Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:25][CH2:24][CH2:22][OH:23])=[O:21]
Reactant: NCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO

Procedure:
As in Example 1, 445.7 g (1.5 mol) of technical grade oleic acid methyl ester (sunflower oil fatty acid, oleic acid content approx. 85%, saponification value 188.8, iodine value 85), 184.2 g (3 mol) of ethanolamine and 5.1 g (0.015 mol, 1 mol-%) of titanium tetrabutylate were reacted under nitrogen and normal pressure at 140° to 150° C. to form oleic acid ethanolamide with removal of methanol by distillation. The excess ethanolamine was then distilled off at 4 hPa/120°-125° C. The temperature was then increased to 220°-265° C. at 0.08-0.1 hPa, the product and water distilling over. 2-(8-Heptadecen-1-yl)-2-oxazoline was obtained in a yield of 394.1 g (86% of the theoretical). n20 : 1.4700.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:25](O)=[O:26]>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:30]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=1
Reactant: COC(=O)CNc1cnccc1-c1ccccc1F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Light yellow solid (39%). MS (ESI): m/z=502.099 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:21]([O-])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:24](O)=O>C(OC)(OC)OC.[Fe]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=3[N:21]=[CH:24]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CC(=O)Nc1cccc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: COC(OC)OC
Product: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid (1.27 g, 4.04 mmol) and iron powder (1.77 g, 31.6 mmol) in HCO2H (30 mL) and HC(OMe)3 (20 mL) was stirred at rt under N2 atmosphere. After 18 h, the reaction mixture was filtered through Celite and the Celite pad was washed with EtOH. The solvent was removed in vacuo. The resultant crude material was purified by silica gel chromatography (10% MeOH in CH2Cl2) to afford 1-[3-(acetylamino)phenyl]-1H-benzimidazole-5-carboxylic acid as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.34 (s, 1H), 8.71 (s, 1H), 10.3 (s, 1H). MS (ES+): m/z 296 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:17].CCO.C([O-])([O-])=O.[Na+].[Na+].[C:27]1(B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]1([C:2]2[CH:7]=[C:6]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=2[NH2:17])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A solution of 50.0 mg (0.156 mmol) of 2-bromo-4-(morpholine-4-sulfonyl)-phenylamine (as prepared in the previous step) in toluene (4 mL) and EtOH (2 mL) was treated with 623 μL (1.25 mmol) of 2.0 M aqueous Na2CO3 and 20.6 mg (0.163 mmol) of cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 12.6 mg (0.0109 mmol) of Pd(PPh3)4, and heated to 80° C. for 3.5 h. The mixture was cooled to RT, stirred for 16 h, diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (1×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane afforded 20.0 mg (40%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C16H22N2O3S, 323.1 (M+H), found 323.1.
Reaction SMILES: O=C1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:70](O)=[O:71])[CH:67]([CH3:69])[CH3:68])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:70]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:71])[CH:67]([CH3:68])[CH3:69])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Br
Agent: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cis)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-L-valine (81 mg) 107b was used as the acid component to afford the title compound in 1:1 mixture with the (2S,3S) diastereomer (91 mg), white solid, m.p. 110-115° C. 1H NMR (300 MHz, d6-DMSO) δ 4.76 (t, 1H, J=7 Hz), 5.12 (d, 1H, J=7 Hz), 6.91-7.49 (m, 12H), 7.67 (d, 1H, J=7 Hz), 8.25 (s, 1H), 10.49 (s, 1H). MS APCI, m/z=524(M+1). LC/MS: 2.54 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O)=[C:6]([N+:18]([O-])=O)[CH:5]=[CH:4][CH:3]=1.O.NN.NN>C(O)C.[Ni]>[CH3:14][C:13]1[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH2:18])=[C:9]([NH2:15])[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc([N+](=O)[O-])c1-c1c(C)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(N)c1-c1c(C)cccc1N

Procedure:
