](O)CCN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(O)CCN1C(=O)c2ccccc2[C@@H]1O
Temperature: 25 °C
Yield: 31.7 %

Procedure:
Sodium borohydride (0.474 g, 12.54 mmol) was added portionwise to a -20° C., stirred solution of (s)-(+)-α-hydroxy-1,3-dioxo-2-isoindolinebutyric acid methyl ester (3.0 g, 11.4 mmol) in THF/water (30/1.38 mL) for 6 hours. Upon cooling to room temperature, the reaction mixture was carefully quenched and acidified with 10% aqueous HCl. Aqueous mixture was extracted with ethyl acetate (300 mL). The ethyl acetate extract was washed with water and brine. Silica gel (15 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 95: 5 petroleum ether: dichloromethane) to provide the title compound as an oil (0.96 g, 32%): MS (EI): [M+], 265.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:11])[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1cnccc1C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1ccncc1CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.7 %

Procedure:
A solution of 0.6 g (3.4 mmoles) of (4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethyl ether was cooed to −30° C. Thereto was added 1.4 g (5.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.61 g (yield: 75.3%) of 3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C(NC(C)C)(C)C.C[Si](C)(C)[C:38]#[C:39][C:40]1([CH3:44])[CH2:43][O:42][CH2:41]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].[Cu]I.CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:38]#[C:39][C:40]2([CH3:44])[CH2:43][O:42][CH2:41]2)[CH:3]=1)([OH:28])[CH3:27]
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)c(Br)c1)C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC1(C#Cc2cc(C(C)(O)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)COC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A 20 mL vial was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (0.500 g, 1.00 mmol), diisopropylamine (2.14 mL, 15.0 mmol), 2 mL of DMF, tetrakis(triphenylphosphine)palladium (0) (0.116 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), copper (I) iodide (0.019 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.506 g, 3.00 mmol, published PCT patent application no. WO2010030954). The vial was sealed and heated at 100° C. for 3 h. After that time, an additional 20 mol % of both tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide were added and heating was continued for an additional 12 h. The mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 60% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g) as a mixture of two enantiomers.
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=3)[CH:15]=[C:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:31]=[CH:30][CH:29]=[C:14]([CH:15]=[C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)[CH:13]=3)=[N:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(N4CCC4)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCC3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 952.8 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(azetidin-1-yl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.135 g, 0.32 mmol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.24 mL, 3.2 mmol). The resulting mixture was stirred for 1 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.98 g, 96%). 1H NMR (500 MHz, DMSO-d6): δ 7.46 (s, 1H), 7.28 (s, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.85 (m, 4H), 6.28 (s, 1H), 3.87 (t, J=7 Hz, 4H), 3.02 (m, 2H), 2.90 (m, 2H), 2.53 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [CH3:1][C@@H:2]([O:17][C@H:18]1[O:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[NH:30][C:28](=[O:29])[N:27]([P:31]([OH:34])([OH:33])=[O:32])[N:26]=2)[C@H:19]1[C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:3]1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O>CO>[CH3:1][C@@H:2]([O:17][C@H:18]1[O:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[N:30]=[C:28]([OH:29])[N:27]([P:31]([OH:33])([OH:34])=[O:32])[N:26]=2)[C@H:19]1[C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: C[C@@H](O[C@H]1OCCN(Cc2nn(P(=O)(O)O)c(=O)[nH]2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Solvent: O
Product: C[C@@H](O[C@H]1OCCN(Cc2nc(O)n(P(=O)(O)O)n2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
6.0 gm of fosaprepitant dimeglumine salt, prepared as in Part B, 120 ml of water and 120 ml of methanol were charged in a clean and dry round bottom flask followed by cooling to about 0° C. The pH of the reaction mixture was adjusted to about 1 by the addition of 1N hydrochloric acid solution at about 0° C.-5° C. The resultant reaction mixture was stirred for about 5 minutes. The separated solid was filtered and the solid was washed with copious amount of water to neutral pH. Finally, the solid was washed with 12 ml of methanol followed by drying the solid obtained at about 35° C.-40° C. under vacuum to afford 2.9 gm of fosaprepitant, neutral form, having the XRPD pattern, which is substantially in accordance with FIG. 3; and a DSC thermogram, which is substantially in accordance with FIG. 4.