The atmosphere of a 500 ml eggplant flask equipped with a three-way cock at the top and an Allihn condenser was dried under reduced pressure and displaced with nitrogen. In the flask was charged 13.6 g (50 mmole) of 6,6'-dimethyl-2,2'-dinitro-1,1'-biphenyl (7) as obtained in Preparation Example 4 and dissolved in 120 ml of warm 99% ethanol having been previously displaced with nitrogen, followed by stirring. To the mixture was added 35 ml (0.7 mole) of hydrazine hydrate having been displaced with nitrogen. A suspension of 3 ml of a Raney nickel W2 type catalyst in ethanol was slowly added thereto by means of a syringe while maintaining the activity. Thereafter, the mixture was heated at reflux in an oil bath until the whole of the hydrazine was consumed.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[C:12]1[CH:13]=[C:14]([F:33])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][CH:19]=2)=[N:16][CH:17]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[F:33][C:14]1[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][CH:19]=2)=[N:16][CH:17]=[C:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:13]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Reactant: CCCCCCCCBr
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(CCCCCCCC)cc2F)cc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
0.30 g (12.30 mmol) of magnesium and 2.16 g (11.18 mmol) of octyl bromide in 10 ml of tetrahydrofuran are used to prepare, at 50° C. for 2 hours, the solution of the Grignard compound, which is added dropwise to a solution, cooled to -10° C. of 2.13 g (5.59 mmol) of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine and 0.03 g (0.06 mmol) of [1,3-bis(diphenylphosphino)propane]nickel(II) chloride in 60 ml of tetrahydrofuran, and the mixture is stirred at -10° C. for 3 hours. The mixture is subsequently partitioned between ether and aqueous ammonium chloride solution, and the organic phase is washed twice with aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Chromatographic purification (silica gel/dichloromethane:hexane 7:3) gives 1.89 g of 3-fluoro-5-octyl-2-(4-octyloxyphenyl)pyridine. ##STR16## The compound has the phase sequence: X 25.5 (5) N 35 I.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[CH2:11]([OH:20])[C@@H:12]([C@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13]>>[CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[O:20]=[CH:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:5][OH:6])[OH:19])[OH:17])[OH:15])[OH:13]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)C(O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The fermentation is continued at a temperature close to 30° C. for 80 to 100 hours under aeration corresponding to 1 to 1.5 volume of air/volume of culture/minute, and at a pH comprised between 4 and 6, preferably close to 4.5, advantageously maintained by ammonia, due to which there is generally obtained a content of D-arabitol of 65 to 90 g/l, this arabitol representing from 70 to 85% of the matter present in the culture medium at the end of this fermentation, the sugar impurities being particularly constituted by xylitol formed similarly with the arabitol and through non-fermented glucose.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14]1)[CH2:10][CH2:11][CH3:12])=O)CCC>C(OCC)(=O)C>[ClH:1].[CH2:10]([NH:9][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14]1)[CH2:11][CH3:12]
Reactant: CCCCOC(=O)N(CCC)C1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN[C@H]1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1

Procedure:
A solution of HCl in ethyl acetate (13% w/v) (250 ml) was added to a solution of (S)-N-t.butoxycarbonyl-N-propyl-5,6-di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphthylamine (23 g; 45.8 mmoles) in ethyl acetate (100 ml), under stirring at room temperature.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][OH:17])[CH3:12].O[C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)[CH3:12]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc2ccccc2c1
Yield: 82.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 459 mg of 2-[1-(2-naphthyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 13), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 858 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[C:18]([Mg]Br)([CH3:20])=[CH2:19]>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([C:18]([CH3:20])=[CH2:19])[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: C=C(C)[Mg]Br
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: C1CCOC1
Solvent: CSC
Product: C=C(C)C1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 71 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one, (X), prepared in Example 1, Step (c), (33.12 mmol, 6.50 g), CuBr.Me2S (3.312 mmol, 681 mg) and Me2S (6.63 ml) were stirred in 97.5 ml of dry THF at -40° C. under nitrogen and treated with 49.68 mmol (66.24 ml of 0.75M in THF, prepared from treating isopropenyl bromide with 1.1 equivalents of Mg) of isopropenylmagnesium bromide added dropwise. The reaction was quenched with 120 ml of 1M HCl (aq.) and extracted with 4×60 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 5.6 g (23.53 mmol, 71%) of colorless oil as a mixture of diastereomers. The diastereomers were separted by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associaes, Milford, Ma., to provide a "less polar isomer" and a "more polar isomer."
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21](Cl)=[O:22])[CH:17]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:17]=[C:16]([CH3:15])[O:20][N:19]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1cc(C(=O)Cl)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 68.2 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.046 g, 0.193 mmol), 5-methylisoxazole-3-carbonyl chloride (0.029 g; 0.193 mmol), and triethylamine (0.068 mL; 0.483 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.040 g (68%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-5-methylisoxazole-3-carboxamide as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8]Br)#[N:2].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])#[N:2]
Reactant: N#Cc1ccc(F)c(CBr)c1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), sarcosine tert-butyl ester hydrochloride (BACHEM; F-1135; 1 527.73 mg; 8.41 mmol; 1.20 eq.) and potassium carbonate (2.91 g; 21.02 mmol; 3 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for one night. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over magnesium sulfate and concentration in vacuo gave the title compound as a slightly yellow oil (1.9 g; 97%). 1H NMR (CDCl3) δ 7.86 (dd, J=6.5, 2.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.13 (t, J=9.0 Hz, 1H), 3.78 (s, 2H), 3.23 (s, 2H), 2.38 (s, 3H), 1.49 (s, 9H). 19F NMR (CDCl3) δ-108.3. GC/MS: 278. LC/MS (Method B): 279.1 (M+H)+. HPLC (Method A) Rt 2.25 min (Purity: 91.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH:21](O)([CH3:23])[CH3:22].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:22][CH:21]([O:19][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: CC(C)O
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.0108 mole), isopropanol (50 ml), benzene (50 ml), and concentrated sulfuric acid (5 ml) was refluxed under a Dean-Stark trap for 24 hrs. The reaction mixture was concentrated and the residue partitioned between 5% potassium hydroxide solution (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous portion extracted with ethyl acetate (2×25 ml). The organic layers were combined and washed with 5% potassium hydroxide (25 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo to give 2.0 g (56%) of a solid, mp 118°-120° C. Recrystallization from isopropyl ether gave 1.7 g of off-white needles, mp 117.5°-119° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1.[F:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([OH:27])=[C:19]([C:28]2[CH:33]=[CH:32][N:31]=[N:30][CH:29]=2)[CH:18]=1.[C:34]([O:38][C:39](=[O:58])[N:40]([S:46]([C:49]1[CH:54]=[C:53]([Cl:55])[C:52](F)=[CH:51][C:50]=1[F:57])(=[O:48])=[O:47])[C:41]1[N:42]=[CH:43][S:44][CH:45]=1)([CH3:37])([CH3:36])[CH3:35].[Cl-].[NH4+]>CN(C)C=O.O>[C:34]([O:38][C:39](=[O:58])[N:40]([S:46]([C:49]1[CH:54]=[C:53]([Cl:55])[C:52]([O:27][C:20]2[CH:21]=[C:22]([C:23]([F:25])([F:26])[F:24])[C:17]([F:16])=[CH:18][C:19]=2[C:28]2[CH:33]=[CH:32][N:31]=[N:30][CH:29]=2)=[CH:51][C:50]=1[F:57])(=[O:47])=[O:48])[C:41]1[N:42]=[CH:43][S:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Oc1cc(C(F)(F)F)c(F)cc1-c1ccnnc1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cc(C(F)(F)F)c(F)cc2-c2ccnnc2)cc1F
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (7.55 mL, 7.55 mmol) was added to a solution of 4-fluoro-2-pyridazin-4-yl-5-(trifluoromethyl)phenol (Preparation 11, 1.30 g, 5.04 mmol) in N,N-dimethylformamide (30 mL). After stirring for 5 minutes, tert-butyl-[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 2.07 g, 5.04 mmol) was added and the reaction mixture stirred at ambient temperature. After 18 hours, the reaction mixture was diluted with water, neutralized with saturated aqueous ammonium chloride, and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated onto diatomaceous earth. The residue was purified by automated silica gel flash chromatography (hexanes to ethyl acetate gradient elution) to afford tert-butyl({5-chloro-2-fluoro-4-[4-fluoro-2-pyridazin-4-yl-5-(trifluoromethyl)phenoxy]phenyl}sulfonyl)1,3-thiazol-4-ylcarbamate (1.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([CH3:16])=[C:14](I)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12]2)=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:14]2[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[CH3:16])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1I
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-methyl-1H-pyrazole-3-carboxylate (Step 55.2) and 4-chlorobenzaldehyde at RT for 30 min. tR: 4.92 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.24 (Hexane/EtOAc 1:1).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[N:11]([CH3:18])[S:10]2(=[O:20])=[O:19])C=CC=CC=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[N:11]([CH3:18])[S:10]1(=[O:20])=[O:19]
Reactant: CC(C)C1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)C1C(=O)N(CCl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 2-phenylthiomethyl-4-isopropyl-5-methyl -1,2,5-thiadiazolidin-3-one 1,1-dioxide (6.38 g, 23.31 mmol) in 150 ml of methylene chloride was added sulfuryl chloride (2.5 ml, 30.4 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in hexane to afford 4.32 g (88%) of 2-chloromethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =isopropyl; R3 =methyl; X'=Cl) as a solid, m.p. 118.5°-119.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]#[N:26])[C:19]=3[CH3:27])=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C([O-])([O-])=O.[Ca+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C@@H:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]#[N:26])[C:19]=3[CH3:27])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C2=CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 40 °C
Reaction time: 38 h

Procedure:
To a 1 L 3 neck RB was charged 5% Pd/CaCO3 (10.0 g., 4.02 mmol), MeOH (405 mL), and (S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (15.0 g., 40.2 mmol). The solution was sparged with N2 for 5 min, then put under an atmosphere of hydrogen with balloon pressure and warmed to 40° C. with stirring. After 38 h, HPLC shows full conversion of the olefin, with a 5:1 cis:trans ratio of diastereomers. The suspension was cooled to room temperature, filtered through a pad of Celite and concentrated. The residue was purified via column chromatography (60-100% EtOAc/Hexanes, linear gradient), to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 8.18 (m, 1H), 7.03 (t, J=7.9 Hz, 1H), 4.87 (s, 1H), 4.10-3.60 (m, 2H), 3.56 (d, J=10.5 Hz, 1H), 3.25-2.88 (m, 3H), 2.80-2.35 (m, 8H), 1.50 (s, 9H).